Pharmacological characterisation of the enantiomers of BM-5, a muscarinic partial agonist with opposed enantioselectivity between affinity and efficacy

The interaction of (R) and (S) enantiomers of the chiral oxotremorine analo gue BM-5 with muscarinic acetylcholine receptors was studied in vitro using radioligand binding and isolated tissue preparations. The in vitro effects of (R)-BM-5 were also studied in anaesthetised cat. No receptor or tissue selectivity was found for either enantiomer in radioligand binding studies in cells expressing human muscarinic receptors (M-1-M-5) or in guinea pig t issues. The affinity of (R)-BM-5 was about 40 times, or 15-60 times higher than that of (S)-BM-5 in recombinant cells or in guinea pig tissues, respec tively. Both enantiomers induced contraction of the guinea pig isolated uri nary bladder and ileum. (R)-BM-5 was more potent than (S)-BM-5 in bladder ( EC50 590 and 3500 nM, respectively) and in ileum (EC50 39 and 2600 nM, resp ectively). The maximal agonist effect was lower for (R)-BM-5 than for (S)-B M-5 in bladder (2.7% and 6.6%, respectively) and in ileum (32% and 48%, res pectively). Contractions were completely inhibited by atropine (1 mu M). In vivo, (R)-BM-5 induced bladder contraction and salivation after intravenou s administration in the anaesthetised car (ED50 4.1 and 6.2 mu g kg(-1), re spectively). In conclusion, (R)- and (S)-BM-5 act as partial muscarinic ago nists in the isolated bladder and ileum. (R)-BM-5 was the more potent enant iomer but had a lower maximal agonist effect giving an opposed enantioselec tivity for affinity and efficacy. (R)-BM-5 showed agonist activity in vivo, confirming in vitro findings. From affinity and efficacy data it can be co ncluded that the effects of racemic BM-5 are mediated by the (R)-enantiomer .