the orvinols are a 
 group of ring - c bridged epoxymorphinan compounds 
 that were originally synthesized by bentley and co - workers and developed by reckitt and colman . the most studied members of the series include the very potent opiate 
 antagonist diprenorphine ( 1a ) and buprenorphine ( 1b ) ( chart 1 ) , the clinical analgesic and treatment agent for opiate abuse and 
 addiction . buprenorphine displays a unique and complex pharmacology 
 derived 
 from the manner in which it binds to opioid receptors . at the  opioid ( mop ) receptor it is a partial agonist with 
 high affinity and slow onset and offset , thus having  irreversible  
 characteristics , manifested in its long duration of action and the 
 mildness of abstinence effects when the drug is withdrawn following 
 chronic administration . at the other opioid receptors ,  ( kop ) 
 and  ( dop ) buprenorphine has negligible efficacy and is a potent 
 antagonist of kop and dop receptor agonists . in addition to its binding 
 to these classical opioid receptors , buprenorphine also binds as a 
 partial agonist of moderate affinity to the nociceptin opioid peptide 
 ( nop ) receptor that , though having a high degree of amino acid sequence 
 homology with the classical opioid receptors , nevertheless has negligible 
 affinity for most opioid ligands . buprenorphine s kop and dop 
 receptor antagonism and nop receptor partial agonism appear to contribute 
 to its demonstrated potential as a treatment for cocaine and ethanol 
 abuse and dependence in addition to its approved use in opiate abuse 
 and dependence that is derived from its mop receptor partial agonism . use of buprenorphine to treat cocaine and 
 alcohol abuse would not 
 be allowed in patients without concurrent opiate abuse problems , since 
 buprenorphine treatment supports a significant level of mop receptor 
 dependence . thus , one of our medicinal 
 chemistry objectives has been to discover , among structural analogues 
 of buprenorphine , ligands having mop and kop receptor antagonist and 
 nop receptor agonist or partial agonist activity . such a compound 
 should be more widely useful than buprenorphine in the treatment of 
 cocaine and alcohol abuse and dependence . activity 
 relationship studies in orvinols of structures 1 and 2 ( chart 1 ) based 
 solely on in vivo antinociception data 
 demonstrated that in structure 1 only when r and r were h or methyl was mopr antagonist activity 
 shown without accompanying antinociceptive activity . these studies did not rule out the possibility that these mopr antagonists 
 may have had low efficacy kopr and dopr activity below the level required 
 to produce an antinociceptive response in the mouse antiwrithing test . nevertheless it was clear that when r and r in structure 1 were alkyl groups larger than methyl , 
 substantial mopr activity was normally found . further insight into 
 orvinol sar has recently been provided with the first publication 
 of affinity and efficacy data for a sizable series of predominantly 
 branched - chain orvinols . kopr agonist 
 efficacy , which would translate in humans as debilitating dysphoric 
 side effects , is dominant . twenty - five of the 39 compounds tested 
 for kopr efficacy showed full kopr agonism ( > 85% of the response 
 to 
 the full kopr agonist , u69593 ) , and the others showed a partial kopr 
 agonist response ( 3075% of u69593 ) . three out 
 of the 40 compounds tested had zero mopr efficacy , and three had 80% 
 or greater ( compared to the full mopr agonist damgo = 100% ) . a comfa ( comparative molecular field analysis ) model developed using 
 this series of ligands suggested that a bulky group immediately adjacent 
 to c20 was key to obtaining low efficacy at kop receptors when r in 1 was larger than methyl . this led 
 to an investigation of orvinol structures having a large 
 lipophilic moiety directly attached to c20 , during which we synthesized 
 a set of phenyl orvinols ( 1d  f , 2a  c ) . one of these ligands ( 1d ) was proven to lack any significant mopr or kopr efficacy in vitro 
 or in vivo . the results of these studies are reported below along with c20-ethyl 
 homologues , as the effect of increasing lipophilicity / bulk through 
 manipulation of the c20-methyl group has also not been explored previously . all tertiary alcohols were accessed by grignard addition to the 
 known methyl ketone ( 8) , itself prepared by the recently 
 reported methods of greedy et al . no addition could be achieved with 
