List of phenyltropanes
Introduction '''Phenyltropanes''' ('''PT'''s) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "''phenyl''"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function. These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.) Certain phenyltropanes can even be used as a smoking cessation aid (''c.f.'' RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-''n'', for 'cocaine' "analog", or specifically RTI-4229-''n'' of the subsequent numbers given below in this article) Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.c.f.
2-Carboxymethyl esters (phenyl-methyl[[ecgonine]]s) Epibatropane containing a nitrogen heteroatom in the benzene ring formation.pM) = 10 times the strength of paroxetine for 5HT.RTI-298 rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact. The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.Blank spacings within tables for omitted data use "'''no data'''", "'''? '''", "'''-'''" or "'''—'''" interchangeably.+2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes ( values)monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z) Structure x100px Short Name''i.e.'' Trivial IUPAC(non-systematic) Name(''Singh's #'') R (''para''-substitution)of benzene DAtritium|3HWIN 35428IC50 nM(''Ki'' nM) 5HT3HparoxetineIC50 nM(''Ki'' nM) NE3HnisoxetineIC50 nM(''Ki'' nM) selectivity5-HTT/DAT selectivityNET/DAT  cocaine(benzoyloxytropane)  H 102 ± 12241 ± 18'''ɑ'''1045 ± 89112 ± 2'''b'''3298 ± 293160 ± 15'''c'''10.20.5'''d'''32.30.7'''e'''x100px  (''para''-hydrogen)phenyltropaneWIN 35,065-2 (β-CPT) Troparil''11a''  H 23 ± 5.049.8 ± 2.2'''ɑ'''1962 ± 61173 ± 13'''b'''920 ± 7337.2 ± 5.2'''c'''85.33.5'''d'''40.00.7'''e'''x100px  ''para''-fluorophenyltropaneWIN 35,428 (β-CFT)''11b'' F 14 (15.7 ± 1.4)22.9 ± 0.4'''ɑ'''156 (810 ± 59)100 ± 13'''b'''85 (835 ± 45)38.6 ± 9.9'''c'''51.64.4'''d'''53.21.7'''e'''x100px  ''para''-nitrophenyltropane''11k''  NO210.1 ± 0.10??? ?x100px  ''para''-aminophenyltropaneRTI-29''11j''  NH29.824.8 ± 1.3'''g'''5110151521.415.4x100px  ''para''-chlorophenyltropaneRTI-31''11c'' Cl 1.12 ± 0.063.68 ± 0.09'''ɑ'''44.5 ± 1.35.00 ± 0.05'''b'''37 ± 2.15.86 ± 0.67'''c'''39.71.3'''d'''33.01.7'''e'''x100px  ''para''-methylphenyltropaneRTI-32 Tolpane''11f''  Me 1.71 ± 0.307.02 ± 0.30'''ɑ'''240 ± 2719.38 ± 0.65'''b'''60 ± 0.53'''e'''8.42 ± 1.53'''c'''1402.8'''d'''35.11.2'''e'''x100px  ''para''-bromophenyltropaneRTI-51 Bromopane''11d''  Br 1.81 (1.69) ± 0.30 10.6 ± 0.2437.4 ± 5.25.820.7x100px  ''para''-iodophenyltropaneRTI-55 (β-CIT) Iometopane''11e''I1.26 ± 0.041.96 ± 0.09'''ɑ'''4.21 ± 0.31.74 ± 0.23'''b'''36 ± 2.77.51 ± 0.82'''c'''3.30.9'''d'''28.63.8'''e'''x100px ''para''-hydroxyphenyltropane''11h''OH12.1 ± 0.86————x100px ''para''-methoxyphenyltropane''11i''OCH38.14 ± 1.3————x100px ''para''-azidophenyltropane''11l''N32.12 ± 0.13————x100px ''para''-trifluoromethylphenyltropane''11m''CF313.1 ± 2.2————x100px ''para''-acetylaminophenyltropane''11n''NHCOCH364.2 ± 2.6————x100px ''para''-propionylaminophenyltropane''11o''NHCOC2H5121 ± 2.7————x100px ''para''-ethoxycarbonylaminophenyltropane''11p''NHCO2C3H5316 ± 48————x100px ''para''-trimethylstannylphenyltropane''11q''Sn(CH3)3144 ± 37————x100px  ''para''-ethylphenyltropaneRTI-83''11g''Et55 ± 2.128.4 ± 3.8(2.58 ± 3.5)4030 (3910) ± 381(2360 ± 230)0.573.3x100px ''para''-''n''-propylphenyltropaneRTI-282'''i'''''11r''''n''-C3H768.5 ± 7.170.4 ± 4.13920 ± 1301.057.2x100px ''para''-isopropylphenyltropane''11s''CH(CH3)2597 ± 52191 ± 9.575000 ± 58200.3126x100px ''para''-vinylphenyltropaneRTI-359''11t''CH-CH21.24 ± 0.29.5 ± 0.878 ± 4.17.762.9x100px ''para''-methylethenylphenyltropaneRTI-283'''j'''''11u''C(=CH2)CH314.4 ± 0.33.13 ± 0.161330 ± 3330.292.4x100px  ''para''-''trans''-propenylphenyltropaneRTI-296'''i'''''11v''''trans''-CH=CHCH35.29 ± 0.5311.4 ± 0.281590 ± 932.1300x100px ''para''-allylphenyltropane''11x''CH2CH=CH232.8 ± 3.128.4 ± 2.42480 ± 2290.975.6x100px ''para''-ethynylphenyltropaneRTI-360''11y''C≡CH1.2 ± 0.14.4 ± 0.483.2 ± 2.83.769.3x100px ''para''-propynylphenyltropaneRTI-281'''i'''''11z''C≡CCH32.37 ± 0.215.7 ± 1.5820 ± 466.6346x100px  ''para''-''cis''-propenylphenyltropaneRTI-304''11w''''cis''-CH=CHCH315 ± 1.27.1 ± 0.712,800'''k''' ± 3000.5186.6'''k'''x140px''para''-(''Z'')-phenylethenylphenyltropane''cis''-CH=CHPh11.7 ± 1.12————x100pxx100px''para''-phenylethenylphenyltropane CH2 -C-Ph474 ± 1332,710 ± 800(246 ± 73)7,060 ± 1,760(4,260 ± 1,060)5.714.8x100pxx100px''para''-(''E'')-phenylethenylphenyltropane'''l'''RTI-436''trans''–CH=CHPh3.09 ± 0.75335 ± 150(30.5 ± 13.6)1960 ± 383(1180 ± 231)108.4634.3x120pxx120pxx100pxx100px ''para''-phenylethynylphenyltropane'''l'''RTI-298–≡–Ph3.7 ± 0.1646.8 ± 5.8(4.3 ± 0.53)347 ± 25(209 ± 15)12.693.7 x100px''para''-phenylpropynylphenyltropane'''l'''–C≡C-CH2Ph1.82 ± 0.4213.1 ± 1.7(1.19 ± 0.42)27.4 ± 2.6(16.5 ± 1.6)7.115 x100px''para''-phenylbutynylphenyltropane'''l'''RTI-430–C≡C(CH2)2Ph6.28 ± 1.252180 ± 345(198 ± 31)1470 ± 109(885 ± 66)347.1234 x100px''para''-phenylpentynylphenyltropane'''l'''–C≡C-(CH2)3-Ph300 ± 371,340 ± 232(122 ± 21)4,450 ± 637(2,680 ± 384)4.4614.8 x100px''para''-trimethylsilylethynylphenyltropane—————— x100px''para''-hydroxypropynylphenyltropane—————— x100px''para''-hydroxyhexynylphenyltropane'''l'''–C≡C-(CH2)4OH57 ± 4828 ± 29(75 ± 2.6)9,500 ± 812(5,720 ± 489)14.5166.6 x100px''para''-(thiophen-3-yl)phenyltropaneTamagnan''p''-thiophene120.0171890.00141615.7x100px ''para''-biphenyltropane''11aa''Ph10.3 ± 2.6'''f'''29.4 ± 3.8'''ɑ'''15.6 ± 0.695.8 ± 36(8.7 ± 3.3)1,480 ± 269(892 ± 162)6.194.8x110px 3β-2-naphthyltropaneRTI-318''11bb''3β-2-naphthyl0.51 ± 0.033.32 ± 0.08'''f'''3.53 ± 0.09'''ɑ'''0.80 ± 0.06(0.07 ± 0.1)21.1 ± 1.0(12.7 ± 0.60)1.541.3x100px ''para''-bimethoxyphenyltropane''15''OCH2OCH3'''h'''—————* '''ɑ'''3HDA uptake displacement ''Ki'' value. * '''b'''3H5-HT uptake displacement ''Ki'' value. * '''c'''3HNE uptake displacement ''Ki'' value. * '''d'''3H5-HT uptake to 3HDA uptake ratio. * '''e'''3HNE uptake to 3HDA uptake ratio. * '''f'''IC50 for displacement of 3Hcocaine. * '''g'''Values from alternate data-set differing from that used in rest of table. * '''h'''Original source (Scheme 4, page 931, 7th of article) name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: ''i.e.'' "methoxymethyl" versus "methoxymethoxy"* '''i'''Protonated as the (-)—tartrate salt (isomer)* '''j'''Protonated as the tartrate salt* '''k'''Was cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867.However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1 which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value. * '''l'''Whereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the ''para''-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the ''para'' area of the aryl of these type of ligands.