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 speci fic binding of [H-3]resiniferatoxin by rat spinal cord membranes: bind ing affinities ranged from 0.6 mu M for cinnamodial to 19.0 mu M for h ebelomic acid F. These values were comparable to the binding affinity of capsaicin (2.7 mu M). With the exception of four ligands, compounds that inhibited resiniferatoxin binding to rat spinal cord membranes w ere also pungent on the human tongue where they showed cross-tachyphyl axis with capsaicin. As expected from their reactive nature, these com pounds possess additional sites of action, as reflected in the complex behavior of the stimulation of calcium influx by cinnamodial and cinn amosmolide at high concentrations. This observation might explain the unexpectedly weak membrane depolarization by cinnamodial compared to c apsaicin. We conclude that a range of sesquiterpene dialdehydes and re lated terpenoids, both pungent and non-pungent, may function as vanill oids. These compounds may represent a new chemical lead for the develo pment of vanilloid drugs, structurally unrelated to either capsaicin o r resiniferatoxin. (C) 1998 Elsevier Science B.V. All rights reserved.