 pyridyl grignard reagents , and so pyridyl lithium addition to the 
 ketone was attempted . this was successful but interestingly gave the 
 opposite diastereomer to that expected ( scheme 1 ) , i.e. , opposite to that obtained from standard grignard addition 
 ( confirmed by x - ray crystallography ; see supporting 
 information ) . ahn model such 
 that the carbonyl oxygen would be oriented between the large ( c6 ) 
 and medium ( c8 ) neighboring groups , orthogonal to the large ( c6 ) group . addition of the less reactive 
 grignard reagents appears to require initial formation of a six - membered 
 chelate ring ( figure 1b ) , providing an ordered 
 and activated complex , with nucleophilic addition then occurring from 
 the less hindered ( c7-h ) face to afford the other epimer . access to 
 the secondary phenyl alcohols ( 1e , 1 g , 2a , 2b ) was via the known aldehydes ( 11a , b ) ( scheme 2 ) . addition of phenylmagnesium bromide to 11a and 11b gave 12a and 12b , 
 respectively , the opposite diastereoisomer to that obtained on grignard 
 addition to the methyl ketone ( as shown in scheme 1 ) . presumably , addition to the more reactive aldehyde does 
 not require formation of the active complex , and so addition follows 
 the felkin subsequent oxidation to 13a and 13b followed by then reduction with lithium aluminum 
 hydride provided the opposite diastereoisomers ( 14a and 14b ) . nucleophilic addition ( a ) without chelation and ( b ) with chelation 
 control . opioid receptor binding affinities of the 
 first series of phenyl orvinol analogues ( 1d  g , 2a d ) were determined 
 by displacement of [ h]damgo , [ h]-dpdpe , [ h]u69,593 , and [ h]n / ofq from human opioid receptors 
 transfected into chinese hamster ovary ( cho ) cells . details of these 
 assays have been described previously . as expected , in these assays the new compounds all had high 
 affinity for all mop , dop , and kop receptors with no evidence of any 
 selectivity for an individual receptor type ( table 1 ) . changing r from methyl to ethyl ( 1d to 1f ) had no effect on binding affinity , whereas secondary 
 alcohol c20 groups were associated with a slightly lower affinity 
 than tertiary alcohol groups ( e.g. , 1e versus 1d , 1f ) , particularly at kop and dop receptors . the diasereoisomers 2a and 2b both displayed nonselective binding , 
 though absolute affinities could not be compared because 2b was evaluated in a separate assay . displacement of [ h]damgo , 
 [ h]-dpdpe , [ h]u69,593 , and [ h]n / ofq 
 from human opioid receptors transfected into chinese hamster ovary 
 ( cho ) cells . % maximal stimulation 
 with respect 
 to the standard agonists damgo ( mop ) , u69,593 ( kop ) , and dpdpe ( dop ) . values in brackets are antagonist ke values versus the standard agonists damgo 
 ( mop ) , u69,593 ( kop ) , and dpdpe ( dop ) . values are the average  
 sem from three separate experiments . binding to hartley guinea pig brain 
 membranes , ki ( nm ) versus [ h]damgo , [ h]dpdpe , [ h]u69,593 . nt : not tested . in the [ s]gtps 
 assay for functional opioid 
 activity at mop , dop , and kop receptors using methods reported previously , only 1d was a potent mop and kop 
 receptor antagonist ( table 1 ) ; it failed to 
 show mop receptor agonist activity and had very low level kop receptor 
 efficacy ( table 2 ) . the other phenyl orvinols 
 were mop receptor partial agonists of efficacy ranging from the low 
 ( 1f , 2a ) to moderately high ( 2c ) . they showed a similar pattern of agonist efficacy at dop 
 receptors , at which 1d was also a partial agonist of 
 modest efficacy . it was striking that 1f and 2c which differ structurally only in the 6,14-bridge differed markedly 
 in efficacy for mop , dop , and kop receptor types with the etheno - bridged 
 ligand 2c having markedly higher efficacy . percent maximal 
 stimulation ( % stim ) 
 at a single high dose ( 10 m ) with respect to the standard agonists 
 damgo ( mop ) and u69,593 ( kop ) and nociceptin ( nop ) . ki ( nm ) 
 versus [ h]diprenorphine ( for mop and kop receptors ) and 
 [ h]n / ofq ( for nop receptors ) . values are an average  
 sem from three separate experiments . the effect of replacing the r methyl group 
 in buprenorphine 
 ( 1b ) by ethyl was also investigated . the homologue ( 1c ) had comparable affinities at mop , dop , and kop receptors . affinity for nop receptors was also measured and compared with that 
