ANALOGS OF CAPSAICIN WITH AGONIST ACTIVITY AS NOVEL ANALGESIC AGENTS - STRUCTURE-ACTIVITY STUDIES .1. THE AROMATIC A-REGION

A series of analogues of capsaicin, the pungent principle of chilli pe ppers, was synthesized and tested in assays for capsaicin-like agonism in vitro. The results of these assays were compared with activities i n an acute nociceptive model and a correlation was observed which esta blished that the results of these in vitro assays were predictive of a nalgesia. Using a modular approach the structure-activity profile of s pecific regions of capsaicin congeners was established using an in vit ro assay measuring Ca-45(2+) uptake into neonatal rat dorsal root gang lia neurones. Substituted benzylnonanamides 2a-z and N-octyl-substitut ed phenylacetamides 4a-v were made to test the requirements for activi ty in the aromatic ''A-region'' of the molecule. Compounds with the na tural substitution pattern (2b and 4c) and the corresponding catechols (2i and 4g) were the most potent, although the catechols were less po tent in vivo. Other substitution patterns have reduced activity. These results have established stringent structural requirements for capsai cin-like activity in this part of the molecule.