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CELLULAR AND MOLECULAR

Development of the First Ultra-Potent "Capsaicinoid" Agonist at Transient Receptor Potential Vanilloid Type 1 (TRPV1) Channels and Its Therapeutic Potential

Dipartimento di Scienze Chimiche Alimentari, Farmaceutiche e Farmacologiche (G.A., A.M., N.D.), Novara, Italy; Endocannabinoid Research Group, Istitute of Cibernetica "Eduardo Caianiello" (L.D.P., A.S.M.) and Institute of Biomolecular Chemistry (A.S.M., A.L., V.D.M.), Consiglio Nazionale delle Ricerche, Pozzuoli (NA), Italy; Department of Clinical and Experimental Medicine (M.T., D.G., B.C.), Pharmacology Unit, University of Ferrara, Ferrara, Italy; Indena Ricerche, S.p.A. (G.F.), Milan, Italy; Dipartimento di Scienze Farmacologiche (C.P.), University of Milan, Milan, Italy; and Department of Critical Care Medicine and Surgery (P.G.), Clinical Pharmacology Unit, University of Florence, Florence, Italy

Olvanil (N-9-Z-octadecenoyl-vanillamide) is an agonist of transient receptor potential vanilloid type 1 (TRPV1) channels that lack the pungency of capsaicin and was developed as an oral analgesic. Vanillamides are unmatched in terms of structural simplicity, straightforward synthesis, and safety compared with the more powerful TRPV1 agonists, like the structurally complex phorboid compound resiniferatoxin. We have modified the fatty acyl chain of olvanil to obtain ultra-potent analogs. The insertion of a hydroxyl group at C-12 yielded a compound named rinvanil, after ricinoleic acid, significantly less potent than olvanil (EC₅₀ = 6 versus 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 re-established 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 with that of resiniferatoxin (EC₅₀, 11 pM). Benzoyl- and phenylpropionylrinvanil 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.

Address correspondence to: Vincenzo Di Marzo, Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Bldg. 70, 80078, Pozzuoli (NA), Italy. E-mail: vdimarzo{at}icmib.na.cnr.it

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