 of buprenorphine ; again affinities were comparable ( table 1 ) . the etheno analogue ( 2d ) of 1c binding affinity for mop , dop , and 
 kop receptors was similar to that of 1c , but nop receptor 
 affinity was lower . in [ s]gtps assays 1c had somewhat higher mop receptor efficacy than buprenorphine while 
 the etheno analogue ( 2d ) was an almost full mop receptor 
 agonist though with very modest potency . 1c had high 
 kop receptor efficacy , whereas buprenorphine is a kop receptor antagonist ; 1c like buprenorphine has no efficacy for dop receptors . in 
 that respect there was a remarkable difference between 1c and the etheno analogue ( 2d ) which was a full dop receptor 
 agonist though of low potency . we followed up on these findings 
 by focusing on close analogues 
 of 1d to identify which had the desired profile of mop 
 and kop receptor antagonism . to expedite this process , a primary assay 
 was established whereby compounds were evaluated in the [ s]gtps assay for mop , kop , and nop receptor efficacy at a 
 very high concentration ( 10 m ) to determine peak efficacy at 
 each receptor ( table 2 ) . nine phenyl substituted 
 analogues of 1d and six analogues with the phenyl group 
 of 1d replaced by heteroaryl rings were evaluated . a 
 limited number of compounds were also evaluated for affinity at mop , 
 dop , and kop receptors by measuring displacement of [ h]diprenorphine 
 binding from c6-rat glioma cells expressing recombinant rat mop and 
 dop receptors and cho cells expressing recombinant human kop receptors , 
 essentially to confirm the expected high affinity of the series at 
 these receptors . nop receptor binding affinity was measured by displacement 
 of [ h]n / ofq from membranes of hek cells expressing recombinant 
 nop receptor . details of these assays have been described previously . with respect to mop receptor efficacy , the rank order for the methyl 
 substituted derivatives of 1d was 4 ( 3c ) > 3 ( 3b ) > 2 ( 3a ) > h 
 ( 1d ) ( table 2 ) . all three methyl 
 substituted derivatives were full kop receptor agonists , whereas nop 
 receptor efficacy was in the order 2 > 3 = 4 
 = h. the 4-isopropyl derivative ( 3d ) had low 
 mop and nop receptor efficacy and lower kop receptor efficacy than 
 the methyl derivative . the 3- and 4-chloro derivatives 
 showed all - round low efficacy though slightly higher than for the 
 parent . the 3- and 4-fluoro derivatives had low efficacy 
 mop and nop receptor agonist activity but high efficacy kop receptor 
 agonist activity ( table 2 ) . screening 
 of the heteroaryl analogues ( 4 , 5 , 6 , 7 ) of 1d was undertaken 
 using the same protocols . the 2-thienyl ligand ( 4a ) had 
 zero mop receptor efficacy in the [ s]gtps assay , 
 whereas its 5-methyl ( 4b ) and 5-chloro ( 4c ) substituted derivatives were mop receptor partial agonists with 
 efficacy respectively similar to and significantly higher than that 
 of buprenorphine ( table 2 ) . 4a had modest kop receptor efficacy , whereas 4b and 4c were almost full agonists . 4a had low nop 
 receptor efficacy but had binding affinity for this receptor ( ki = 75 nm ) equal to or better than that of buprenorphine 
 ( 1b ) ( ki = 212 nm ) . the 3-thienyl 
 analogue ( 5 ) had mop and nop receptor efficacy similar 
 to that of 4a but higher kop receptor efficacy . the isomeric 2- and 4-pyridyl ligands ( 6 , 7 ) both had low efficacy for mop receptor and nop 
 receptor , but whereas 7 also had no efficacy for kop 
 receptor , 6 showed distinct kop receptor activity . in 
 binding assays , 7 showed all - round high affinity for 
 opioid receptors and affinity for nop receptors equivalent to 1d . compound 1d was evaluated in vivo 
 to confirm the lack of mop and kop receptor agonism . in the hot - plate 
 test 1d showed no antinociceptive activity and instead 
 was an antagonist of both the mop receptor agonist morphine and the 
 kop receptor agonist ethylketocyclazocine ( ekc ) . at 10 mg / kg , response 
 curve for morphine ( figure 2a ) , and for ekc there was a complete flattening of the dose the effect of 1d antagonism at both receptors was gone by 24 h. antinociceptive effect 
 using the hot - plate assay in mice of ( a ) 
 morphine and ( b ) ekc in the absence and presence of 10 mg / kg 1d . morphine 
 and ekc were administered by a cumulative dosing procedure by intraperitoneal 
 ( ip ) and subcutaneous ( sc ) injections , respectively , as described.1d was given ip . vehicle is a 1:1:9 
