Functionalized congener approach for the design of novel muscarinic agents. Synthesis and pharmacological evaluation of N-methyl-N-[4-(1-pyrrolidinyl)-2-butynyl] amides.
A functionalized congener approach was used to design ligands for muscarinic cholinergic receptors (mAChRs). A series of omega-functionalized alkyl amides of N-methyl-4-(1-pyrrolidinyl)-2-butynamine (22) were prepared as functionalized analogues of UH 5 [N-methyl-N-[4-(1-pyrrolidinyl)-2-butynyl]acetamide], a muscarinic agonist related to oxotremorine. Intermediate 22 was coupled to a series of Boc-protected omega-amino acids, and the resulting amides were deprotected and acylated. Intermediate 22 was also acylated with succinic anhydride and derivatized. The synthetic intermediates and final compounds were evaluated in vitro for their effects on the turnover of phosphatidylinositides in SK-N-SH human neuroblastoma cells that express m3AChRs, and on the production of cyclic AMP in NG108-15 neuroblastoma x glioma cells that express only m4AChRs. The displacement of [3H]-N-methylscopolamine was also measured in membrane preparations from each of these cell lines. Conjugates of glycine and beta-alanine were agonists at m4AChRs, having little or no activity at m3AChRs. The potency in displacement of [3H]-N-methylscopolamine from both m3- and m4AChRs generally increased with increasing chain lengths of the omega-aminoalkyl congeners. The amides of 7-aminoheptanoic acid and 8-aminooctanoic acid, and their Boc-protected derivatives, had comparable affinities to UH 5 (Ki = 5.0 and 4.5 microM at m3AChRs and at m4AChRs, respectively) at both receptors but lacked any agonist effects.
Bradbury
B J
BJ
Laboratory of Chemistry, NIDDK, National Institute of Health, Bethesda, Maryland 20892.
Baumgold
J
J
Jacobson
K A
KA
D000527:Alprostadil / Q000494:pharmacology; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D019832:N-Methylscopolamine; D009447:Neuroblastoma; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D010277:Parasympathomimetics; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D000242:Cyclic AMP; D000527:Alprostadil; D019832:N-Methylscopolamine