Dialdehyde sesquiterpenes and other terpenoids as vanilloids.
Selected naturally occurring unsaturated dialdehyde sesquiterpenes and related bioactive terpenoids were assayed for vanilloid-like activity. Out of the 25 compounds tested, eight inhibited completely the specific binding of [3H]resiniferatoxin by rat spinal cord membranes: binding affinities ranged from 0.6 microM for cinnamodial to 19.0 microM for hebelomic acid F. These values were comparable to the binding affinity of capsaicin (2.7 microM). With the exception of four ligands, compounds that inhibited resiniferatoxin binding to rat spinal cord membranes were also pungent on the human tongue where they showed cross-tachyphylaxis with capsaicin. As expected from their reactive nature, these compounds possess additional sites of action, as reflected in the complex behavior of the stimulation of calcium influx by cinnamodial and cinnamosmolide at high concentrations. This observation might explain the unexpectedly weak membrane depolarization by cinnamodial compared to capsaicin. We conclude that a range of sesquiterpene dialdehydes and related terpenoids, both pungent and non-pungent, may function as vanilloids. These compounds may represent a new chemical lead for the development of vanilloid drugs, structurally unrelated to either capsaicin or resiniferatoxin.
Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
A
A
Szallasi
T
T
Bíró
S
S
Modarres
L
L
Garlaschelli
M
M
Petersen
A
A
Klusch
G
G
Vidari
M
M
Jonassohn
S
S
De Rosa
O
O
Sterner
P M
PM
Blumberg
J E
JE
Krause
D000447:Aldehydes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001547:Benzaldehydes / Q000494:pharmacology; D001667:Binding, Competitive; D002118:Calcium / Q000493:pharmacokinetics; D002211:Capsaicin / Q000494:pharmacology*; D004224:Diterpenes / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism; D013649:Taste / Q000187:drug effects; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D014059:Tongue / Q000187:drug effects / Q000502:physiology; D014316:Tritium
D000447:Aldehydes; D001547:Benzaldehydes; D004224:Diterpenes; D012717:Sesquiterpenes; D013729:Terpenes; C115865:cinnamodial; D014316:Tritium; C024353:resiniferatoxin; D002211:Capsaicin; D002118:Calcium