 solution of ethanol , emulphor ( oil ) , and sterile water . the hot - plate test uses 
 heat as the nociceptive stimulus and so 
 requires high agonist efficacy in a compound to provide antinociception . therefore , we checked for agonism in 1d using the lower agonist efficacy requiring acetic acid stretch test . in this test 1d also showed no agonist activity ( figure 3a ) up to 32 mg / kg . in contrast buprenorphine was 
 potent and fully efficacious 
 in this assay ( figure 3b ) , affording an ed50 value ( determined by nonlinear regression analysis ) of 0.16 
 mg / kg , similar to the value ( 0.07 mg / kg ) previously reported . these findings confirm that 1d has 
 no , or extremely low , efficacy at mop or kop receptors in vivo . ( a ) lack of 
 antinociceptive effect of 1d at 32 mg / kg 
 in the acetic acid stretch assay in mice . compound 1d was evaluated in vivo 
 to confirm the lack of mop and kop receptor agonism . in the hot - plate 
 test 1d showed no antinociceptive activity and instead 
 was an antagonist of both the mop receptor agonist morphine and the 
 kop receptor agonist ethylketocyclazocine ( ekc ) . at 10 mg / kg , response 
 curve for morphine ( figure 2a ) , and for ekc there was a complete flattening of the dose the effect of 1d antagonism at both receptors was gone by 24 h. antinociceptive effect 
 using the hot - plate assay in mice of ( a ) 
 morphine and ( b ) ekc in the absence and presence of 10 mg / kg 1d . morphine 
 and ekc were administered by a cumulative dosing procedure by intraperitoneal 
 ( ip ) and subcutaneous ( sc ) injections , respectively , as described.1d was given ip . vehicle is a 1:1:9 
 solution of ethanol , emulphor ( oil ) , and sterile water . the hot - plate test uses 
 heat as the nociceptive stimulus and so 
 requires high agonist efficacy in a compound to provide antinociception . therefore , we checked for agonism in 1d using the lower agonist efficacy requiring acetic acid stretch test . 
 in this test 1d also showed no agonist activity ( figure 3a ) up to 32 mg / kg . in contrast buprenorphine was 
 potent and fully efficacious 
 in this assay ( figure 3b ) , affording an ed50 value ( determined by nonlinear regression analysis ) of 0.16 
 mg / kg , similar to the value ( 0.07 mg / kg ) previously reported . these findings confirm that 1d has 
 no , or extremely low , efficacy at mop or kop receptors in vivo . ( a ) lack of 
 antinociceptive effect of 1d at 32 mg / kg 
 in the acetic acid stretch assay in mice . in this study of analogues of buprenorphine 
 the aim was to identify 
 orvinols with zero or very low efficacy for mop and kop receptors 
 together with buprenorphine - like affinity and efficacy for nop receptors . the criterion of low mop and kop receptor efficacy was achieved in 
 several orvinols , but the nop receptor criterion proved to be very 
 difficult to achieve . the only ligands with nop receptor efficacy 
 equal or greater than that of buprenorphine ( 1b ) had 
 very much higher kop receptor efficacy which would be associated with 
 dysphoric side effects in clinical use . from the little data reported 
 to date , finding either significant mop or kop receptor efficacy in 
 orvinols that also have affinity and efficacy at nop receptors is 
 the norm . the most interesting candidate is 1d which satisfies the mop and kop receptor efficacy criteria 
 and also has higher binding affinity for nop receptors than buprenorphine . however , its nop receptor efficacy is lower than that of buprenorphine . 
 the lack of any activity in the acetic acid induced abdominal stretch 
 assay , which would be expected to indicate even low level mop or kop 
 receptor agonist activity and the 52 c hot - plate antinociceptive 
 assay , confirms , in vivo , the very low efficacy of 1d at mop and kop receptors and the promise of 1d as a 
 lead for further investigation . a surprising finding was the 
 low efficacy of the pyridyl ligands 6 and 7 , in particular the latter , at both kop 
 and mop receptors . it has previously been shown that the 2 alcohols 
 having opposite relative stereochemistry to buprenorphine , i.e. , 15 ( chart 1 ) , are agonists at both 
 receptors , typically full agonists at the kop receptor . this view was strengthened with the finding 
 that 1 g , the phenyl ring analogue of 6 and 7 , had high efficacy at kop receptors as predicted . efficacy 
 ranged from < 20% to 100% with clear differences between type of 
 substituent and less consistent differences due to substitution pattern . 