===(4′-Monosubstituted 2,3-Thiophene phenyl)-tropanes===+Tamagnan (thiophene) analogues of ''para''-phenyltropanes. Compound structure Alphanumeric code(name) ''para''-substitution N8 SERT DAT NET SelectivitySERT versus DAT SelectivitySERT versus NET  1(cocaine)  (—)-Cocaine  CH3 10508933200.083.2  2(β-CIT), (Iometopane)  Iodo  CH3 0.46 ± 0.060.96 ± 0.152.80 ± 0.402.16.1  (''R'',''S''-Citalopram) ——1.6016,5406,19010,3383,869 x100px  4a  2-Thiophene  CH3 0.15 ± 0.01552 ± 12.8158 ± 123461,053x100px 4b(Tamagnan)  3-Thiophene  CH3 0.017 ± 0.00412.1 ± 3189 ± 8271011,118 x100px  4c  2-(5-Br)-Thiophene  CH3 0.38 ± 0.0086.43 ± 0.9324 ± 1917853 x100px  4d  2-(5-Cl)-Thiophene  CH3 0.64 ± 0.044.42 ± 1.64311 ± 256.9486 x100px  4e  2-(5-I)-Thiophene  CH3 4.56 ± 0.8422.1 ± 3.21,137 ± 1234.9249 x100px  4f  2-(5-NH2)-Thiophene  CH3 64.7 ± 3.7>10,000>30,000>155>464 x100px  4g  2-(4,5-NO2)-Thiophene  CH3 5,000>30,000>10,000>6.0>2.0 x100px  4h  3-(4-Br)-Thiophene  CH3 4.02 ± 0.34183 ± 69>10,00046>2,488 x100px  5a  2-Thiophene  H 0.11 ± 0.00612.2 ± 0.975.3 ± 9.6111685 x100px  5b  3-Thiophene  H 0.23 ± 0.026.4 ± 0.2739 ± 0.828170=== (3′,4′-Disubstituted phenyl)-tropanes ===200px250px250px300pxCompound''(+ S. Singh's name)''X(4′-''para'')Y(3′-''meta'') 2 Position  config  8  DA  5-HT  NE RTI-318''11bb'' β-naphthyl CO2Me  β,β  NMe  0.50.8120 Dichloropane (RTI-111'''ɑ''')''17c''  ClCl  CO2Me  β,β  NMe 0.793.1318.0 RTI-88 recheck''17e'' NH2I CO2Me  β,β  NMe 1.35 1329'''c''' 320'''c''' RTI-97''17d'' NH2Br CO2Me  β,β  NMe 3.91181 282 RTI-112'''b'''''17b''  ClMe CO2Me  β,β  NMe 0.8210.536.2 RTI-96''17a'' FMeCO2Me  β,β  NMe  2.9576520 RTI-295 EtICO2Me  β,β  NMe 21.32.961349 RTI-353 (EINT)EtICO2Me  β,β  NH 3310.69148 RTI-279 MeICO2Me  β,β  NH 5.981.0674.3RTI-280 MeICO2Me  β,β  NMe 3.126.81484MeltzercatecholCO2Me  β,β  NMe >100? ?MeltzerOAcOAcCO2Me  β,β  NMe ? ?? * '''ɑ'''as ·HCl (salt)* '''b'''as ·HCl·2 H2O (salt)* '''c'''Singh gives the reverse value with respect to ''i.e.'' 1,329 for NET & 320 for 5-HT+''Para''-''meta''-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes Compound 150px Short Name(S. Singh) R2 R1 DA 5HT NE Selectivity5-HTT/DAT SelectivityNET/DAT 150px''meta''-fluorophenyltropane16a  F  H  150px''meta''-chlorophenyltropane16b  Cl  H  150px''meta''-bromophenyltropane16c Br  H 150px''meta''-iodophenyltropane16d I  H  160px''meta''-tributylstannylphenyltropane16e  SnBu3 H  160px''meta''-ethynylphenyltropaneC≡CH 150px''meta''-methyl-''para''-fluorophenyltropaneRTI-9617a  CH3  F  150px''meta''-methyl-''para''-chlorophenyltropaneRTI-112'''c'''17b  CH3  Cl 0.81 ± 0.0510.5 ± 0.0536.2 ± 1.013.044.7 150px''meta''-''para''-dichlorophenyltropaneRTI-111'''b''' Dichloropane17c  Cl  Cl 0.79 ± 0.08'''b'''3.13 ± 0.36'''b'''18.0 ± 0.817.96 ± 0.85'''b''''''d'''4.0'''b'''22.8'''b''' 160px''meta''-bromo-''para''-aminophenyltropaneRTI-9717d  Br  NH2 3.91 ± 0.5918128246.272.1 160px''meta''-iodo-''para''-aminophenyltropaneRTI-8817e  I  NH2 1.35 ± 0.11120 ± 41329 ± 12488.9984 160px''meta''-iodo-''para''-azidophenyltropane17f I  N3 * '''ɑ'''IC50 determined in Cynomolgous monkey caudate-putamen* '''b'''as ·HCl (salt)* '''c'''as ·HCl·2 H2O (salt)* '''d'''NEN+3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes Structure 150px Compound R X n Inhibition of 3HWIN 35,428@ DATIC50 (nM) Inhibition of 3HParoxetine@ 5-HTTK''i'' (nM) Inhibition of 3HNisoxetine@ NETK''i'' (nM) NET/DAT(uptake ratio) NET/5-HTT(uptake ratio) CocaineDes-thio/sulfinyl/sulfonylHHDesmethyl089.19519902221 ''para''-methoxyphenyltropaneSingh: ''11i''Des-thio/sulfinyl/sulfonylOCH3H06.5 ± 1.34.3 ± 0.51110 ± 64171258190px 7a  CH3  H  0 9 ± 30.7 ± 0.2220 ± 1024314200px 7b  C2H5  H  0 232 ± 344.5 ± 0.51170 ± 3005260200px 7c  CH(CH3)2  H  0 16 ± 223 ± 2129 ± 287200px 7d  CF3  H  0 200 ± 708 ± 21900 ± 30010238180px 7e  CH3  Br  0 10.1 ± 10.6 ± 0.2121 ± 1212202180px 7f  CH3  Br  1 76 ± 183.2 ± 0.4690 ± 809216180px 7g  CH3  H  1 91 ± 164.3 ± 0.6515 ± 606120180px 7h  CH3  H  2 >10,000208 ± 45>10,000148=== (2′,4′-Disubstituted phenyl)-tropanes ===+''Ortho''-''para''-substituted (2′,4′-disubstituted phenyltropanes) Compound structurex130px Trivial IUPAC(non-systematic)Name R2''ortho'' R1''para'' DA 5HT NE Selectivity5-HTT/DAT SelectivityNET/DAT185px ''ortho'',''para''-dinitrophenyltropane  NO2 === (3′,4′,5′-Trisubstituted ''para''-methoxyphenyl)-tropanes ===+''Para''-''meta''(3′)-''meta''(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes''Para''-methoxy/(ethoxy)-''meta''-substituted phenyltropanes Structure210px Short Name(All compounds tested as HCl salts) R23′-(''meta'') R35′-(di-''meta'') OR14′-(''para'') DATIC503H(compound #)12 5-HTT''Ki''3HParoxetine NET''Ki''3HNisoxetine SelectivityNET/DATRatio''Ki''/IC50 SelectivityNET/5-HTTRatio''Ki''/''Ki'' 89.19519902221 0.82 ± 0.050.95 ± 0.0421.8 ± 0.62723 left  7a''11i''  H  H CH36.5 ± 1.34.3 ± 0.51110 ± 64171258 left  7b  H  H  C2H5 92 ± 81.7 ± 0.41690 ± 5018994 left  7c  F  H  CH3 16 ± 14.8 ± 0.5270 ± 501756 left  7d  Br  H  CH3 47 ± 153.1 ± 0.1160 ± 20352 left  7f  Br  Br  CH3 92 ± 222.9 ± 0.14100 ± 400ɑ451413 left  7e  I  H  CH3 170 ± 603.5 ± 0.4180 ± 20151 left  7g  I  I  CH3 1300 ± 2007.5 ± 0.8180 ± 204667ɑN=2=== (2′,4′,5′-Trisubstituted phenyl)-tropanes ===+''Ortho''-''para''(4′)-''meta''(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes Structure Short Name R12′-(''ortho'') R24′-(''para'') R35′-(''meta'') DAT 5-HTT NET SelectivityNET/DATRatio SelectivityNET/5-HTTRatio x130px ''para''-ethyl-''ortho, meta''-diiodophenyltropane iodoethyl
2-Carbmethoxy modified (replaced/substituted) === General 2-carbmethoxy modifications ======= 2β-substitutions of ''p''-methoxy-phenyltropanes ====+''Para''-OCH3-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues Structure200px Short Name(All compounds tested as HCl salts) CO2''R'' (2β-substituted)(compound 9 is 2β=''R'') DATIC503H(compound #)12 5-HTT''Ki''3HParoxetine NET''Ki''3HNisoxetine SelectivityNET/DATRatio''Ki''/IC50 SelectivityNET/5-HTTRatio''Ki''/''Ki'' left  7a''11i'' CH36.5 ± 1.34.3 ± 0.51110 ± 64171258 left  8a (CH3)2CH14 ± 3135 ± 352010 ± 20014415 left  8b cyclopropane6.0 ± 229 ± 31230 ± 14020542 left  8c cyclobutane13 ± 3100 ± 8 >3000 23130 left  8d O2N...1,4-xylene...(CH2)242 ± 82.9 ± 0.2330 ± 208114 left  8e H2N...1,4-xylene...(CH2)27.0 ± 28.3 ± 0.42200 ± 300ɑ314265 left  8f CH3CONH...1,4-xylene...(CH2)26.0 ± 15.5 ± 0.51460 ± 30243265 left  8g H2N...2-bromo-1,4-dimethylbenzene...(CH2)23.3 ± 1.44.1 ± 0.61850 ± 90561451 left  8h H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)215 ± 62.0 ± 0.42710 ± 250ɑ1811360 left  8i H2N...2-iodo-1,4-dimethylbenzene...(CH2)22.5 ± 0.73.5 ± 12040 ± 300ɑ816583 left  8j H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2102 ± 151.0 ± 0.12600 ± 200ɑ252600 left  9 3-(4-methylphenyl)-1,2-oxazole18 ± 6860 ± 170>30001673ɑN=2==== 2β-carboxy side-chained (''p''-chloro/iodo/methyl) phenyltropanes ====+Multi-substituted structures of 2β-ester-3β-phenyltropanes Compound150px Short Name(S. Singh) R X IC50 (nM)DAT3HWIN 35428 IC50 (nM)5-HTT3Hparoxetine IC50 (nM)NET3Hnisoxetine Selectivity5-HTT/DAT SelectivityNET/DATx100px 23a  CH(CH3)2  H 85.1 ± 2.523121 ± 397632047 ± 1491 272  376x120px 23b  C6H5  H 76.7 ± 3.6106149 ± 725619262 ± 593 1384  251x100px 24a  CH(CH3)2  Cl 1.4 ± 0.136.04 ± 0.31'''ɑ'''1400 ± 7128 ± 15'''b'''778 ± 21250 ± 0.9'''c''' 100021.2'''d'''  55641.4'''e'''x100px 24b  cyclopropyl  Cl 0.96 ± 0.10168 ± 1.8235 ± 8.39 175  245x120px 24c  C6H5  Cl 1.99 ± 0.055.25 ± 0.76'''ɑ'''2340 ± 27390 ± 34'''b'''2960 ± 220242 ± 30'''c''' 117674.3'''d''' 1.341.6'''e'''x150px 24d  C6H4-4-I  Cl 32.6 ± 3.91227 ± 176967.6 ± 26.3 37.6  29.7x120px 24e  C6H4-3-CH3  Cl 9.37 ± 0.522153 ± 1432744 ± 140 230   293x140px 24f  C6H4-4-CH3  Cl 27.4 ± 1.51203 ± 421277 ± 118 43.9  46.6x120px 24g  C6H4-2-CH3  Cl 3.91 ± 0.233772 ± 3844783 ± 387 965  1223x140px 24h  C6H4-4-Cl  Cl 55 ± 2.316914 ± 10564883 ± 288 307  88.8x150px 24i  C6H4-4-OCH3  Cl 71 ± 5.619689 ± 18431522 ± 94 277  21.4x150px 24j  (CH2)2C6H4-4-NO2  Cl 2.71 ± 0.13 -  -  -  -x150px 24k  (CH)2C6H4-4-NH2  Cl 2.16 ± 0.25 -  -  -  -x150px 24l  (CH2)2C6H3-3-I-4-NH2  Cl 2.51 ± 0.25 -  -  -  -x150px 24m  (CH2)2C6H3-3-I-4-N3  Cl 14.5 ± 0.94 -  -  -  -x150px 24n  (CH2)2C6H4-4-N3  Cl 6.17 ± 0.57 -  -  -  -x150px 24o  (CH2)2C6H4-4-NCS  Cl 5.3 ± 0.6 -  -  -  -x170px 24p  (CH2)2C6H4-4-NHCOCH2Br  Cl 1.73 ± 0.06 -  -  -  -x100px 25a  CH(CH3)2  I 0.43 ± 0.052.79 ± 0.13'''ɑ'''66.8 ± 6.5312.5 ± 1.0'''b'''285 ± 7.641.2 ± 3.0'''c'''  1554.5'''d'''   66314.8'''e'''x100px 25b  cyclopropyl  I 0.61 ± 0.0815.5 ± 0.72102 ± 11 25.4  167x120px 25c  C6H5  I 1.51 ± 0.346.85 ± 0.93'''ɑ'''184 ± 2251.6 ± 6.2'''b'''3791 ± 14932.7 ± 4.4'''c'''  1227.5'''d'''  25104.8'''e''' 26a  CH(CH3)2  CH3 6.45 ± 0.8515.3 ± 2.08'''ɑ'''6090 ± 488917 ± 54'''b'''1926 ± 3873.4 ± 11.6'''c''' 94459.9'''d'''  2994.8'''e'''x120px 26b  CH(C2H5)2  CH3 19.1 ± 14499 ± 5573444 ± 44 235  180x100px 26c  cyclopropyl  CH3 17.8 ± 0.76485 ± 212628 ± 252 27.2  148x110px 26d  cyclobutyl  CH3 3.74 ± 0.522019 ± 1334738 ± 322 540  1267x120px 26e  cyclopentyl  CH3 1.68 ± 0.141066 ± 109644 ± 28 634  383x120px 26f  C6H5  CH3 3.27 ± 0.069.13 ± 0.79'''ɑ'''24500 ± 15261537 ± 101'''b'''5830 ± 370277 ± 23'''c''' 7492168'''d'''  178330.3'''e'''x120px 26g  C6H4-3-CH3  CH3 8.19 ± 0.905237 ± 4532136 ± 208 639  261x140px 26h  C6H4-4-CH3  CH3 81.2 ± 1615954 ± 6144096 ± 121 196   50.4x120px 26i  C6H4-2-CH3  CH3 23.2 ± 0.9711040 ± 50425695 ± 1394 476  1107x150px 26j  C6H4-4-Cl  CH3 117 ± 7.942761 ± 23999519 ± 864 365  81.3x150px 26k  C6H4-4-OCH3  CH3 95.6 ± 8.882316 ± 78523151 ± 282 861  33.0* '''ɑ'''''Ki'' value for displacement of 3HDA uptake. * '''b'''''Ki'' value for displacement of 3H5-HT uptake. * '''c'''''Ki'' value for displacement of 3HNE uptake. * '''d'''3H5-HT uptake to 3HDA uptake ratio. * '''e'''3HNE uptake to 3HDA uptake ratio.