title: Development of the first ultra-potent "capsaicinoid" agonist at transient receptor potential vanilloid type 1 (TRPV1) channels and its therapeutic potential.
abstract: 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 (EC(50) = 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 EC(50) (90 pM), phenylacetylrinvanil (PhAR, IDN5890) is the most potent vanillamide ever described with potency comparable with that of resiniferatoxin (EC(50), 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.
authors.affiliation: Dipartimento di Scienze Chimiche Alimentari, Farmaceutiche e Farmacologiche, Novarra, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Appendino
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.forename: Marcello
authors.initials: M
authors.lastname: Trevisani
authors.forename: Alberto
authors.initials: A
authors.lastname: Minassi
authors.forename: Nives
authors.initials: N
authors.lastname: Daddario
authors.forename: Aniello Schiano
authors.initials: AS
authors.lastname: Moriello
authors.forename: David
authors.initials: D
authors.lastname: Gazzieri
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.forename: Barbara
authors.initials: B
authors.lastname: Campi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fontana
authors.forename: Christian
authors.initials: C
authors.lastname: Pinna
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D063388:Endocannabinoids; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007473:Ion Channels / Q000819:agonists*; D009474:Neurons / Q000187:drug effects; D053284:Polyunsaturated Alkamides; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels; D001743:Urinary Bladder / Q000187:drug effects; D014549:Urinary Incontinence / Q000188:drug therapy; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001095:Arachidonic Acids; D002211:Capsaicin; D002352:Carrier Proteins; D063388:Endocannabinoids; D007202:Indicators and Reagents; D007473:Ion Channels; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C494482:TRPV1 protein, human; C054256:olvanil; C078814:anandamide