 of the monosubstituted phenyl analogues the larger substituents such 
 as i - pr ( 3d ) and chloro ( 3f , 3 g ) gave the lowest efficacy analogues while methyl 
 ( 3a 3c ) and fluoro ( 3h , 3i ) 
 gave full efficacy agonists . molecular modeling of the small - molecule 
 ligands in complex with kop receptor in the inactive state ( pbd code 4djh ) and in the activated 
 conformation was performed as described . the molecular models suggest that the ligands such as 1d interact with the receptor in such a way as to orientate the phenyl 
 ring into a pocket defined by residues from transmembrane helices 
 ii ( q115 , l135 ) , iii ( c210 and l135 ) , vii ( y312 ) , and extracellular 
 loops 1 ( w124 ) and 2 ( v118 , l212 ) ( figure 4a ) ( a ) predicted binding mode for 1d and analogues ( magenta ) 
 in the kopr in comparison to the crystal structure ligand jdtic ( green ) . ( b ) chloro - substituted analogues of 1d and potential 
 interactions with the kopr . this is the region 
 occupied by the phenolic ring of jdtic in the 
 reported crystal structure . in this antagonist 
 conformation of the receptor , the presence of substituents on the 
 phenyl ring appears to be well tolerated , for example , potentially 
 having interactions with w124 ( for 4-substituents ) or q115 
 ( for 3-substituents ) or l212 and l135 ( for 2-substituents ) 
 ( figure 4b ) . the kopr binding pocket in the 
 antagonist conformation , defined by the binding of jdtic , is large 
 but narrow and deep and somewhat covered by part of extracellular 
 loop 3 . it has been proposed that the 
 active ( agonist bound ) conformation of the receptor provides an even 
 more restricted binding pocket . it is therefore possible 
 that the larger substituents , cl and i - pr in this 
 study , can not readily fit into the agonist conformation and are therefore 
 predominantly antagonist in character , whereas the smaller substituents 
 ( ch3 and f ) are easily accommodated in the agonist conformation 
 leading to strong binding to the agonist conformation . however , the 
 low efficacy of the unsubstituted parent ( 1d ) suggests 
 that a small substituent is required for good binding to the agonist 
 conformation . the c20-ethyl analogues 1c , 1f , 2c , and 2d were all higher efficacy 
 kop receptor 
 agonists than their c20-methyl homologues . clearly the ethyl group 
 does not provide the extra bulk around c20 that has been reported 
 to minimize kop receptor efficacy but 
 is more likely accessing the site below c8 previously identified as 
 a region associated with kop receptor activation . in vivo 
 evaluation of the lead compound , 1d , confirmed 
 a lack of agonist activity in the hot - plate test and the acetic acid 
 stretch assay which is responsive to low efficacy mop and kop receptor 
 agonists . the antagonist action of 1d was observed 
 as soon as 30 min after administration but dissipated by 24 h , confirming 
 that 1d is accessing the cns , in line with its lower 
 predicted log  d7.4 than buprenorphine 
 ( 4.39 versus 4.81 ) and its predicted level of brain penetration ( acd / i - lab ) 
 sufficient for cns activity . the aim of generating a ligand 
 with a buprenorphine - like profile 
 but having substantially lower efficacy at mop receptor has been achieved 
 in part in the current study . 1d is an antagonist at 
