Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.

The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of muscarinic receptors mediating vasodilation in rat perfused kidney.

The muscarinic receptor mediating vasodilation of resistance vessels in the rat isolated, constant-pressure perfused kidney (preconstriction by 10(-7) M cirazoline) was characterized by subtype-preferring agonists and selective antagonists. The agonists produced vasodilation with the following rank order of potency: arecaidine propargyl ester (APE) > 5-methylfurtrethonium = methacholine = oxotremorine > (S)-aceclidine > arecaidine 2-butyne-1,4-diyl bisester > 4-Cl-McN-A-343 = (R)-nipecotic acid ethyl ester = N-ethyl-guvacine propargyl ester approximately (R)-aceclidine = (S)-nipecotic acid ethyl ester > McN-A-343. Agonist-induced vasodilation disappeared after destruction of the endothelium with detergent. Highly significant correlations of agonist potencies for vasodilation were found between rat kidney and guinea-pig ileum submucosal arterioles as well as agonist potencies at smooth muscle muscarinic M3 receptors of the guinea-pig ileum. The rank order of antagonist potencies (4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) > (R)-hexahydro-difenidol approximately hexahydro-sila-difenidol > pirenzepine approximately p-fluoro-hexahydro-sila-difenidol approximately himbacine approximately AF-DX 384 approximately AQ-RA 741 > (S)-hexahydro-difenidol) to attenuate vasodilation to APE in rat kidney, correlated significantly with affinities at M3 receptors in submucosal arterioles and in smooth muscle of the guinea-pig ileum, but differed from those at M1 and M2 receptors in rabbit vas deferens. The agonist and antagonist potencies suggest that vasodilation elicited by muscarinic stimuli in endothelium-intact rat renal vasculature is mediated by functional muscarinic M3 receptors.