As expected, the leaving group for 7-substituted indolyl carbamates, 5, had a decreased inhibitory potency compared to deshydroxy analogues , as the polar 7-hydroxy group occupies the highly lipophilic acyl-binding pocket (Table ). The archetypal dimethyl carbamate 6 had single digit nanomolar affinity and a roughly 300-fold higher selectivity for hBChE over hAChE. Replacing one of the methyls with larger substituentse.g., ethyl in 7, isopropyl in 8, tert-butyl in 9 and benzyl in 10, led to decreased potency, except in the case of benzyl methyl carbamate 10, where the benzyl group appeared to favourably interact with aromatic residues either in the acyl-or choline-binding pocket. The increased steric bulk of 9 tert-butyl precluded the carbamoylation of the catalytic Ser198. Increasing the steric repulsion further, the diethyl analogue 11 had an approximately 30-fold decreased affinity vs. parent compound 6; however, it selectively carbamoylated only hBChE (Figure ). The selectivity factor for hAChE was only 90, nevertheless the differential duration of action intertwined with PD-PK processes might be worth exploring further. The bulkiest diisopropyl carbamate 12 lost the ability to carbamoylate either of the ChEs. Locking the flexible diethyl substituent in a six membered ring (13, 14) decreased the steric factors back to the level of ethyl methyl carbamate.