 mop and kop receptors ( though it does have some low efficacy at kop 
 receptors ) and has good affinity , equivalent or better than buprenorphine , 
 for nop receptors . efficacy at nop receptors is , however , lower than 
 displayed by buprenorphine so that the desired profile is not fully 
 realized . reagents 
 and solvents were purchased from sigma - aldrich or alfa 
 aesar and used as received . buprenorphine ( 1b ) was supplied 
 by the national institute on drug abuse , bethesda , md . h and c nmr spectra were obtained with a bruker 400 
 mhz instrument ( h at 400 mhz , c at 100 mhz ) ; 
  in ppm , j in hz with tms as an internal standard . instrumentation was as follows : esims , microtof ( bruker ) ; eims , fisons 
 autosampler ; microanalysis , perkinelmer 240c analyzer . column chromatography 
 was performed using redisep prepacked columns with a teledyne isco 
 combiflash instrument . ligands were tested as their hydrochloride 
 salts , prepared by adding 5 equiv of hcl ( 1 n solution in diethyl 
 ether ) to a solution of compound in anhydrous methanol . all reactions 
 were carried out under an inert atmosphere of nitrogen unless otherwise 
 indicated . a solution of the appropriate thevinol 
 ( 0.25 mmol ) in anhydrous hmpa ( 1 ml ) under an inert atmosphere was 
 treated with sodium hydride ( 21 mg , 0.875 mmol ) followed by 1-propanethiol 
 ( 79 l , 0.875 mmol ) . after the addition was complete , the reaction 
 mixture was heated to 120 c and stirred for 3 h. when the mixture 
 was cooled to room temperature , nh4cl ( sat . the organic phase was 
 dried ( mgso4 ) , filtered , and evaporated to dryness . the 
 hcl salts were prepared by the addition of 2 m hcl in diethyl ether 
 ( 1.2 equiv ) to a solution of the orvinol in diethyl ether . the white 
 precipitate that formed was collected by filtration , washed with ether , 
 and dried under high vacuum . n - cpm dihydronorthevinone 8a ( 220 mg , 0.52 mmol ) in anhydrous toluene ( 5.2 ml ) was treated with 
 phenylmagnesium bromide ( 1.5 ml , 1.04 mmol ) at room temperature for 
 22 h. purification using column chromatography ( 30% etoac  petroleum 
 ether0.5% nh3 ) gave thevinol 9a ( r 
 = ph ) , ( 110 mg , 42% ) . h ( cdcl3 ) 7.50 ( 2h , d ) , 7.33 ( 2h , t ) , 7.187.26 ( 1h , m ) , 6.69 
 ( 1h , d ) , 6.52 ( 1h , d ) , 5.50 ( 1h , s ) , 4.42 ( 1h , s ) , 3.87 ( 3h , s ) , 3.61 
 ( 3h , s ) , 2.91 ( 1h , d ) , 2.86 ( 1h , d ) , 2.392.44 ( 1h , m ) , 2.112.55 
 ( 5h , m ) , 1.871.99 ( 1h , m ) , 1.791.86 ( 2h , m ) , 1.79 
 ( 3h , s ) , 1.541.58 ( 1h , m ) , 0.771.07 ( 3h , m ) , 0.550.73 
 ( 1h , m ) , 0.330.39 ( 2h , m ) , 0.10 to 0.03 ( 2h , 
 m ) . c ( cdcl3 ) 147.46 , 146.94 , 141.66 , 
 132.76 , 128.98 , 127.92 , 126.79 , 126.17 , 119.18 , 113.97 , 97.14 , 80.87 , 
 59.54 , 57.97 , 56.90 , 53.00 , 48.57 , 46.95 , 43.52 , 36.03 , 35.70 , 32.65 , 
 30.06 , 23.58 , 22.72 , 17.97 , 9.35 , 4.18 , 3.32 . 9a ( r = ph ) 
 ( 103 mg , 0.21 mmol ) was treated as in procedure a to yield 1d after silica gel chromatography ( 30% etoac  petroleum ether0.5% 
 nh3 ) ( 40.0 mg , 39% ) . rf ( 30% 
 etoac  petroleum ether0.5% nh3 ) 0.2 . h ( cdcl3 ) 7.50 ( 2h , d ) , 7.32 ( 2h , t ) , 7.187.26 
 ( 1h , m ) . 6.62 ( 1h , d ) , 6.45 ( 1h , d ) , 5.58 ( 1h , s ) , 4.60 ( 1h , s ) , 4.42 
 ( 1h , s ) , 3.56 ( 3h , s ) , 2.89 ( 1h , d ) , 2.84 ( 1h , d ) , 2.402.42 