=== Carboxyaryl ===leftrightrightCompoundX2 Positionconfig8 DA  5-HT  NE RTI-122  RTI-113  RTI-277  RTI-120 recheck  RTI-116  RTI-203  Cl CO2(''m''-C6H4Me) β,β  NMe 9.3721532744 RTI-204  RTI-205 RTI-206==== 2-Phenyl-3-Phenyltropanes ====+2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake Compound Structure Short Name(S. Singh) Stereochemistry X(''para'') DAT3HWIN 35428 IC50 (nM) DAT3HMazindol ''Ki'' (nM) 5-HTT3HParoxetine IC50 (nM) 3HDA uptake ''Ki'' (nM) 3H5-HT uptake ''Ki'' (nM) Selectivity3H5-HT/3HDA  Cocaine  (2β,3β)  (H) 89 ± 4.82811050 ± 894231550.4 x105px  67a  2β,3β  H 12.6 ± 1.814.921000 ± 332028.9110038.1 x155px  67b  2β,3α  H  - 11.775364.3 x135px  67c  2α,3α  H  x170px  68  2β,3α 4.5812226.6 x100px  69a  2β,3β  CH3 1.96 ± 0.082.5811000 ± 832.8773.825.7 x170px  69b  2β,3α 4.1628769.0 x145px  69c  2α,3α  CH3 === Carboxyalkyl ===leftrightrightCodeX2 Positionconfig8 DA  5-HT  NERTI-77ClCH2C2(3-iodo-''p''-anilino)β,βNMe2.51—2247 RTI-121 IPCIT  RTI-153  RTI-191  RTI-114  RTI-278  RTI-190  RTI-193  RTI-117  RTI-150  RTI-127 RTI-338Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.Use of a cycBu resulted in greater DAT selectivity than did the cycPr homologue.==== 2-Alkyl Esters & Ethers ========= Esters (2-Alkyl) =====+2β-Alkyl Ester Phenyltropanes Structure Short Name(S. Singh) 2β=R ''Ki'' (nM)DAT3HWIN 35428 IC50 (nM)3HDA uptake Selectivityuptake/binding x110px  59a  CH=CHCO2CH3 22 ± 2123 ± 655.6 x110px  59b  CH2CH2CO2CH3 23 ± 2166 ± 687.2 x120px  59c  (CH2)2CH=CHCO2CH3 20 ± 2203 ± 7710.1 x120px  59d  (CH22)4CO2CH3 30 ± 2130 ± 74.3 x90px  59e  CH=CHCH2OH 26 ± 3159 ± 436.1 x90px  59f  CH2CH2CH2OH 11 ± 164 ± 325.8 x110px  59g  CH2CH2COC6H5 28 ± 247 ± 151.7===== Ethers (2-Alkyl) =====See the ''N''-desmethyl Paroxetine homologues+2-Alkyl Ether Phenyltropanes Molecular Structure Short Name(S. Singh) Stereochemistry DAT3HWIN 35428 IC50 (nM) 5-HTT3HParoxetine IC50 (nM) NET3HNisoxetine IC50 (nM) Selectivity5-HTT/DAT SelectivityNET/DAT  Paroxetine  623 ± 250.28 ± 0.02535 ± 150.00040.8 x130px ''R''-60a  2β,3β 308 ± 20294 ± 185300 ± 4500.917.2 x115px  ''R''-60b  2α,3β 172 ± 8.852.9 ± 3.626600 ± 12000.3155 x195px  ''R''-60c  2β,3α 3.01 ± 0.242.2 ± 16123 ± 9.514.140.9 x130px  ''S''-60d  2β,3β 1050 ± 4588.1 ± 2.827600 ± 11000.0826.3 x115px  ''S''-60e  2α,3β 1500 ± 74447 ± 472916 ± 19500.31.9 x195px  ''S''-60f  2β,3α 298 ± 17178 ± 1312400 ± 7200.641.6=== Carboxamides ===200px200px200pxStructure x100pxCode(''S. Singh #'') X2 Positionconfig8DA3HWIN 35428 (IC50 nM)NE3Hnisoxetine5-HT3Hparoxetine (IC50 nM)Selectivity5-HTT/DATSelectivityNET/DAT x100pxRTI-106''27b'' ClCON(H)Me β,β  NMe 12.4 ± 1.171584 ± 621313 ± 46106128 x100pxRTI-118''27a'' ClCONH2β,β  NMe11.5 ± 1.64270 ± 3591621 ± 110141371 x100pxRTI-222''29d''Memorpholinylβ,β  NMe11.7 ± 0.8723601 ± 1156>100K>85472017 x100pxRTI-129''27e'' ClCONMe2β,β  NMe 1.38 ± 0.1942 ± 481079 ± 102792683 x100pxRTI-146''27d''  Cl CONHCH2OH β,β  NMe 2.05 ± 0.23144 ± 397.8 ± 1047.770.2 x100pxRTI-147''27i''  Cl CON(CH2)4 β,β  NMe 1.38 ± 0.033,950 ± 7212400 ± 120789852862 x100pxRTI-156 ClCON(CH2)5β,β  NMe  6.6158323468  x100pxRTI-170 ClCON(H)CH2C≡CHβ,β NMe16.518394827  x100pxRTI-172 ClCON(H)NH2β,β  NMe 44.139143815  x130pxRTI-174 ClCONHCOMeβ,β  NMe 158>43K>125K  x160pxRTI-182 ClCONHCH2COPhβ,β  NMe 7.791722827  x110pxRTI-183✲''27 g'' ClCON(OMe)Meβ,β  NMe 0.85 ± 0.06549 ± 18.5724 ± 94852646 x110pxRTI-186''29c'' MeCON(OMe)Meβ,β  NMe 2.55 ± 0.43422 ± 263402 ± 3531334165 x100pxRTI-198''27h'' ClCON(CH2)3β,β  NMe 6.57 ± 0.67990 ± 4.8814 ± 57124151 x100pxRTI-196''27c'' ClCONHOMeβ,β  NMe 10.7 ± 1.259907 ± 63243700 ± 19604084926 x160pxRTI-201 ClCONHNHCOPhβ,β  NMe 91.8>20K>48K  x110pxRTI-208''27j'' ClCONO(CH2)3β,β  NMe 1.47 ± 0.131083 ± 762470 ± 561680737 x110pxRTI-214''27l''  Cl CON(-CH2CH2-)2O β,β  NMe 2.90 ± 0.38545 ± 20688769 ± 1855306102946 x110pxRTI-215''27f'' ClCONEt2β,β  NMe 5.48 ± 0.195532 ± 2999433 ± 77017211009 x150pxRTI-217 ClCONH(''m''-C6H4OH)β,β  NMe 4.78>30K>16K  x100pxRTI-218✲  Cl  CON(Me)OMe β,β  NMe 1.195201911  x150pxRTI-226''27 m'' ClCONMePhβ,β  NMe 45.5 ± 32202 ± 49523610 ± 212851948.4 x100pxRTI-227 ICONO(CH2)3β,β  NMe 0.75446230  x100pxRTI-229''28a''  I CON(CH2)4 β,β  NMe 0.37 ± 0.04991 ± 211728 ± 3946702678 x100px''27k''    6.95 ± 1.211752 ± 2023470 ± 226499252 x100px''28b''    1.08 ± 0.15103 ± 6.273.9 ± 8.168.495.4 x110px''28c''    0.75 ± 0.02357 ± 42130 ± 15.8173476 x100px''29a''    41.8 ± 2.454398 ± 2716371 ± 374152105 x110px''29b''    24.7 ± 1.936222 ± 72933928 ± 21921374252✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.+2β-Carboxamide-3β-Phenyltropanes Compound Short Name(S. Singh) R X IC50 (nM)DAT3HWIN 35428 IC50 (nM)5-HTT3HParoxetine IC50 (nM)NET3HNisoxetine Selectivity5-HTT/DAT SelectivityNET/DATx100px 29a  NH2  CH3 41.8 ± 2.456371 ± 3744398 ± 271 152  105 29b  N(CH2CH3)2  CH3 24.7 ± 1.9333928 ± 21926222 ± 729 1374  252 29cRTI-186  N(OCH3)CH3  CH3 2.55 ± 0.433402 ± 353422 ± 26 1334  165 29dRTI-222 4-morpholine  CH3 11.7 ± 0.87 >100000 23601 ± 1156 >8547  2017====Carboxamide linked phenyltropanes dimers====300px300px280px350px300pxDimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs ''in vivo''.=== Heterocycles ===These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize to the energetically more favorable trans configuration. This can happen to cocaine also.Atomic positions A—C(compound model '''34''')Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound '''34''' (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the ''minima'' of electrostatic potential near atom position A (Δ''V''min(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and Δ''V''min(A): wherein the values for the latter for '''32c''' = 0, '''32g''' = -4, '''32h''' = -50 & '''32i''' = -63 kcal/mol.In contrast to this trend, it is understood that an increasingly negative Δ''V''min is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.==== 3-Substituted-isoxazol-5-yl ====File:3-R-isoxazol-5-yl.svg+N-methylphenyltropanes with 1''R'' β,β stereochemistry. Code''(S.S. #)'' X R DA NE 5HT RTI-165  Cl 3-methylisoxazol-5-yl0.59181572 RTI-171 Me3-methylisoxazol-5-yl0.932543818 RTI-180  I 3-methylisoxazol-5-yl0.7367.936.4 RTI-177 β-CPPIT''32g'' Cl3-phenylisoxazol-5-yl1.28 ± 0.18504 ± 292420 ± 136 RTI-176 Me3-phenylisoxazol-5-yl1.583985110 RTI-181 I3-phenylisoxazol-5-yl2.57868100 RTI-184 Hmethyl43.3—6208RTI-185 HPh285—>12KRTI-334  Cl  3-ethylisoxazol-5-yl0.501203086RTI-335  Cl  isopropyl 1.199542318 RTI-336  Cl  3-(4-methylphenyl)isoxazol-5-yl4.0917145741RTI-337  Cl  3-t-butyl-isoxazol-5-yl7.31632137KRTI-345  Cl  ''p''-chlorophenyl6.425290>76KRTI-346  Cl  ''p''-anisyl1.577625880RTI-347  Cl  ''p''-fluorophenyl1.869187257RTI-354 Me 3-ethylisoxazol-5-yl1.622996400RTI-366MeR = isopropyl4.52523 (1550)42,900 (3900)RTI-371Me''p''-chlorophenyl8.74>100K (60,200)>100K (9090)RTI-386Me''p''-anisyl3.93756 (450)4027 (380)RTI-387Me''p''-fluorophenyl6.45917 (546)>100K (9400)==== 3-Substituted-1,2,4-oxadiazole ====leftleft+Heterocyclic (N-methyl)phenyltropanes with 1''R'' stereochemistry. Structure Code(''Singh's #'') X R DAT (IC50 ''nM'')displacement of H3WIN 35428 NET (IC50 ''nM'')H3nisoxetine 5-HTT (IC50 ''nM'')H3paroxetine Selectivity5-HTT/DAT SelectivityNET/DAT160pxααRTI-87 H3-methyl-1,2,4-oxadiazole20436K30K 