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

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...

Full description

Saved in:
Bibliographic Details
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
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00107a029