Muscarinic Receptor Binding and Activation of Second Messengers by Substituted N-Methyl-N-acetamides

Article abstract of DOI:10.1021/jm00107a029

A series of substituted azacycloalkyl analogues of the muscarinic agonist UH 5 (N-methyl-N-<4-(1-pyrrolidinyl)-2-butynyl>acetamide, 1a) were synthesized and evaluated pharmacologically.These compounds were developed as intermediates for further derivatization leading to functionalized congeners of 1a.The compounds were synthesized by using a Mannich-type condensation of N-acetyl-N-methylpropargylamine to various substituted saturated azaheterocycles.The compounds were screened at a single concentration in competitive binding assays in rat cerebral cortical membranes against either <3H>N-methylscopolamine (at 100 μM) or <3H>oxotremorine-M (at 1 μM) labels.Candidates were then selected for further evaluation of their effect on phosphoinositide (PI) turnover in membranes from A9L cells transfected with cDNA of either m₁-muscarinic cholinergic receptors (m₁AChRs) or m₃AChRs.The analogues were also tested for the inhibition of adenylate cyclase in NG108-15 cells expressing m₄AChRs.The azetidine analogue of 1a had a K_i value of 12 nM for the inhibition of <3H>oxotremorine-M binding in rat brain and had an agonist potency at m₁-, m₃-, and m₄AChRs comparable to 1a.The substituted 5- and 6-member ring analogues generally had lower binding affinities and were less potent than 1a in stimulating PI turnover.Several compounds were moderately effective in inhibiting cyclic AMP production in NG108-15 cells.