Functionalized congener approach for the design of novel muscarinic agents. Synthesis and pharmacological evaluation of N-methyl-N-[4-(1-pyrrolidinyl)-2-butynyl] amides

Article abstract of DOI:10.1021/jm00164a044

A functionalized congener approach was used to design ligands for muscarinic cholinergic receptors (mAChRs). A series of ω-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-pyrrodinyl)-2-butynyl]acetamide], a muscarinic agonist related to oxotremorine. Intermediate 22 was coupled to a series of Boc-protected α-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 β-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 α-aminoalkyl congeners. The amides of 7-aminoheptanoic acid and 8-aminooctanoic acid, and their Boc-protected derivatives, had comparable affinities to UH 5 (K(i) = 5.0 and 4.5 μM at m₃AChRs and at m₄AChRs, respectively) at both receptors but lacked any agonist effects.