Muscarinic receptor binding and activation of second messengers by substituted N-methyl-N-[4-(1-azacycloalkyl)-2-butynyl]acetamides
| Autor: | Udai Kammula, Kenneth A. Jacobson, Jeff Zimmet, Robert Paek, Barton J. Bradbury, Jesse Baumgold |
|---|---|
| Rok vydání: | 1991 |
| Předmět: |
Agonist
Male Chemical Phenomena Stereochemistry medicine.drug_class Azetidine Carboxamide Phosphatidylinositols Transfection Cyclase Muscarinic agonist Binding Competitive Second Messenger Systems Cell Line chemistry.chemical_compound Heterocyclic Compounds Drug Discovery Acetamides medicine Muscarinic Receptor Binding Animals Cerebral Cortex Molecular Structure Cell Membrane Rats Inbred Strains Fibroblasts Receptors Muscarinic Rats Chemistry chemistry Parasympathomimetics Alkynes Second messenger system Molecular Medicine Female Acetamide |
| Zdroj: | Scopus-Elsevier |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|