160pxβαRTI-119 H3-methyl-1,2,4-oxadiazole1677K41K 160pxαβRTI-124  H3-methyl-1,2,4-oxadiazole102871K33K 170pxRTI-125''(32a)''  Cl 3-methyl-1,2,4-oxadiazole4.05 ± 0.57363 ± 362584 ± 80063789.6145pxββRTI-126''(31)''  H 3-methyl-1,2,4-oxadiazole100 ± 67876 ± 5513824 ± 42038.3788170pxRTI-130''(32c)''  Cl 3-phenyl-1,2,4-oxadiazole1.62 ± 0.02245 ± 13195 ± 5120151170pxRTI-141 ''(32d)''Cl3-(''p''-anisyl)-1,2,4-oxadiazole1.81 ± 0.19835 ± 8337 ± 40186461170pxRTI-143''(32e)''Cl3-(''p''-chlorophenyl)-1,2,4-oxadiazole4.06 ± 0.2240270 ± 180(4069)404 ± 5699.59919170pxRTI-144 ''(32f)''Cl3-(''p''-bromophenyl)-1,2,4-oxadiazole3.44 ± 0.361825 ± 170106 ± 1030.8532170pxβRTI-151 ''(33)'' Me 3-phenyl-1,2,4-oxadiazole2.33 ± 0.2660 ± 21074 ± 13045925.7160pxαRTI-152 Me 3-phenyl-1,2,4-oxadiazole494—1995 170pxRTI-154''(32b)''Cl3-isopropyl-1,2,4-oxadiazole6.00 ± 0.55135 ± 133460 ± 25057722.5160pxRTI-155Cl3-cyclopropyl-1,2,4-oxadiazole3.411774362 leftright+N-methylphenyltropanes with 1''R'' β,β stereochemistry. Structure Code X 2 Group DAT (IC50 ''nM'')displacement of H3WIN 35428 NET (IC50 ''nM'')displacement of H3nisoxetine 5-HTT (IC50 ''nM'')displacement of H3paroxetine Selectivity5-HTT/DAT SelectivityNET/DAT150pxRTI-157Metetrazole1557>37K>43K 170pxRTI-163  Cl tetrazole911—5456 170pxRTI-178  Me 5-phenyl-oxazol-2-yl35.46771699 170pxRTI-188  Cl 5-phenyl-1,3,4-oxadiazol-2-yl12.69303304 170pxRTI-189(''32i'')  Cl 5-phenyl-oxazol-2-yl19.7 ± 1.98496 ± 421120 ± 10756.825.5170pxRTI-194  Me 5-methyl-1,3,4-oxadiazol-2-yl4.452534885 170pxRTI-195  Me 5-phenyl-1,3,4-oxadiazol-2-yl47.51310>22,000 170pxRTI-199  Me 5-phenyl-1,3,4-thiadiazol-2-yl35.9>24,000>51,000 170pxRTI-200  Cl 5-phenyl-1,3,4-thiadiazol-2-yl15.34142>18,000 170pxRTI-202  Cl benzothiazol-2-yl1.374031119 170pxRTI-219  Cl 5-phenylthiazol-2-yl5.71851610,342  RTI-262Cl 188.2 ± 5.01595.25 ± 57385207 ± 48831628170pxRTI-370  Me 3-(''p''-cresyl)isoxazol-5-yl8.746980>100K 170pxRTI-371  Cl 3-(''p''-chlorophenyl)isoxazol-5-yl13>100K>100K 170pxRTI-436170pxRTI-470Cl''o''-Cl-benzothiazol-2-yl0.0941590 (994)1080 (98) 170pxRTI-451Mebenzothiazol-2-yl1.53476 (287)7120 (647) 170px''32g''  1.28 ± 0.18504 ± 292420 ± 1361891394170px''32h''  12.6 ± 10.3929 ± 88330 ± 19626273.7RTI, Kuhar, et al. (1999).N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu3SnN3 is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).=== Acyl (C2-propanoyl) ===x150pxx150pxx175pxx175pxTamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.#(''#'')XY2 Positionconfig8DA5-HTNEWF-23(''39n'')β-naphthyl C(O)Et  β,β  NMe  0.115  0.394  No data WF-31 PIT | WF-11''✲'' PTT(''39e'') Me WF-25(''39a'') H  WF-33  6-MeoBN  C(O)Et  α,β  NMe  0.13  2.24  No data''✲''Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine ''i.e.'' tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)+2β-acyl-3β-phenyltropane structures Structure S. Singh'salphanumericassignation(name) R1 R2 DAT125IRTI-55 IC50 (''nM'') 5-HTT3HParoxetine ''Ki'' (''nM'') Selectivity5-HTT/DAT  cocaine     173 ± 19 — —  Troparil11a(WIN 35065-2)    98.8 ± 12.2 — — x100px  WF-2539a C2H5C6H548.3 ± 2.81005 ± 11220.8 x100px  39b CH3C6H5114 ± 221364 ± 61612.0 x100px  39c C2H5C6H4-4-F15.3 ± 2.8630 ± 6741.2 x100px  39d CH3C6H4-4-F70.8 ± 13857 ± 18712.1x100px  WF-1139e C2H5C6H4-4-CH38.2 ± 1.6131 ± 116.0(+)-39e C2H5C6H4-4-CH34.21 ± 0.0574 ± 1217.6(-)-39e C2H5C6H4-4-CH31337 ± 122>10000— x100px  39f CH3C6H4-4-CH39.8 ± 0.5122 ± 2212.4 x100px  39g CH3C6H4-4-C2H5152 ± 2478.2 ± 220.5 x100px  39h C2H5C6H4-4-CH(CH3)2436 ± 4135.8 ± 4.40.08 x100px  39i C2H5C6H4-4-C(CH3)32120 ± 6301771 ± 4740.8 x100px  39j C2H5C6H4-4-C6H52.29 ± 1.084.31 ± 0.011.9 x130px  39k C2H5C6H4-2-CH31287 ± 322710000>7.8 x130px  39l C2H51-naphthyl5.43 ± 1.2720.9 ± 2.93.8 x130px  39m CH31-naphthyl10.1 ± 2.225.6 ± 5.12.5 x100px  WF-2339n C2H52-naphthyl0.115 ± 0.0210.394 ± 0.0743.5 x100px  39o CH32-naphthyl0.28 ± 0.111.06 ± 0.363.8 x100px  39p C2H5C6H4-4-CH(C2H5)2270 ± 38540 ± 512.0 x100px  39q C2H5C6H4-4-C6H11320 ± 5597 ± 120.30 x100px  39r C2H5C6H4-4-CH=CH20.90 ± 0.343.2 ± 1.33.5 x100px  39s C2H5C6H4-4-C(=CH2)CH37.2 ± 2.10.82 ± 0.380.1==== 2β-Acyl-3β-naphthyl substituted ====+2β-Acyl-3β-(substituted naphthyl)-8-azabicyclooctanes Structure Short Assignation(Numeric code, Davies UB)''S. Singh'' R DAT125HRTI-55'''ɑ'''IC50 nM SERT3Hparoxetine'''b'''''Ki'' nM NET3Hnisoxetine'''c'''''Ki'' nM potency ratioSERT/DAT potency ratioSERT/NETFile:WF-11.svgWF-11(6)4′-Me 8.2 ± 1.6131 ± 1065 ± 9.20.060.5File:WF-31.svgWF-31(7)4′-iPr 436 ± 4136 ± 4>10,00012>250File:WF-23.svgWF-23(8)2-naphthalene 0.12 ± 0.020.39 ± 0.072.9 ± 0.50.37x150px2β-acyl-3β-1-naphthalene(9a)4′-H5.3 ± 1.321 ± 2.949 ± 100.318x150px(9b)4′-Me25.1 ± 0.58.99 ± 1.70163 ± 36318x150px(9c)4′-Et75.1 ± 11.9175 ± 254769 ± 6880.727x150px(9d)4′-iPr225 ± 36136 ± 64>10,0002>73.5x110px(10a)6′-Et 0.15 ± 0.040.38 ± 0.1927.7 ± 9.60.474x110px(10b)6′-iPr0.39 ± 0.041.97 ± 0.33no data0.2—x110px(10c'''e''')6′- OMe0.13 ± 0.042.24 ± 0.34no data0.05—x110px(10d)5′-Et, 6′-OMe30.8 ± 6.67.55 ± 1.573362 ± 1484.1445x110px(10e)5′-C(Me)=CH2, 6′-OMe45.0 ± 3.788.0 ± 13.32334 ± 3780.526.5x110px(10f)6′-I0.35 ± 0.070.37 ± 0.02no data1.0—x120px(10g)7′-I 0.45 ± 0.050.47 ± 0.02no data0.5'''d'''—x110px(10h)5′-NO2, 6′-OMe148 ± 5015 ± 1.6no data10—x110px(10i)5′-I, 6′-OMe 1.31 ± 0.332.27 ± 0.31781 ± 1810.6344x110px(10j)5′-COMe, 6′-OMe12.6 ± 3.815.8 ± 1.65498 ± 240.832x145px(11a)2β-COCH3, 1-naphthyl10 ± 2.226 ± 5.1165 ± 400.46.3x135px(11b)2α-COCH3, 1-naphthyl97 ± 21217 ± 55no data0.45—x120px(11c)2α-COCH2CH3, 2-naphthyl2.51 ± 0.8216.4 ± 2.068.0 ± 10.80.154.1x110px(11d)2β-COCH3, 2-naphthyl1.27 ± 0.151.06 ± 0.364.9 ± 1.21.24.6x110px(11e)2β-COCH(CH3)2, 2-naphthyl0.25 ± 0.082.08 ± 0.8037.6 ± 10.50.1218.1x110px(11f)''79a''2β-COCH2CH3, 2-naphthyl, ''N''8-demethyl0.03 ± 0.010.23 ± 0.072.05 ± 0.90.138.9* '''ɑ''' nonspecific binding was determined in the presence of 1.0 μM WF-23(source equates WF-23 as analogue 3a, but table gives # as analogue 8)* '''b''' nonspecific binding was determined in the presence of 10.0 μM fluoxetine* '''c''' nonspecific binding was determined in the presence of 1.0 μM desipramine* '''d''' ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values* '''e''' sources differ on whether C2 position acyl is alpha or beta configured=== Ester reduction ===Note: ''p''-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.200pxCodeX2 Positionconfig8 DA  5-HT  NE RTI-100  RTI-101  RTI-99  RTI-93  RTI-105  RTI-123 RTI-145=== 2-Alkane/Alkene ===+ 2-Alkane/Alkene-3-Phenyltropanes Structure Singh's # R X DATmazindol displacement DA uptake 5-HT Uptake SelectivityDA uptake/DAT binding right  11aWIN 35062-2    89.453.7186 0.6 left  11c   0.83 ± 00.728.5 ± 0.9—34.3 left  11f   5.766.9223.21.2 left 41a  (CH2)2CH3  H  12.2  6.89  86.8 0.6 left 41b  (CH2)3C6H5  H 16 ± 2''a''43 ± 13''b''—2.7 left 42  (CH2)2CH3  F  5.28  1.99  21.7 0.4 left 43a  CH=CH2  Cl  0.59 ± 0.15 2.47 ± 0.5—4.2 left 43b  E-CH=CHCl  Cl  0.42 ± 0.04 1.13 ± 0.27—2.7 left 43c  Z-CH=CHCl  Cl 0.22 ± 0.02  0.88 ± 0.05—4.0 left 43d  E-CH=CHC6H5  Cl 0.31 ± 0.04 0.66 ± 0.01 —2.1 left 43e  Z-CH=CHC6H5  Cl 0.14 ± 0.07  0.31 ± 0.09—2.2 left 43f  CH2CH3  Cl 2.17 ± 0.20 2.35 ± 0.52—1.1 left 43 g  (CH2)2CH3  Cl 0.94 ± 0.08  1.08 ± 0.05—1.1 left 43h  (CH2)3CH3  Cl  1.21 ± 0.180.84 ± 0.05 —0.7 left 43i  (CH2)5CH3  Cl 156 ± 15 271 ± 3 —1.7 left 43j  (CH2)2C6H5  Cl 1.43 ± 0.03 1.54 ± 0.08 —1.0 left 44a  (CH2)2CH3  CH3  1.57 1.1010.3 0.7 left 44b  (CH2)3CH3  CH3 1.82 1.31 15.1 0.7 left 45  (CH2)2CH3  H 74.9 30.2 389 0.4 left 46  (CH2)2CH3  F  21.112.1  99.60.6 left 47a  (CH2)2CH3  CH3 8.91 11.8 50.1 1.3 left 47b  (CH2)3CH3  CH3 11.4 10.1 51.0 0.9''a''''Ki'' value for displacement of WIN 35428. ''b''IC50 value. === Irreversible covalent (''cf.'' ionic) C2 ligands ===300pxIrreversible (phenylisothiocyanate) binding ligand () RTI-76: ''4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo3.2.1octane-2-carboxylate''. Also known as: ''3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester''.