132377-31-2Relevant academic research and scientific papers
Muscarinic Receptor Binding and Activation of Second Messengers by Substituted N-Methyl-N-acetamides
Bradbury, Barton J.,Baumgold, Jesse,Paek, Robert,Kammula, Udai,Zimmet, Jeff,Jacobson, Kenneth A.
, p. 1073 - 1079 (2007/10/02)
A series of substituted azacycloalkyl analogues of the muscarinic agonist UH 5 (N-methyl-N-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 N-methylscopolamine (at 100 μM) or 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 Ki value of 12 nM for the inhibition of 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.
