Syntheses, activity and modeling studies of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists

Abstract

A series of 3- and 4-(sulfo- and sulfonamidoalkyl)pyridine and piperidine-2-carboxylic acid derivatives as analogs of NMDA receptor antagonists was prepared. Affinity for the NMDA receptor was determined by binding assays using the specific radioligand [ 3H] ( 2SR,4RS)-4-(phosphonomethyl)piperidine-2-carboxylic acid (CGS-19755). The 3-alkylsulfonyl moiety was introduced by selective reduction of a carboxylic acid function followed by bromination, substitution by Na 2SO 3 and catalytic reduction. For the 4-alkylsulfonic derivatives the crucial step was the introduction of the 2-cyano function and its further conversion to 2-carboxylic acid. The most potent compound of the series was the pyridine ( 11a) [4-(sulfomethyl)pyridine-2-carboxylic acid] with a modest IC 50 of 40 μM. A molecular modeling study has been undertaken to understand the pharmacological results. In a first step, a comparative modeling study of the active pyridine and the poorly active piperidine sulfonic acid derivatives 11a and 10a [4-(sulfomethyl)piperidine-2-carboxylic acid] and of the phosphonic homologues was performed. We propose that the binding geometry of the sulfonic moiety within the NMDA receptor is different from that of the phosphonic containing antagonists. In order to test this assumption, we have made, in a second step, a complete conformational analysis of the sulfonic acid derivatives, as well as some analogs taken from the literature, either active or inactive as NMDA antagonists. A preferred conformation of the sulfonic acids is proposed.