====C2 Acyl, N8 phenylisothiocyanate====x170px'''HD-205''' (Murthy et al., 2007)Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.=== Benztropine based (C2-position hetero-substituted) phenyltropanes ===500px280px+2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-3-(Diarylmethoxy)propyl-3β-aryltropanes. Structure Compound R X Y 3HWIN 35,428@ DAT''Ki'' (nM) 3HCitalopram@ SERTK''i'' (nM) 3HNisoxetine@ NETK''i'' (nM) 3HPirenzepine@ M1K''i'' (nM)200px 9a CH3HH34 ± 2121 ± 19684 ± 10010,600 ± 1,100 9b FHH49 ± 12——— 9c ClHH52 ± 2.1147 ± 81,190 ± 7211,000 ± 1,290 9d CH3ClH80 ± 9443 ± 604,400 ± 23831,600 ± 4,300 9e FClH112 ± 11——— 9f ClClH76 ± 7462 ± 362,056 ± 23639,900 ± 5,050 9g CH3FF62 ± 7233 ± 241,830 ± 17715,500 ± 1,400 9h FFF63 ± 13——— 9i ClFF99 ± 18245 ± 162,890 ± 22216,300 ± 1,300200px 10a CH3HH455 ± 36530 ± 722,609 ± 19512,600 ± 1,790 10c ClHH478 ± 72408 ± 163,998 ± 25611,500 ± 1,720 10d CH3ClH937 ± 841,001 ± 10922,500 ± 2,82118,200 ± 2,600 10f ClClH553 ± 1061,293 ± 405,600 ± 1839,600 ± 600 10g CH3FF690 ± 76786 ± 6716,000 ± 6379,700 ± 900 10i ClFF250 ± 40724 ± 10052,300 ± 13,6009,930 ± 1,090200px 12a HHH139 ± 1561 ± 9207 ± 307,970 ± 631 12b HClH261 ± 1945 ± 3—24,600 ± 2,930 12c HFF60 ± 7———=== F&B series (Biotin side-chains etc.) ===One patent claims a series of compounds with biotin-related sidechains are pesticides. Images of the biotin C2 side-chained phenyltropanes, click tox170pxx170pxx170pxx170pxx240pxx200pxx290pxx290pxx280pxx240pxx200pxx200pxx260pxx260pxStructureCode''para''-XC2-Tropane Positionconfig DA  NE 5-HT x150px  —  H  F1  β,β  —  —  — x140px  RTI-224 MeF1c β,β 4.49—155.6 x160px  RTI-233 MeF2 β,β 4.3851673.6 x160px  RTI-235 MeF3d β,β 1.7540272.4 x150px  —  — F3 β,β  —  —  — x140px  RTI-236 MeB1d β,β 1.6386.8138 x140px  RTI-237 MeB2d β,β 7.27258363 x160px  RTI-244 MeB3d β,β 15.6180933.7 x140px  RTI-245 ClF4c β,β 77.3——  RTI-246 MeF4c β,β 50.33000— x150px —   —   F5  β,β  —  —  —  x120px  RTI-248 ClF6c β,β 9.7346746.96 x140px  RTI-249 ClF1c β,β 8.32502381.6  RTI-266 MeF2 β,β 4.80836842  RTI-267 MeF7 wrong β,β 2.52324455 x210px  RTI-268 MeF7 right β,β 3.891014382 x220px  RTI-269 MeF8 β,β 5.55788986800px800px=== Miscellany (''i.e.'' Misc./Miscellaneous) C2-substituents ===220px220px170px220pxStructureCodeX2 Positionconfig8 DA  5-HT  NE170pxRTI-102ICO2Hβ,β  NMe 474192843,400170px RTI-103BrCO2Hβ,β  NMe 278307017,400170pxRTI-104FCO2Hβ,β  NMe 2744>100K>100K170pxRTI-108 170pxRTI-241 170pxRTI-139 170pxRTI-161 170pxRTI-230  Cl H3C–C=CH2 β,β  NMe 1.2857141170pxRTI-240 170pxRTI-145170pxRTI-158 170pxRTI-131 170pxRTI-164 170pxRTI-132 170pxRTI-239 180pxRTI-338 150pxRTI-348
C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes) === Aryl-Tropenes === Test compoundDA-uptake IC50(μM)NA-uptake IC50(μM) 5-HT-uptake IC50(μM)   (+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo3.2.1oct-2-ene0.260.0280.010   (+)-3-Napthalen-2-yl-8-azabicyclo3.2.1oct-2-ene0.0580.0130.00034   (–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo3.2.1oct-2-ene0.0340.0180.00023 + 8-AZABICYCLO3.2.1OCT-2-ENE DERIVATIVES Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo3.2.1oct-2-ene0.0790.0260.0047 Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo3.2.1oct-2-ene184.90.047(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo3.2.1oct-2-ene1.50.50.016(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo3.2.1oct-2-ene22.008.000.0036
Enantioselective nonstandard configurations (non-2β-,3β-) === β,α Stereochemistry ===300px300px'''Structure''' 100px'''Compound(RTI #)'''''(S. Singh's #)'''''X''''''2 Group''''''config''''''8''''''DAT''' IC50 (''nM'')3HWIN 35428 '''5-HTT''' IC50 (''nM'')3Hparoxetine '''NET''' IC50 (''nM'')3Hnisoxetine  selectivity5-HTT/DAT  selectivityNET/DAT 100pxRTI-140''20a'' H  CO2Me  β,α  NMe 101 ± 165,701 ± 7212,076 ± 28556.420.6 100pxRTI-352'''ɑ'''''20d'' I  CO2Me  β,α  NMe 2.86 ± 0.1664.9 ± 1.9752.4 ± 4.922.818.4100pxRTI-549  Br  CO2Me  β,α  NMe  —  —  —  —  —100pxRTI-319'''b''' 3α-2-naphthyl CO2Me β,α  NMe1.1 ± 0.0911.4 ± 1.370.2 ± 6.28 —  — 100pxRTI-286'''c'''''20b'' F  CO2Me β,α  NMe21 ± 0.575062 ± 4851231 ± 9124158.6140pxRTI-274'''d'''FCH2O(3′,4′-MD-phenyl)β,α  NH3.965.6214.4 —  —100pxRTI-287  Et  CO2Meβ,α  NMe327168717,819 —  — 100px''20c'' ClCO2Meβ,αNMe2.4 ± 0.2998 ± 12060.1 ± 2.441625.0 100px''20e'' MeCO2Meβ,αNMe10.2 ± 0.084250 ± 422275 ± 2441727.0120px BnCO2Meβ,αNMe —  —  —  —  —800px=== α,β Stereochemistry ===200px  CompoundDA (μM)M.E.D. (mg/kg)Dose (mg/kg)Activity Activity(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo3.2.1octane0.392  methyl aldoxime  α,β  NMe  —  —  —   Tesofensine  Cl2  ethoxymethyl  α,β  NMe 65111.7  NS-2359 (GSK-372,475) Cl2  Methoxymethyl  α,β  NH  —  —  — ==== fumaric acid salts (of α,β configured phenyltropanes) ==== Test Compound DA uptake IC50(μM) NE uptake IC50(μM) 5-HT uptake IC50(μM)(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo3.2.1octane fumaric acid salt0.0620.0350.00072(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo3.2.1octane fumaric acid salt0.0620.150.0063(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo3.2.1octane fumaric acid salt0.100.0480.0062(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo3.2.1octane fumaric acid salt0.0880.0510.013
Arene equivalent alterations === ''η''6-3β-(transition metal complexed phenyl)tropanes ===×–substitution image of both the chromium & ruthenium benzene pi-symmetry facilitating PTs. '''21b''' can be prepared from ferrocenes and perrhenate by a double ligand transfer (DLT) reaction.Unlike metal complexed PTs created with the intention of making useful radioligands, '''21a''' & '''21b''' were produced seeing as their ''η''6-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule. (''cf.'' the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (''cf.'' Bloom and Wheeler.). '''21a''' was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity ''Ki'' values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. '''21b''' by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.Tricarbonyl-3β-chromium containing phenyltropane, having roughly twice the strength ''Ki'' affinity as parent compound at same mean affect.The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (''i.e.'' '''''θ''''') is '''''θ'''''=131° for Cr(CO)3 whereas Cp*Ru was '''''θ'''''=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.Diagram indicating the triflate, in bracket, superimposed as a direct connection between the ''η''6 benzene containing its transition metal fixed upon the ''η''5-penta-methyl (five-methyls) cyclopenta-dienyl (five sided ring) alongside the benzene in three dimension.+Displacement of Receptor-Bound 3HWIN 35428 and Inhibition of  3HDA Uptake by Transition Metal Complexes of 3β-Phenyltropanes Structure Compound #(S. Singh)'''Systematic name''' ''Ki'' (''nM'')'''ɑ''' IC50 (''nM'') selectivitybinding/uptake left  21a'''c'''17 ± 15'''b'''224 ± 8341824.6 left  21b'''d'''2280 ± 18338901.7Cocaine32 ± 5388 ±22140512.6Troparil (11a)33 ± 17314 ± 22237311.3* '''ɑ'''The binding data fit a two-site model better than a one-site model* '''b'''The ''Ki'' value for the one-site model was 124 ± 10 ''nM''* '''c'''IUPAC: '''''η''6-(2β-carbomethoxy-3β-phenyl)tropanetricarbonylchromium'''* '''d'''IUPAC: '''''η''5-(pentamethylcyclopentadienyl)-''η''6-(2β-carbomethoxy-3β-phenyl)tropaneruthenium-(II) triflate'''=== 3-(2-thiophene) and 3-(2-furan) === CodeCompoundDA (μM)NE (μM)5-HT (μM)1(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo3.2.1octanefumaric acid salt0.300.00190.000522(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-3.2.1octane fumaric acid salt0.360.00360.000423(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-3.2.1octane fumaric acid salt0.310.000900.000364(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-3.2.1octane fumaric acid salt0.920.00300.000535(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo3.2.1octane fumaric acid salt0.0740.00180.000746(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo3.2.1octane fumaric acid salt0.190.00160.00054=== Thiophenyltropanes ===800px=== Diaryl ===Fluoxetine homologue, also: Hanna et al. (2007) ''cf.'' the paroxetine homologue PTsZIENT:
6/7-tropane position substituted === 2β-carbomethoxy 6/7 substituted ===+6/7-Substituted 2-carbomethoxy-phenyltropanes Structure Compound #(S. Singh) Substitution DAT (IC50 ''nM'')displacement of H3WIN 35428 5-HTT (IC50 ''nM'')H3Citalopram Selectivity5-HTT/DAT  Cocaine H160px 103a 3β,2β, 7-OMe3′,4′-Cl286 ± 4.7884 ± 10010.3160px 103b 3β,2β, 7-OH3′,4′-Cl21.42 ± 0.0328.6 ± 7.820.1130px 103c 3α,2β, 7-OH3′,4′-Cl21.19 ± 0.161390 ± 561168160px 104a 3β,2β, 6-OH4′-Me160px 104b 3β,2α, 6-OH4′-Me130px 104c 3α,2β, 6-OH4′-Me130px 104d 3α,2α, 6-OH4′-Me* '''ɑ'''IC50 value for displacement of H3mazindol. IC50 for cocaine 288 nM for displacement of H3mazindol=== 3-butyl 6/7 substituted ===+6/7-Substituted 3-butyl-phenyltropanes Structure Compound #(S. Singh) Substituent Ki ''nM''displacement of H3mazindol binding Ki ''nM''H3DA uptake Selectivityuptake/binding  Cocaine H270 ± 0.03400 ± 201.5x70px 121a 7β-CN2020 ± 10710 ± 400.3x70px 121b 6β-CN3040 ± 4806030 ± 8802.0x70px 121c 7β-SO2Ph4010 ± 3108280 ± 13402.1x90px 121d 6β-SO2Ph4450 ± 4308270 ± 6901.8x80px 121e 7α-OH830 ± 40780 ± 600.9x130px 121f H100 ± 1061 ± 100.6x130px 121g 7β-CN24000 ± 342032100 ± 85401.3x130px 121h 6β-CN11300 ± 154026600 ± 33302.3x130px 121i 7β-SO2Ph7690 ± 27707050 ± 4500.9x130px 121j 6β-SO2Ph4190 ± 7008590 ± 13602.0x130px 121k 7α-SO2Phx130px 121l 7β-SO2Ph, 7α-F840 ± 2602520 ± 2903.0x130px 121m 7α-F200 ± 10680 ± 103.4x130px 121n 7β-F500 ± 10550 ± 1401.1=== intermediate 6- & 7-position synthesis modified phenyltropanes ===+6/7-synthetic intermediates Structure Compound #(S. Singh) Substituent W Substituent X Substituent Y Substituent Zx120px(±)-122a CNHHHx120px(±)-122b HHCHHx120px(±)-122c HCHHHx120px(±)-122d HHHCHx120px(±)-122e SO2PhHHHx120px(±)-122f HHSO2PhHx120px(±)-122g HSO2PhHHx120px(±)-122h SO2PhFHHx120px(±)-122i FSO2PhHHx120px(±)-122j HHSO2PhF
8-tropane (bridgehead) position modified === Nortropanes (''N''-demethylated) ===x200pxNS2359 (GSK-372,475)It is well established that electrostatic potential around the ''para'' position tends to improve MAT binding. This is believed to also be the case for the ''meta'' position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant. Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally ''in vivo'' via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.+Selected ββ Nortropanes Code''(S.S. #)'' X''para'' DA 5HT NERTI-142''75b''F4.3968.618.8RTI-98''75d''Nor'''ɑ'''-RTI-55I0.69  0.36 11.0RTI-110''75c''Cl0.624.135.45RTI-173''75f''Et49.98.13122RTI-279Nor'''ɑ'''-RTI-280''para''-Me''meta''-I5.98 ± 0.481.06 ± 0.1074.3 ± 3.8RTI-305Nor'''ɑ'''-RTI-360/''11y''Ethynyl1.24 ± 0.111.59 ± 0.221.8 ± 1.0RTI-307Nor'''ɑ'''-RTI-281/''11z''Propynyl6.11 ± 0.673.16 ± 0.33115.6 ± 5.1RTI-309Nor'''ɑ'''-''11t''Vinyl1.73 ± 0.052.25 ± 0.1714.9 ± 1.18RTI-330Nor'''ɑ'''-''11s''Isopropyl310.2 ± 2115.1 ± 0.97—RTI-353''para''-Et''meta''-I330.54 ± 17.120.69 ± 0.07148.4 ± 9.15'''ɑ'''The ''N''-demethylated variant of (''i.e.'' compound code-name after dash)+''N''-demethylating various  β,β ''p''-HC-phenyltropanes''N''-Me compound code#→''N''-demethylated derivativecompound code #''para''-X3HParoxetine3HWIN 35,4283HNisoxetine''11 g''→''75f''Ethyl28.4 → 8.1355 → 49.94,029 → 122''11t''→''75i''Vinyl9.5 → 2.251.24 → 1.7378 → 14.9''11y''→''75n''Ethynyl4.4 → 1.591.2 → 1.2483.2 → 21.8''11r''→''75 g''1-Propyl70.4 → 2668.5 → 2123,920 → 532''11v''→''75k''''trans''-propenyl11.4 → 1.35.29 → 28.61,590 → 54''11w''→''75l''''cis''-propenyl7.09 → 1.1515 → 31.62,800 → 147''11x''→''75 m''Allyl28.4 → 6.232.8 → 56.52,480 → 89.7''11z''→''75o''1-Propynyl15.7 → 3.162.37 → 6.11820 → 116''11s''→''75h''''i''-Propyl191 → 15.1597 → 31075,000 → ? ''11u''→''75j''2-Propenyl3.13 → 0.614.4 → 231,330? → 144+''N''-Demethylating phenyltropanes to find a NRI Isomer4′3′NEDA5HTβ,βMeH60 → 7.21.7 → 0.84240 → 135β,βFH835 → 18.815.7 → 4.4760 → 68.6β,βClH37 → 5.451.12 → 0.6245 → 4.13β,αMeH270 → 910.2 → 33.64250 → 500β,αFH1200 → 9.821 → 32.65060 → 92.4β,αClH60 → 5.412.4 → 3.1998 → 53.3β,αFMe148 → 4.2313.7 → 9.381161 → 69.8β,αMeF44.7 → 0.867.38 → 91150 → 97.4"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).+''N''-norphenyltropanes Structure Short Name(S. Singh) ''Para''-X DAT3HWIN 35428 IC50 (nM) 5-HTT3HParoxetine IC50 (nM) NET3HNisoxetine IC50 (nM) Selectivity5-HTT/DAT SelectivityNET/DAT  Norcocaine H206 ± 29127 ± 13139 ± 90.60.7 x100px  75a H30.8 ± 2.3156 ± 884.5 ± 7.55.12.7 x100px  75b F4.39 ± 0.2068.6 ± 2.018.8 ± 0.715.64.3 x100px  75c Cl0.62 ± 0.094.13 ± 0.625.45 ± 0.216.78.8 x100px  75d I0.69 ± 0.20.36 ± 0.057.54 ± 3.190.510.9 x110px  75e ''para''-I&2β-CO2CH(CH3)21.06 ± 0.123.59 ± 0.27132 ± 53.4124 x100px  75f C2H549.9 ± 7.38.13 ± 0.30122 ± 120.22.4 x100px  75g ''n''-C3H7212 ± 1726 ± 1.3532 ± 8.10.12.5 x100px  75h CH(CH3)2310 ± 21 x100px  75i CH=CH21.73 ± 0.052.25 ± 0.1714.9 ± 1.181.38.6 x100px  75j C-CH3CH223 ± 0.90.6 ± 0.06144 ± 120.036.3 x100px  75k ''trans''-CH=CHCH328.6 ± 3.11.3 ± 0.154 ± 160.041.9 x100px  75l ''cis''-CH=CHCH331.6 ± 2.21.15 ± 0.1147 ± 4.30.044.6 x100px  75m CH2CH=CH256.5 ± 566.2 ± 0.389.7 ± 9.60.11.6 x100px  75n CH≡CH1.24 ± 0.111.59 ± 0.221.8 ± 1.01.317.6 x100px  75o CH≡CCH36.11 ± 0.673.16 ± 0.33116 ± 5.10.519.0 x110px  75p'''ɑ'''3,4-Cl20.66 ± 0.24'''ɑ'''These values determined in Cynomolgus monkey caudate-putamen'''b'''The radioligand used for 5-HTT was 3Hcitalopram+2β-Propanoyl-''N''-norphenyltropanes Compound Structure Short Name(S. Singh) DAT125IRTI-55 IC50 (nM) 5-HTT3HParoxetine ''Ki'' (nM) NET3HNisoxetine ''Ki'' (nM) Selectivity5-HTT/DAT SelectivityNET/DAT x100px  79a 0.07 ± 0.010.22 ± 0.162.0 ± 0.093.128.6 x100px  79b 4.7 ± 0.5819 ± 1.45.5 ± 2.04.01.2 x100px  79c 380 ± 1105.3 ± 1.03400 ± 2700.018.9 x100px  79d 190 ± 17150 ± 505100 ± 2200.826.8 x100px  79e 490 ± 12085 ± 164300 ± 11000.18.8 x100px  79f 1.5 ± 1.10.32 ± 0.0610.9 ± 1.50.27.3 x100px  79g 16 ± 4.90.11 ± 0.0294 ± 180.075.9====Paroxetine homologues====See the ''N''-methyl paroxetine homologues''cf.'' di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.+2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies Compound Structure Short Name(S. Singh) Stereochemistry DAT3HWIN 35428 IC50 (nM) 5-HTT3HParoxetine IC50 (nM) NET3HNisoxetine IC50 (nM) Selectivity5-HTT/DAT SelectivityNET/DAT x130px 623 ± 250.28 ± 0.02535 ± 150.00040.8 x130px  ''R''-81a 2β,3β835 ± 90480 ± 2137400 ± 14000.644.8 x130px  ''R''-81b 2α,3β142 ± 1390 ± 3.42500 ± 2500.617.6 x180px  ''R''-81c 2β,3α3.86 ± 0.25.62 ± 0.214.4 ± 1.31.43.7 x130px  ''S''-81d 2β,3β1210 ± 33424 ± 1517300 ± 18000.314.3 x130px  ''S''-81e 2α,3β27.6 ± 2.455.8 ± 5.731690 ± 1502.061.2 x180px  ''S''-81f 2β,3α407 ± 3319 ± 1.81990 ± 1760.054.9=== ''N''-replaced (S,O,C) === The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.leftcenter   '''Compound'''  '''X'''  '''2 Group'''  '''config'''  '''8'''  DA5-HTNE   Tropoxane  Cl,Cl CO2Me (racemic) β,β  O 3.36.5No data   O-4210  ''p''-F  3-methyl-5-isoxazole  β,β  S  7.0  >1000  No data Mid-synth stage in similar compound preparation as like to above.center====8-oxa bridgehead replacements====+8-Oxanortropanes, binding inhibition using monkey caudate-putamen Structure Compound #(S. Singh) ''Para''-(''meta''-) DAT (IC50 ''nM'')displacement of H3WIN 35428 5-HTT (IC50 ''nM'')H3Citalopram Selectivity5-HTT/DAT 120px  ''R/S''-90a H>1000 140px  ''R/S''-90b F54625804.7 140px  ''R/S''-90c Cl1010710.7 140px  ''R/S''-90d Br22301.4 140px  ''R/S''-90e I7121.7 140px  ''R/S''-90f 3,4-Cl23.356.521.9 140px  ''R''-90g 3,4-Cl23.274.671.4 140px  ''S''-90h 3,4-Cl247581.2 90px  ''R/S''-91a H1990114405.7 90px  ''R/S''-91b F>1000 90px  ''R/S''-91c Cl28.581628.6 90px  ''R/S''-91d Br927630.7 90px  ''R/S''-91e I42721.7 100px  ''R/S''-91f 3,4-Cl23.0864.520.9 100px  ''R''-91g 3,4-Cl22.343113.2 100px  ''S''-91h 3,4-Cl256286051.1====8-carba bridgehead replacements====+8-carba 3-Aryl bicyclooctanes Structure Compound #(S. Singh) DAT (IC50 ''nM'')displacement of H3WIN 35428 5-HTT (IC50 ''nM'')H3Citalopram Selectivity5-HTT/DAT140px ''R/S''-98a 7.1 ± 1.75160 ± 580726140px ''R/S''-98b 9.6 ± 1.833.4 ± 0.63.5100px ''R/S''-98c 14.3 ± 1.1180 ± 6512.6=== ''N''-alkyl ===200px250px270pxCompoundX2 Groupconfig8 DATSERTNET FP-β-CPPIT  Cl  3′-phenylisoxazol-5′-yl  β,β  NCH2CH2CH2F  -  -  - FE-β-CPPIT  Cl  (3′-phenylisoxazol-5′-yl)  β,β  NCH2CH2F  -  -  - Altropane (IACFT)  F  CO2Me  β,β  NCH2CH=CHF  -  -  - FECNT I CO2Me  β,β NCH2CH2F -  -  - RTI-310 I  CO2Me  β,β  N-Prn 1.17 -  - RTI-311  I  CO2Me  β,β  NCH2CH=CH2 1.79 -  - RTI-312 I  CO2Me  β,β  NBun 0.76 -  - RTI-313  I  CO2Me  β,β  NCH2CH2CH2F 1.67 -  - Ioflupane (FP-CIT)  123I  CO2Me  β,β  NCH2CH2CH2F  -  -  - PE2IMe CO2Me  β,β NCH2CH=CHI -  -  - RTI-251  Cl  CO2Me  β,β  NCH2CO2Et 1.93 10.1114 RTI-252  Cl  CO2Me  β,β  NCH2CH2CO2Et 2.5635.2125 RTI-242  Cl  β,β (bridged) -C(O)CH(CO2Me)CH2N  7.67227510Bi- and tri-cyclic aza compounds and their uses.