 ( 1h , m ) , 2.102.19 ( 5h , m ) , 1.902.08 ( 1h , m ) , 1.721.84 
 ( 3h , m ) , 1.80 ( 3h , s ) , 1.541.58 ( 1h , m ) , 1.021.10 
 ( 1h , m ) , 0.890.94 ( 1h , dd ) , 0.690.76 ( 1h , m ) , 0.560.65 
 ( 1h , m ) , 0.300.40 ( 2h , m ) , 0.1 to 0 ( 2h , m ) ; c ( cdcl3 ) 147.27 , 132.44 , 127.93 , 126.83 , 126.14 , 
 119.56 , 116.51 , 97.39 , 80.92 , 59.52 , 58.01 , 52.91 , 48.48 , 47.24 , 43.53 , 
 36.10 , 35.60 , 32.60 , 29.95 , 23.59 , 22.80 , 17.97 , 9.32 , 4.15 , 3.31 . ( c31h38clno4 ) c , h , n. the alcohol 14b ( 500 mg , 1.03 
 mmol ) was treated as in procedure a to yield 2a , which 
 was purified by gravity elution chromatography with meoh  ch2cl2 . nmr h ( cdcl3 ) 0.380.40 ( 2h , m ) , 
 0.400.53 ( 2h , m ) , 0.640.66 ( 1h , m ) , 3.01 ( 1h , d ) , 
 3.35 ( 1h , d ) , 3.80 ( 3h , s ) , 4.35 ( 1h , d ) , 4.65 ( 1h , d ) , 5.43 ( 1h , 
 s ) , 5.56 ( 1h , d ) , 6.00 ( 1h , d ) , 6.43 ( 1h , d ) , 6.55 ( 1h , d ) , 7.267.32 
 ( 5h , m ) . c ( cdcl3 ) 3.52 , 3.98 , 9.18 , 
 23.03 , 30.38 , 33.00 , 42.59 , 43.83 , 43.92 , 47.76 , 54.86 , 57.04 , 59.85 , 
 77.70 , 84.53 , 97.79 , 116.26 , 119.83 , 124.37 , 125.77 , 127.70 , 128.09 , 
 128.23 , 134.32 , 137.54 , 137.78 , 141.71 , 146.33 . ( c30h34clno4h2o ) c , h , n. the alcohol 12b ( 550 mg , 1.13 
 mmol ) was treated as in procedure a to yield 2b which 
 was purified by gravity elution chromatography with meoh nmr h ( cdcl3 ) 0.010.08 ( 2h , m ) , 
 0.450.49 ( 2h , m ) , 0.740.76 ( 1h , m ) , 1.37 ( 1h , dd ) , 
 3.05 ( 1h , d ) , 3.53 ( 1h , d ) , 3.69 ( 3h , s ) , 4.62 ( 1h , d ) , 5.20 ( 1h , 
 s ) , 5.49 ( 1h , d ) , 5.81 ( 1h , d ) , 6.44 ( 1h , d ) , 6.58 ( 1h , d ) , 7.317.33 
 ( 5h , m ) . c ( cdcl3 ) 3.34 , 4.20 , 9.30 , 
 22.97 , 24.99 , 33.43 , 43.04 , 43.41 , 44.01 , 48.39 , 52.24 , 56.91 , 59.85 , 
 70.18 , 80.85 , 94.43 , 116.41 , 119.88 , 125.72 , 126.44 , 126.84 , 127.91 , 
 128.18 , 134.19 , 136.89 , 137.41 , 143.32 , 146.74 . 2-bromopyridine ( 1.13 mmol ) in dry et2o was cooled to 78 c under a nitrogen atmosphere . n - butyllithium ( 1.13 mmol ) was added dropwise and the mixture 
 stirred for 10 min before adding n - cpm dihydronorthevinone ( 8a , 1 mmol ) in dry thf . the reaction mixture was allowed to 
 warm to room temperature and stirred for 20 h. after completion , the 
 reaction mixture was quenched with saturated nh4cl solution 
 ( aqueous ) and extracted with etoac . organic layer was washed with 
 brine , dried ( na2so4 ) , and evaporated to yield 
 crude product ( 10 ) that was purified by flash chromatography 
 using meoh / ch2cl2 ( 0.5:99.5 ) ( 35% ) . h nmr ( cdcl3 )  0.080.11 ( 2h , m ) , 
 0.450.52 ( 2h , m ) , 0.810.86 ( 2h , m ) , 1.181.22 
 ( 2h , m ) , 1.571.73 ( 4h , m ) , 2.212.41 ( 8h , m ) , 2.612.70 
 ( 2h , m ) , 2.91 ( 1h , d , j = 18.24 hz ) , 3.02 ( 1h , d ) , 
 3.36 ( 3h , s ) , 3.82 ( 3h , s ) , 4.36 ( 1h , s ) , 5.87 ( 1h , s ) , 6.47 ( 1h , 
 d ) , 6.62 ( 1h , d ) , 7.107.12 ( 1h , m ) , 7.597.63 ( 2h , 
 m ) , 8.47 ( 1h , d ) . this was 3-o - demethylated using general procedure 
 a to give 6 as a white solid . h nmr ( cdcl3 )  0.080.11 ( 2h , m ) , 0.400.51 ( 2h , 
 m ) , 0.800.88 ( 2h , m ) , 1.201.27 ( 2h , m ) , 1.62 ( 1h , 
 d ) , 1.67 ( 3h , s ) , 2.022.41 ( 8h , m ) , 2.61 ( 1h , dd ) , 2.78 ( 1h , 
 dt ) , 2.91 ( 1h , d ) , 3.02 ( 1h , d ) , 3.35 ( 3h , s ) , 4.39 ( 1h , s ) , 4.55 
 ( 1h , bd ) , 5.83 ( 1h , s ) , 6.43 ( 1h , d ) , 6.61 ( 1h , d ) , 7.107.14 
