Pharmacological Characterisation of the Enantiomers of BM‐5, a Muscarinic Partial Agonist with Opposed Enantioselectivity between Affinity and Efficacy

• Published in: Pharmacology & toxicology 2000-01, Vol.86 (1), p.44-50
• Main Authors: Sundquist, Staffan, Modiri, Ali‐Reza, Nilsson, Björn M., Hacksell, Uli, Gillberg, Per‐Göran, Nilvebrant, Lisbeth
• Format: Article
• Language: English
• Subjects: Animals; Binding, Competitive; Biological and medical sciences; Cats; CHO Cells; Cholinergic system; Cricetinae; Dose-Response Relationship, Drug; Guinea Pigs; Humans; Ileum - drug effects; Ileum - metabolism; Ileum - physiology; In Vitro Techniques; Kinetics; Male; Medical sciences; Muscarinic Agonists - metabolism; Muscarinic Agonists - pharmacology; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Parasympathomimetics - metabolism; Parasympathomimetics - pharmacology; Pharmacology. Drug treatments; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Quinuclidinyl Benzilate - antagonists & inhibitors; Quinuclidinyl Benzilate - metabolism; Quinuclidinyl Benzilate - pharmacology; Radioligand Assay; Receptors, Muscarinic - classification; Receptors, Muscarinic - metabolism; Stereoisomerism; Tritium; Urinary Bladder - drug effects; Urinary Bladder - metabolism; Urinary Bladder - physiology
• ISSN: 0901-9928; 1600-0773
• DOI: 10.1034/j.1600-0773.2000.pto860108.x

: The interaction of (R) and (S) enantiomers of the chiral oxotremorine analogue BM‐5 with muscarinic acetylcholine receptors was studied in vitro using radioligand binding and isolated tissue preparations. The in vivo 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 (M1‐M5) or in guinea pig tissues. 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, respectively. Both enantiomers induced contraction of the guinea pig isolated urinary 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, respectively). The maximal agonist effect was lower for (R)‐BM‐5 than for (S)‐BM‐5 in bladder (2.7% and 6.6%, respectively) and in ileum (32% and 48%, respectively). Contractions were completely inhibited by atropine (1 μM). In vivo, (R)‐BM‐5 induced bladder contraction and salivation after intravenous administration in the anaesthetised cat (ED50 4.1 and 6.2 μg kg−1, respectively). In conclusion, (R)‐ and (S)‐BM‐5 act as partial muscarinic agonists in the isolated bladder and ileum. (R)‐BM‐5 was the more potent enantiomer but had a lower maximal agonist effect giving an opposed enantioselectivity for affinity and efficacy. (R)‐BM‐5 showed agonist activity in vivo, confirming in vitro findings. From affinity and efficacy data it can be concluded that the effects of racemic BM‐5 are mediated by the (R)‐enantiomer.