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Structure/activity analysis of resiniferatoxin analogs
Author(s) -
Szallasi Arpad,
Sharkey Nancy A.,
Blumberg Peter M.
Publication year - 1989
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/ptr.2650030607
Subject(s) - resiniferatoxin , capsaicin , chemistry , desensitization (medicine) , phorbol , potency , pharmacology , stimulation , protein kinase c , stereochemistry , biochemistry , signal transduction , biology , in vitro , receptor , endocrinology , trpv1 , transient receptor potential channel
Resiniferatoxin (RTX), unlike the structurally related phorbol esters, acts as an ultrapotent analog of capsaicin, the pungent principle of the red pepper. A homovanillyl group is an essential structural feature of capsaicin and the most prominent feature distinguishing resiniferatoxin from typical phorbol‐related compounds. In this report, we examine the RTX‐like activity of two 20‐homovanillyl esters of diterpene derivatives with particular similarities to RTX. The potency of 12‐deoxyphorbol 13‐phenylacetate 20‐homovanillate (dPP‐HV) was comparable to RTX for local induction and desensitization of chemical pain but was 2–4 orders of magnitude less potent for the other RTX responses tested (stimulation and desensitization of neurogenic inflammation and hypothermia). Mezerein 20‐homovanillate (Mez‐HV) displayed very weak activity in pain induction and was inactive in the other assays. The parent derivatives ‐ resiniferonol orthophenylacetate, 12‐deoxyphorbol 13‐phenylacetate and mezerein ‐ were inactive in inducing RTX‐like effects. Reciprocally, the presence of the 20‐homovanillate ester reduced binding affinities to protein kinase C by 11‐, 130‐ and 690‐fold for RTX, dPP‐HV and Mez‐HV, respectively. Our findings provide further evidence for heterogeneity among capsaicin‐sensitive pathways. Most significantly, our results demonstrate that esterincation of phorbol‐related diterpenes with homovanillic acid can yield capsaicin analogs with unique activities.