Muscarinic receptor binding and activation of second messengers by substituted N-methyl-N-[4-(1-azacycloalkyl)-2-butynyl]acetamides

• Published in: Journal of medicinal chemistry 1991-03, Vol.34 (3), p.1073-1079
• Main Authors: Bradbury, Barton J, Baumgold, Jesse, Paek, Robert, Kammula, Udai, Zimmet, Jeff, Jacobson, Kenneth A
• Format: Article
• Language: English
• Subjects: Acetamides - chemical synthesis; Acetamides - metabolism; Acetamides - pharmacology; Alkynes - chemical synthesis; Alkynes - metabolism; Alkynes - pharmacology; Animals; Binding, Competitive; Cell Line; Cell Membrane - metabolism; Cerebral Cortex - metabolism; Chemical Phenomena; Chemistry; Exact sciences and technology; Female; Fibroblasts - metabolism; Heterocyclic compounds; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - metabolism; Heterocyclic Compounds - pharmacology; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Male; Molecular Structure; Organic chemistry; Parasympathomimetics - chemical synthesis; Parasympathomimetics - metabolism; Parasympathomimetics - pharmacology; Phosphatidylinositols - metabolism; Preparations and properties; Rats; Rats, Inbred Strains; Receptors, Muscarinic - genetics; Receptors, Muscarinic - metabolism; Second Messenger Systems - drug effects; Transfection
• ISSN: 0022-2623; 1520-4804
• 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 microM) or [3H]oxotremorine-M (at 1 microM) 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 Ki 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.