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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on September 8, 2004; DOI: 10.1124/jpet.104.074864

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Received for publication July 26, 2004.
Revised September 2, 2004.
Accepted for publication September 2, 2004.

Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential type V1 (TRPV1) channels, and its therapeutic potential

Giovanni Appendino 1, Luciano De Petrocellis 2, Marcello Trevisani 3, Alberto Minassi 1, Nives Daddario 1, Aniello Schiano-Moriello 2, David Gazzieri 3, Alessia Ligresti 2, Barbara Campi 3, Gabriele Fontana 4, Christian Pinna 5, Pierangelo Geppetti 6, Vincenzo Di Marzo 2*

1 University of Piemonte Orientale 2 Consiglio Nazionale delle Ricerche 3 University of Ferrara 4 Indena, Milano 5 University of Milan 6 University of Florence

* Address correspondence to: E-mail: vdimarzo{at}icmib.na.cnr.it

Abstract

Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lacks the pungency of capsaicin, and was developed as an oral analgesic. Compared to more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin, vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety. We have modified the fatty acyl chain of olvanil to obtain ultrapotent analogues. The insertion of an hydroxyl group at C-12 yielded a compound, named rinvanil after ricinoleic acid, significantly less potent than olvanil (EC50=6 nM vs. 0.7 nM), but more versatile in terms of structural modifications because of the presence of an additional functional group. Acetylation and phenylacetylation of rinvanil, restablished and dramatically enhanced, respectively, its potency at hTRPV1. With a two-digit picomolar EC50 (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described, with potency comparable to that of resiniferatoxin (EC50 11 pM). Benzoyl- and phenylpropionyl-rinvanil were as potent, and less potent, than PhAR, respectively, whereas configurational inversion to ent-PhAR and cyclopropanation (but not hydrogenation or epoxidation) of the double bond were tolerated. Finally, iodination of the aromatic hydroxyl caused a dramatic switch in functional activity, generating compounds that behaved as TRPV1 antagonists rather than agonists. Since the potency of PhAR was maintained in rat dorsal root ganglion neurons and, particularly, in the rat urinary bladder, this compound was investigated in an in vivo rat model of urinary incontinence, and proved as effective as resiniferatoxin at reducing bladder detrusor overactivity.


Key words: N-acyl-vanillamines, bladder, cannabinoid, capsaicin, pain, vanilloid


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