 ( 1h , m ) , 7.627.64 ( 2h , m ) , 8.48 ( 1h , d ) . c nmr , 
 400 mhz ( cdcl3 )  3.21 , 4.33 , 9.35 , 16.42 , 22.45 , 
 28.39 , 28.86 , 29.92 , 35.24 , 35.65 , 43.81 , 46.78 , 49.36 , 52.28 , 57.95 , 
 59.89 , 80.1 , 97.70 , 116.01 , 119.37 , 120.54 , 121.55 , 128.54 , 132.45 , 
 135.78 . 136.93 , 145.30 , 147.32 , 166.46 . hrms , m / z for ( c30h36n2o4 ) , [ mh ] : calcd 489.2753 , found 489.2821 . ( c30h36cl2n2o43h2o ) c , h , n. aldehyde 11b(13 ) ( 5.0 g , 1.61 mmol ) was treated with phmgbr ( thf solution ) 
 in toluene 
 ( 20 ml ) for 24 h at room temperature . the reaction was quenched with 
 a saturated nh4cl solution and extracted with et2o to yield 12b ( 2.97 g , 50% ) which was purified by silica gel chromatography . h nmr h ( cdcl3 ) 0.010.08 
 ( 2h , m ) , 0.450.53 ( 2h , m ) , 0.740.76 ( 1h , m ) , 1.36 
 ( 1h , dd ) , 3.07 ( 1h , d ) , 3.53 ( 1h , d ) , 3.72 ( 3h , s ) , 3.83 ( 3h , s ) , 
 4.62 ( 1h , d ) , 5.23 ( 1h , s ) , 5.52 ( 1h , d ) , 5.88 ( 1h , d ) , 6.49 ( 1h , 
 d ) , 6.61 ( 1h , d ) , 7.317.34 ( 5h , m ) . c ( cdcl3 ) 3.39 , 4.20 , 9.34 , 15.27 , 23.03 , 25.18 , 33.64 , 43.05 , 43.95 , 
 44.04 , 48.20 , 52.78 , 56.65 , 57.04 , 59.93 , 70.39 , 80.73 , 94.99 , 113.47 , 
 119.28 , 125.81 , 126.78 , 128.16 , 128.43 , 134.46 , 136.85 , 141.87 , 143.47 , 
 148.30 . found m for c31h35no4 , 485.2566 ; calculated 485.2566 ketone 13b(27 ) ( 800 
 mg , 1.61 mmol ) in thf ( 10 ml ) was added dropwise to a solution of 
 lialh4 ( 2.5 equiv ) in thf ( 10 ml ) at room temperature . the solution was allowed to stir for 16 h before quenching with a 
 solution of rochelle salt ( 10 ml ) . extraction with et2o 
 yielded 14b ( 700 mg , 90% ) which was purified by recrystallization , rf ( etoac  hexane , 1:1 , 0.5% nh3 ) 0.48 . nmr h ( cdcl3 ) 0.020.07 
 ( 2h , m ) , 0.370.45 ( 2h , m ) , 0.640.69 ( 1h , m ) , 3.03 
 ( 1h , d ) , 3.34 ( 1h , d ) , 3.83 ( 3h , s ) , 3.84 ( 3h , s ) , 4.34 ( 1h , d ) , 4.63 
 ( 1h , d ) , 5.37 ( 1h , s ) , 5.56 ( 1h , d ) , 6.04 ( 1h , d ) , 6.48 ( 1h , d ) , 6.62 
 ( 1h , d ) , 7.267.33 ( 5h , m ) . c ( cdcl3 ) 3.50 , 3.91 , 9.24 , 22.95 , 30.43 , 33.17 , 42.55 , 43.77 , 44.13 , 47.46 , 
 54.97 , 56.82 , 57.05 , 59.87 , 77.70 , 84.56 , 97.62 , 113.83 , 119.33 , 124.62 , 
 127.58 , 128.07 , 128.17 , 128.35 , 134.65 , 137.72 , 141.88 , 141.96 , 147.82 .
emerging clinical and preclinical 
 evidence suggests that a compound 
 displaying high affinity for  ,  , and  opioid 
 ( mop , kop , and dop ) receptors and antagonist activity at each , coupled 
 with moderate affinity and efficacy at nociceptin opioid peptide ( nop ) 
 receptors will have utility as a relapse prevention agent for multiple 
 types of drug abuse . 
 members of the orvinol family of opioid ligands 
 have the desired affinity profile but have typically displayed substantial 
 efficacy at mop and or kop receptors . in this study 
 it is shown that 
 a phenyl ring analogue ( 1d ) of buprenorphine displays 
 the desired profile in vitro with high , nonselective affinity for 
 the mop , kop , and dop receptors coupled with moderate affinity for 
 nop receptors . in vivo , 
 1d lacked any opioid agonist 
 activity and was an antagonist of both the mop receptor agonist morphine 
 and the kop receptor agonist ethylketocyclazocine , confirming the 
 desired opioid receptor profile in vivo .