+''N''-substituted 3β-phenylnortropanes(including ''N''-phthalimidoalkyl analogues of β-CIT) Structure Short Name(S. Singh) Nitrogen side-chain(N8) DAT3HGBR 12935 ''Ki'' (nM) 5-HTT3HParoxetine ''Ki'' (nM) NET3HNisoxetine ''Ki'' (nM) Selectivity5-HTT/DAT SelectivityNET/DAT  Cocaine H350 ± 80>10000>30000 0.06 ± 0.0252.8 ± 4.4>20000  WIN 3542811bH14.7 ± 2.9181 ± 21635 ± 11012.343.2  RTI-5511eH1.40 ± 0.200.46 ± 0.062.80 ± 0.400.32 150px  82aCH2CH=CH2 150px  82bCH2CH2CH3 160px  82cCH2C6H558.9 ± 1.65'''b''' 200px  82d(CH2)3C6H51.4 ± 0.2'''b''' 210px  82e(CH2)5C6H53.4 ± 0.83'''b''' 160px  83aCH2CH2CH2F1.20 ± 0.2948.7 ± 8.41000040.68333 160px  83bCH2CH2F4.40 ± 0.3521.7 ± 8.3>10000 160px  84aCH2CH2CH2F3.50 ± 0.390.110 ± 0.0263.0 ± 4.00.0318 160px  84bCH2CH2F4.00 ± 0.730.140 ± 0.0293.0 ± 17.00.0323.2 160px  84cCH2CHF215.1 ± 3.79.6 ± 1.5>5000 170px  84dCH2CH2CH2Cl3.10 ± 0.570.32 ± 0.0696.0 ± 29.00.131.0 170px  84eCH2CH2CH2Br2.56 ± 0.570.35 ± 0.08164 ± 470.164.1 170px  84fCH2CH2CH2I38.9 ± 6.38.84 ± 0.5350000.2128 170px  84gCH2...methylcyclopropane4.30 ± 0.871.30 ± 0.25198 ± 9.60.346.0 180px  84hCH2CH2CH2OH5.39 ± 0.212.50 ± 0.20217 ± 190.540.2 200px  84iCH2CH2(OCH3)26.80 ± 1.101.69 ± 0.09110 ± 7.70.216.2 180px  84jCH2CO2CH311.9 ± 1.40.81 ± 0.1029.1 ± 1.00.072.4 185px  84kCH2CON(CH3)212.2 ± 3.86.40 ± 1.70522 ± 1450.542.8 200px  84lCH2CH2CH2OMs36.3 ± 2.117.3 ± 1.250000.5138 170px  84mCOCH(CH3)22100 ± 140102 ± 23>10000 210px  84n(CH2)2Pht4.23 ± 0.480.84 ± 0.02441 ± 66.00.2104 210px  84o(CH2)3Pht9.10 ± 1.100.59 ± 0.0774.0 ± 11.60.068.1 230px  84p(CH2)4Pht2.38 ± 0.220.21 ± 0.02190 ± 18.00.0979.8 230px  84q(CH2)5Pht2.40 ± 0.170.34 ± 0.0360.0 ± 3.100.125.0 270px  84r(CH2)8Pht2.98 ± 0.300.20 ± 0.0275.0 ± 3.60.0725.2 170px  84s'''d'''CH2CH=CH-CH315 ± 175 ± 5400 ± 805.026.7 170px  84t'''d'''CH2C(Br)=CH230 ± 5200 ± 40>1000 170px  84u'''d'''CH2CH=CH2I(E)30 ± 5960 ± 60295 ± 3332.09.8 170px  84v'''d'''CH2C≡CH14 ± 1100 ± 30>1000 170px  84w'''d'''CH2C6H542 ± 12100 ± 17600 ± 1002.414.3 170px  84x'''d'''CH2C6H4-2-CH393 ± 19225 ± 40>1000 160px  85a'''d'''''para''-H113 ± 41100 ± 20>1000 170px  85b'''d'''''para''-Cl, ''meta''-Cl29 ± 450 ± 6500 ± 1201.717.2 170px  85c'''d'''''para''-Me17 ± 7500 ± 30>1000 180px  85d'''d'''''para''-CH(CH3)2500 ± 120450 ± 80>1000 190px  85e'''d'''''para''-''n''-C3H7500 ± 100300 ± 12750 ± 1600.61.5* '''ɑ'''IC50 for displacement of 3Hcocaine. IC50 for cocaine = 67.8 ± 8.7 (nM)* '''b'''IC50 values for displacement of 3HWIN 35428* '''c'''IC50 values for displacement of 3Hcitalopram* '''d'''The standard ''Ki'' value for the displacement of 3HGBR 12935, 3Hparoxetine, and 3Hnisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments+3β-(4-alkylthiophenyl)nortropanes Structure 150px Compound R1 R2 Inhibition of 3HWIN 35,428@ DATIC50 (nM) Inhibition of 3HParoxetine@ 5-HTTK''i'' (nM) Inhibition of 3HNisoxetine@ NETK''i'' (nM) NET/DAT(uptake ratio) NET/5-HTT(uptake ratio)See '''7a—7h''' table 7a  CH3 CH3 9 ± 30.7 ± 0.2220 ± 1024314 7b  C2H5 CH3 232 ± 344.5 ± 0.51170 ± 3005260160px 8a  CH3  H 28 ± 60.19 ± 0.0121 ± 60.8110170px 8b  C2H5  H 177 ± 621.26 ± 0.05118 ± 130.794210px 9a  CH3  FCH2CH2CH2112 ± 23 ± 1960 ± 1009320215px 9b  C2H5  FCH2CH2CH21,200 ± 20027 ± 2>2,000274200px 10a  CH3  CH2=CH2CH271 ± 255.5 ± 0.82,000 ± 50028364205px 10b  C2H5  CH2=CH2CH21,100 ± 10047 ± 3>2,000243200px 11a  CH3  CH3CH2CH274 ± 205.7 ± 0.61,200 ± 14016211205px 11b  C2H5  CH3CH2CH2900 ± 30049 ± 6>2,000241=== Bridged ''N''-constrained phenyltropanes (fused/tethered) ===See: Bridged cocaine derivatives & ''N''8 Tricyclic (2β—crossed-over) ''N''8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues==== ''p''-methyl aryl front & back ''N''-bridged phenyltropanes ====Structures mentioned in US6150376 table of ''Ki'' data.Alternate 2D rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the constrained nitrogen. Compare JNJ-7925476, tametraline and similar compounds.RTI-242+Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes ''Ki'' (nM)Compound #(''S. Singh's #'')2β=R3HMazindol binding3HDA uptake3H5-HT uptake3HNE uptakeselectivity3H5-HT/3HDAcocaine CO2CH3 375 ± 68423 ± 147155 ± 4083.3 ± 1.50.4(–)-40''(–)-128''  54.3 ± 10.260.3 ± 0.41.76 ± 0.235.24 ± 0.070.03(+)-40''(+)-128''  79 ± 19114 ± 281.48 ± 0.074.62 ± 0.310.01(±)-40''(±)-128''  61.7 ± 8.560.3 ± 0.42.32 ± 0.232.69 ± 0.120.0429β  62014208030 —  —30β  18649297.7 —  —31β  47.021128.5 —  —29α  4140201003920 —  —30α  396088506961150 —45''129''  6.86 ± 0.4324.0 ± 1.31.77 ± 0.041.06 ± 0.030.0742a''131a'' ''n''-Bu 4.00 ± 0.072.23 ± 0.1214.0 ± 0.62.99 ± 0.176.341a''130a'' ''n''-Bu 17.2 ± 1.1310.2 ± 1.478.9 ± 0.915.0 ± 0.47.842b''131b'' Et 3.61 ± 0.4311.3 ± 1.125.7 ± 4.34.43 ± 0.012.350a''133a'' ''n''-Bu 149 ± 6149 ± 2810 ± 8051.7 ± 125.449a''132a'' ''n''-Bu 13.7 ± 0.814.2 ± 0.1618 ± 873.84 ± 0.3543.5(–)-4  1050016500189070900 —(+)-4  1850027600463038300 —(–)-5  97409050119004650 —(+)-5  677010500251004530 —RTI-4229/Coc-242N8/2β-C(O)CH(CO2Me)CH2N''para''-chloro—7.67 ± 0.31'''ɑ'''226.54 ± 27.37'''b'''510.1 ± 51.4'''c''' —* '''ɑ'''Value for displacement of 3HWIN 35,428 binding @ DAT* '''b'''Value for displacement of 3Hparoxetine binding to SERT* '''c'''Value for displacement of 3Hnisoxetine from NETFused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. ''(+)-128'' additionally exhibited 100× greater potency @ SERT, whereas ''132a'' & ''133a'' had 4—5.2× weaker 5-HTT (''i.e.'' SERT) activity. Front-bridged (''e.g.'' 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (''e.g.'' 130—133) preferred placement with DAT interaction.==== 3,4-Cl2 aryl front-bridged phenyltropanes ====Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. Frontbridged phenyltropane synthesis intermediate product compound #'''140''' CodeCompoundDA (μM)NE (μM)5-HT (μM)1(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo5.4.0.04,8- undecan-11 -one O-methyl-oxime0.0120.00200.00332(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo5.4.0.04,8- undecan-11-one0.180.0350.00753(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo5.3.0.04,8- decan-5-one O-methyl-oxime 0.01600.00090.00324(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo5.4.0.04,8- undecan-11-ol 0.0750 0.0041 0.00285(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo5.3.0.04,8- decan-5-one 0.12 0.0052 0.00266(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo5.3.0.04,8-decan-5-ol 0.250.00740.00187(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo5.3.0.04,8dec- 5-yl acetate 0.21 0.0061 0.00758(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo5.3.0.04,8decane 0.0220.00140.0001# 1-Chloroethyl chloroformate is used to remove ''N''-methyl of ''trans''-aryltropanes.# 2° amine is reacted with Br(CH2)nCO2Et.# Base used to abstract proton α- to CO2Et group and complete the tricyclic ring closure step (Dieckmann cyclization).To make a different type of analog (see Kozikowski patent above)# Remove N-Me# Add ɣ-bromo-chloropropane# Allow for cyclization with K2CO3 base and KI cat.====C2 + C3 (side-chain) fused (carboxylate & benzene conjoined)====Nitrogen-front-bridged indole phenyltropane.250px(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.02,10.04,9)pentadeca-4(9),5,7-trien-3-one====C3 to 1′ + 2′ (''ortho'') tropane locant dual arene bridged====250pxParent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ''ortho''-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the ''Endo–exo'' isomerism of their structures.250px
