2. Academic Validation
  3. 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

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

  • ACS Chem Neurosci. 2016 Jun 15;7(6):737-48. doi: 10.1021/acschemneuro.5b00333.
Francesca Aiello 1,  Mariateresa Badolato 1,  Federica Pessina,  Claudia Sticozzi 2,  Vanessa Maestrini,  Carlo Aldinucci,  Livio Luongo 3,  Francesca Guida 3,  Alessia Ligresti 4,  Anna Artese 5,  Marco Allarà 4,  Giosué Costa 5,  Maria Frosini,  Aniello Schiano Moriello 4,  Luciano De Petrocellis 4,  Giuseppe Valacchi 2,  Stefano Alcaro 5,  Sabatino Maione 3,  Vincenzo Di Marzo 4,  Federico Corelli,  Antonella Brizzi
Affiliations

Affiliations

  • 1 Dipartimento di Farmacia e Scienza della Salute e della Nutrizione, Università della Calabria , Edificio Polifunzionale, 87036 Arcavacata di Rende, Cosenza, Italy.
  • 2 Dipartimento Scienza della Vita e Biotecnologie, Università degli Studi di Ferrara , Via L. Borsari 46, 44121 Ferrara, Italy.
  • 3 Dipartimento di Medicina Sperimentale, Sezione di Farmacologia "L. Donatelli", Seconda Università di Napoli , 80138 Napoli, Italy.
  • 4 Istituto di Chimica Biomolecolare, Endocannabinoid Research Group, Consiglio Nazionale delle Ricerche , Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
  • 5 Dipartimento di Scienze della Salute, Università degli Studi "Magna Graecia" di Catanzaro , Viale Europa, 88100 Catanzaro, Italy.
PMID: 26942555 DOI: 10.1021/acschemneuro.5b00333
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.

Keywords

TRPV1 ligands; antinociceptive; antioxidant; capsaicin; neuroprotective; oxidative stress.

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