SIMILARITIES AND DIFFERENCES IN THE STRUCTURE-ACTIVITY-RELATIONSHIPS OF CAPSAICIN AND RESINIFERATOXIN ANALOGS

Structure-activity relationships in analogues of the irritant natural product capsaicin have previously been rationalized by subdivision of the molecule into three structural regions (A, B, and C). The hypothes is that resiniferatoxin (RTX), which is a high-potency ligand for the same receptor and which has superficial structural similarities with c apsaicin, could be analogously subdivided has been investigated. The e ffects of making parallel changes in the two structural series have be en studied in a cellular functional assay which is predictive of analg esic activity. Parallel structural changes in the two series lead to m arkedly different consequences on biological activity; the 3- and 4-po sition aryl substituents (corresponding to the capsaicin 'A-region') w hich are strictly required for activity in capsaicin analogues are not important in RTX analogues. The homovanillyl C-20 ester group in RTX (corresponding to the capsaicin 'B-region') is more potent than the co rresponding amide, in contrast to the capsaicin analogues. Structural variations to the diterpene moiety suggest that the functionalized 5-m embered diterpene ring of RTX is an important structural determinant f or high potency. Modeling studies indicate that the 3D position of the alpha-hydroxy ketone moiety in the 5-membered ring is markedly differ ent in the phorbol (inactive) analogues and RTX (active) series. This difference appears to be due to the influence of the strained ortho es ter group in RTX, which acts as a local conformational constraint. The reduced activity of an analogue substituted in this region and the in activity of a simplified analogue in which this unit is entirely remov ed support this conclusion.