title: Design and Synthesis of New Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channel Modulators: Identification, Molecular Modeling Analysis, and Pharmacological Characterization of the N-(4-Hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl)butanamide, a Small Molecule Endowed with Agonist TRPV1 Activity and Protective Effects against Oxidative Stress.
abstract: 4-(Thiophen-2-yl)butanoic acid was identified as a cyclic substitute of the unsaturated alkyl chain of the natural ligand, capsaicin. Accordingly, a new class of amides was synthesized in good yield and high purity and their molecular recognition against the target was investigated by means of docking experiments followed by molecular dynamics simulations, in order to rationalize their geometrical and thermodynamic profiles. The pharmacological properties of these new compounds were expressed as activation (EC50) and desensitization (IC50) potencies. Several compounds were found to activate TRPV1 channels, and in particular, derivatives 1 and 10 behaved as TRPV1 agonists endowed with good efficacy as compared to capsaicin. The most promising compound 1 was also evaluated for its protective role against oxidative stress on keratinocytes and differentiated human neuroblastoma cell lines expressing the TRPV1 receptor as well as for its cytotoxicity and analgesic activity in vivo.
authors.affiliation: Dipartimento di Farmacia e Scienza della Salute e della Nutrizione, Università della Calabria , Edificio Polifunzionale, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Aiello
authors.affiliation: Dipartimento di Farmacia e Scienza della Salute e della Nutrizione, Università della Calabria , Edificio Polifunzionale, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Badolato
authors.forename: Federica
authors.initials: F
authors.lastname: Pessina
authors.affiliation: Dipartimento Scienza della Vita e Biotecnologie, Università degli Studi di Ferrara , Via L. Borsari 46, 44121 Ferrara, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sticozzi
authors.forename: Vanessa
authors.initials: V
authors.lastname: Maestrini
authors.forename: Carlo
authors.initials: C
authors.lastname: Aldinucci
authors.affiliation: Dipartimento di Medicina Sperimentale, Sezione di Farmacologia "L. Donatelli", Seconda Università di Napoli , 80138 Napoli, Italy.
authors.forename: Livio
authors.initials: L
authors.lastname: Luongo
authors.affiliation: Dipartimento di Medicina Sperimentale, Sezione di Farmacologia "L. Donatelli", Seconda Università di Napoli , 80138 Napoli, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guida
authors.affiliation: Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Ligresti
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro , Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Artese
authors.affiliation: Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Allarà
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro , Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Giosué
authors.initials: G
authors.lastname: Costa
authors.forename: Maria
authors.initials: M
authors.lastname: Frosini
authors.affiliation: Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Aniello
authors.initials: A
authors.lastname: Schiano Moriello
authors.affiliation: Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: De Petrocellis
authors.affiliation: Dipartimento Scienza della Vita e Biotecnologie, Università degli Studi di Ferrara , Via L. Borsari 46, 44121 Ferrara, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Valacchi
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro , Viale Europa, 88100 Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Dipartimento di Medicina Sperimentale, Sezione di Farmacologia "L. Donatelli", Seconda Università di Napoli , 80138 Napoli, Italy.
authors.forename: Sabatino
authors.initials: S
authors.lastname: Maione
authors.affiliation: Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Brizzi
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002211:Capsaicin / Q000494:pharmacology; D003412:Cricetulus / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D018384:Oxidative Stress / Q000187:drug effects*; D017208:Rats, Wistar; D050916:TRPV Cation Channels / Q000819:agonists* / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000700:Analgesics; C000614837:N-(4-hydroxy-3-methoxybenzyl)-4-(thiophen-2-yl)butanamide; D050916:TRPV Cation Channels; D013876:Thiophenes; C493922:Trpv1 protein, rat; D002211:Capsaicin
keywords: TRPV1 ligands; antinociceptive; antioxidant; capsaicin; neuroprotective; oxidative stress