Inhibition of [3H]resiniferatoxin binding to rat dorsal root ganglion membranes as a novel approach in evaluating compounds with capsaicin-like activity.
We have recently reported the specific binding of [3H]resiniferatoxin to sensory ganglion membranes; this binding appears to represent the postulated vanilloid (capsaicin) receptor. In the present report, we compare the structure/activity relations for binding to rat dorsal root ganglion membranes and for biological responses in the rat, using a series of vanilloids of the capsaicin (homovanilloyl-decylamide, homovanilloyl-dodecylamide, homovanilloyl-cyclododecylamide, homovanilloyl-hexadecylamide, homovanilloyl-piperidine and nonenoyl-homoveratrylamide) and resiniferatoxin (tinyatoxin, 12-deoxyphorbol 13-phenylacetate 20-homovanillate) classes. We find that all the tested biologically active vanilloids, but not the inactive structure analogs, compete for the [3H]resiniferatoxin binding sites in rat dorsal root ganglion membranes, and we conclude that the [3H]resiniferatoxin binding assay may provide an efficient approach for evaluating such compounds. We also provide evidence that the [3H]resiniferatoxin receptor is likely to recognize vanilloids which are inserted into the membranes; and that the apparent activity of capsaicinoids may be significantly influenced by factors other than equilibrium binding affinities.
Szallasi
A
A
Molecular Mechanisms of Tumor Promotion Section, National Cancer Institute, Bethesda, MD 20892.
Szolcsanyi
J
J
Szallasi
Z
Z
Blumberg
P M
PM
D000818:Animals; D001665:Binding Sites; D002211:Capsaicin / Q000031:analogs & derivatives / Q000378:metabolism*; D002462:Cell Membrane; D004224:Diterpenes / Q000378:metabolism* / Q000633:toxicity; D004347:Drug Interactions; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism*; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D004224:Diterpenes; C024353:resiniferatoxin; D002211:Capsaicin; C026001:tinyatoxin