Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus

Summary The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M₁ (rabbit vas deferens), M₂ (guinea-pig atria) and M₃ receptors (guinea-pig ileum).The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD₂ = 5.73) were competitively antagonized by pirenzepine (pA₂ = 7.04), AF-DX 116 (11-2-(diethylamino)methyl]-1-piperidinyl]acetyl]- 5,11-dihydro-6H-pyrido2,3-b]1,4]benzo. diazepin-6-one) (pA₂ = 6.96), himbacine (pA₂ = 7.92), methoctramine (pA₂ = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA₂ = 8.87) and sila-hexocyclium (pA₂ = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M₁, M₂ or M₃ receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M₄ receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M₄ receptors.This work has been presented in part at the Spring Meeting of the German Society for Pharmacology and Toxicology in Mainz, March 1990 (Dörje et al. 1990) Send offprint requests to F. Dörje at the present address