Quest for agonist and antagonist selectivity at muscarinic receptors in guinea-pig smooth muscles and cardiac atria

Summary Potencies of 11 muscarinic agonists in eliciting contraction of smooth muscle in guinea-pig ileum, trachea, urinary bladder and uterus and in inhibiting the rate of contractions of cardiac atria were compared. While acetylcholine (ACh) was the most potent agonist on the ileum, uterus and cardiac atria, cis-l(+)-dioxolane was equally as potent as ACh on the ileum and more potent on the urinary bladder and trachea. Compared to ACh, methylfurmethide, oxotremorine, acetoxybut-2-inyl-trimethylammonium and cis-l(+)-dioxolane acted weakly on the atria. Aceclidine, arecoline and acetyl--methylcholine displayed selectivity for the urinary bladder and pilocarpine for the tracheal and urinary bladder smooth muscles. Oxotremorine had very low activity on the uterus. The stereoselectivity of muscarinic ACh receptors (mAChRs) for cis-l(+)- and cis-d(–)-dioxolane was low in the urinary bladder and uterus and high in the ileum and trachea.Most antagonists showed little selectivity between different organs, but S(–)-phenylcyclohexylglycoloyl choline was 6 times more active on the urinary bladder than on the ileum and AF-DX 116 was 12–30 times more active on the atria than on the smooth muscles. Among the N-alkyl derivatives of benzilylcholine, the octyl derivative was 400 times more active on the ileum than on the atria, while among the N-alkyl derivatives of QNB, the N-decyl derivative was 41 times more active on the ileum.The observed differences in the potency of various agonists and their stereoisomers on different smooth muscles cannot be explained by differences in the accessibility of receptors or in receptor reserve. It is suggested that they reflect the heterogeneity of muscarinic receptors in different smooth muscles and differences between smooth muscles regarding the preferential coupling of their mAChRs to different G proteins. The observed selectivity of S(–)-phenylcyclohexylglycoloyl choline suggests a difference between the mAChRs responsible for the contraction of ileal and urinary bladder smooth muscles.