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 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.
Bradbury
B J
BJ
Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Baumgold
J
J
Paek
R
R
Kammula
U
U
Zimmet
J
J
Jacobson
K A
KA
D000081:Acetamides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000480:Alkynes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010277:Parasympathomimetics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects*; D014162:Transfection
D000081:Acetamides; D000480:Alkynes; D006571:Heterocyclic Compounds; D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011976:Receptors, Muscarinic