Analogues of Capsaicin with Agonist Activity as Novel Analgesic Agents; Structure—Activity Studies. 2. The Amide Bond “B-Region”

Christopher S.J. Walpole, Roger Wrigglesworth, Stuart Bevan, Elizabeth A. Campbell, Andy Dray, Iain F. James, Kay J. Masdin, Martin N. Perkins, Janet Winter

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

Abstract

A series of compounds incorporating replacements for the amide bond “B-region” moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), which is predictive of analgesic activity, to investigate the requirements in this region of capsaicin for activity. N-(4-Hydroxy-3-methoxybenzyl)-N′-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 µM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor.

Original languageEnglish
Pages (from-to)2373-2380
Number of pages8
JournalJournal of Medicinal Chemistry
Volume36
Issue number16
DOIs
StatePublished - 1993

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