Cycloalkane-ring alterations of the tropane ring system === Azanonane (outer ring extended) ===3-Phenyl-9-azabicyclo3.3.1nonane derivativesTo better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs. Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.+3.3.1azanonane analoguesdisplacement of bound 3HWIN 35428 Structure Compound #(S. Singh) ''Ki'' (''nM'') right  Cocaine 32 ± 5390 ± 220 right  WIN 35065-2 33 ± 17310 ± 220 left  146a 4600 ± 510 left  146b 5730 ± 570 left  146c 3450 ± 310 left  146d 3470 ± 350 left  147 13900 ± 2010=== Azabornane (outer ring contracted) ===3-Phenyl-7-azabicyclo2.2.1heptane derivativesRing-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for '''155a''' was 4.2 and '''155c''' was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound '''20a''' 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.File:2-exo-phenyl-7-azabicyclo(2-2-1)heptane.png|thumb|''2-exo-phenyl-7-azabicyclo2.2.1heptane'':The non-carboxylic (and DAT substrate, releasing agent) variant of ''exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid'' (N.B. the carboxy in the latter shares the C1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost ''(R)'' substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands) ''cf.'' EXP-561 & BTQ.Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (''i.e.'' arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents.+2.2.1azabornane analoguesdisplacement of bound 3HWIN 35428 Structure Compound #(S. Singh) ''Ki'' (''nM'') right  Cocaine 32 ± 5390 ± 220 right WIN 35065-2 33 ± 17310 ± 220 left  155a 60,400 ± 4,800 left right  155b 96,500 ± 42 left  155c 5,620 ± 390 left  155d 18,900 ± 1,700=== Piperidine homologues (inner two-carbon bridge excised) ===Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.==== ''p''-chloro & related (piperidine homologues of phenyltropanes) ====+Phenyltropane 4-aryl-3-carboalkoxy-piperidine analogues Structure Compound #(S. Singh) X = ''para''- / 4′-Substitution R = 2-tropane position DAT (IC50 ''nM'')H3WIN 35428 binding displacement DA (IC50 ''nM'')H3DA uptake SelectivityUptake/Bindingright Cocaine  H CO2Me102 ± 9239 ± 12.3left (±)-166a  Cl  β-CO2CH3 53.7 ± 1.937.8 ± 7.90.7 (-)-166a  Cl  β-CO2CH3 24.8 ± 1.685.2 ± 2.63.4 (+)-166a  Cl  β-CO2CH3 1360 ± 1255090 ± 1723.7left (-)-167a  Cl  β-CO2OH 75.3 ± 6.249.0 ± 3.00.6 (+)-167a  Cl  β-CO2OH 442 ± 32——left (-)-168a  Cl  β-CO2OAc 44.7 ± 10.562.9 ± 2.71.4 (+)-168a  Cl  β-CO2OAc 928 ± 432023 ± 822.2left (-)-169a  Cl  β-''n''-Pr 3.0 ± 0.58.3 ± 0.62.8left (-)-170a  H  β-CO2CH3 769 ± 19——left (±)-166b  Cl  α-CO2CH3 197 ± 8—— (+)-166b  Cl  α-CO2CH3 57.3 ± 8.134.6 ± 3.20.6 (-)-166b  Cl  α-CO2CH3 653 ± 38195 ± 80.3left (+)-167b  Cl  α-CO2OH 240 ± 18683 ± 472.8left (+)-168b  Cl  α-CO2OAc 461 ± 11——left (+)-169b  Cl  α-''n''-Pr 17.2 ± 0.523.2 ± 2.21.3'''Heterocyclic ''N''-Desmethyl'''x150px==== naphthyl & related (piperidine homologues of phenyltropanes) ====+Activity @ MAT for piperidine homologues of phenyltropanes, including naphthyl derivatives Structure Compound # H3DA uptake (nM)IC50 H3DA uptake (nM)''Ki'' H3NE uptake (nM)IC50 H3NE uptake (nM)''Ki'' H35-HTT uptake (nM)IC50 H35-HTT uptake (nM)''Ki'' Uptake RatioDA/5-HT (''Ki'') Uptake RatioNE/5-HT (''Ki'') right Cocaine 459 ± 159423 ± 147127 ± 4.1108 ± 3.5168 ± 0.4155 ± 0.42.70.69 right  Fluoxetine  >4500  >2500 193 ± 4.1176 ± 3.58.1 ± 0.77.3 ± 0.762424 left  20 75 ± 9.169 ± 8.1101 ± 3.388 ± 2.9440 ± 30391 ± 270.180.23 left  6 23 ± 1.034 ± 0.88.2 ± 0.37.6 ± 0.22.84.5 left  7  >1000 241 ± 1.78.2 ± 0.37.6 ± 0.222.65.7 left  8 94 ± 9.627 ± 1.6209 ± 17192 ± 160.450.14 left  9 293 ± 6.438 ± 4.013 ± 0.712 ± 0.7233.2 left  19 97 ± 8.690 ± 8.034 ± 2.530 ± 2.33.9 ± 0.53.5 ± 0.5268.6 left  10 326 ± 1.2304 ± 1.1337 ± 37281 ± 30113 ± 4.3101 ± 3.83.02.8 left  14 144 ± 20131 ± 18204 ± 5.6175 ± 4.8155 ± 3.9138 ± 3.50.951.3 left  15  >1800  >1700  >1300  >1100 275 ± 39255 ± 37>6>4 left  16  >1000 964 ± 100 >1200  >1000 334 ± 48309 ± 443.13.5 left  17 213 ± 30187 ± 26399 ± 12364 ± 9.2189 ± 37175 ± 341.12.1 left  18 184 ± 30173 ± 26239 ± 42203 ± 3667 ± 4.562 ± 4.12.83.3==== distal-nitrogen 'dimethylamine' (piperidine-like cyclohexyl homologues of phenyltropanes) ====x155pxx155pxx155px''cf.'' Fencamfamine
Radiolabeled Radiolabel Tropane: Page 64.G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.LBT-999, a radio-ligand. CodeSERT Ki (nM)NET Ki (nM)DAT  Ki (nM)RadiolabelIn vivo studyRefs.1  0.2  102.2  29.9   11C  Non-human primate 2  0.2  31.7  32.6  11C  Non-human primate  30.05243.47 123I  Rat  40.082813 18F  Non-human primate 50.1145022 11CRat, monkeyIPT (''N''-3-iodoprop-(2''E'')-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with 123I or 125I and used as a ligand to map several MATsN-4-Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane (PR04.MZ) often radiolabeled.JHC1-64.A fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types.=== Transition metal complexes ===These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound '''89c'''" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit ('''89d''') was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The ''N''-methyl analog of '''89c''' having an IC50 of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making '''89c''' upwards of thirty-three times weaker at those MAT uptake sites.+"Transition metal" chelated phenyltropanes Structure Compound #(S. Singh) X = ''para''- / 4′-Substitution Configuration DAT (IC50 ''nM'')displacement of H3WIN 35428 5-HTT (IC50 ''nM'')H3Citalopram Selectivity5-HTT/DAT right  WIN 35428  F  - 11.0 ± 1.0160 ± 2014.5+2β-chelated phenyltropanes left  73TRODAT-1'''ɑ'''  Cl  -  left  74TROTEC-1  F  - '''''N''-chelated phenyltropanes''' left  89a  F  2β 5.99 ± 0.81124 ± 1720.7 left  89b  F  2α 2960 ± 1575020 ± 18801.7 left  89c  3,4-Cl2  2β 37.2 ± 3.4264 ± 167.1 left  89d  Cl  - 0.31 ± 0.03'''d'''* '''ɑ'''IUPAC: * '''b'''''R''- & ''S''- isomer values are ''Ki'' (nM) for displacement of 125IIPT with technetium-99m replaced by rhenium* '''c'''IC50 (nM) values for displacement of 3HWIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC50 for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)* '''d'''''Ki'' value for displacement of 125IIPT radioligand.
Select annotations of above Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. , , , and .Potency ''in vitro'' should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency ''in vivo''. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.
Sister substances Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.See: List of cocaine analoguesMost any variant with a tropane locant—3-β (or α) connecting linkage differing from, e.g. longer than, a single methylene unit (i.e. "phenyl"), including alkylphenyls (see the styrene analog, first image given in example below) is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule:x120pxx165pxx180pxx155pxx120pxx180pxx160pxx190pxx210px More cocaine analogue examplesx150pxx260pxx140pxx140pxx120pxx230pxx150pxx150px
See also * List of cocaine analogues** List of local anesthetics* List of methylphenidate analoguesx200px
References === Citations ====== Im-pact indices  (exact locations within sources cited) & foot-notations ===
External links *  U. S. Provisional Patent Application listing examples of compounds that are tropanes for prospective use in research*  Article on cocaine analogue research