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 Na2SO3 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 IC50 of 40 microM. 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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
el Hadri A,Maldivi P,Leclerc G,Rocher JPdoi
10.1016/0968-0896(95)00087-wsubject
Has Abstractpub_date
1995-09-01 00:00:00pages
1183-201issue
9eissn
0968-0896issn
1464-3391pii
096808969500087Wjournal_volume
3pub_type
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