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.

Aiello, F., Badolato, M., Pessina, F., Sticozzi, C., Maestrini, V., Aldinucci, C., et al. (2016). 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 CHEMICAL NEUROSCIENCE, 7(6), 737-748 [10.1021/acschemneuro.5b00333].

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

PESSINA, FEDERICA;MAESTRINI, VANESSA;Aldinucci, C.;FROSINI, MARIA;CORELLI, FEDERICO;BRIZZI, ANTONELLA
2016

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.
Aiello, F., Badolato, M., Pessina, F., Sticozzi, C., Maestrini, V., Aldinucci, C., et al. (2016). 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 CHEMICAL NEUROSCIENCE, 7(6), 737-748 [10.1021/acschemneuro.5b00333].
File in questo prodotto:
File Dimensione Formato  
P_206_ACS_Chem_Neuros.pdf

non disponibili

Descrizione: Articolo
Tipologia: PDF editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.8 MB
Formato Adobe PDF
2.8 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Frosini post print ACS Chemical Neuroscience revised.pdf

accesso aperto

Descrizione: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, copyright © 2016 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/acschemneuro.5b00333
Tipologia: Post-print
Licenza: PUBBLICO - Pubblico con Copyright
Dimensione 1.11 MB
Formato Adobe PDF
1.11 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/998208