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 Activi
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- 作者：Francesca Aiello ; Mariateresa Badolato ; Federica Pessina ; Claudia Sticozzi ; Vanessa Maestrini ; Carlo Aldinucci ; Livio Luongo ; Francesca Guida ; Alessia Ligresti ; Anna Artese ; Marco Allarà ; Giosué Costa ; Maria Frosini ; Aniello Schiano Moriello ; Luciano De Petrocellis ; Giuseppe Valacchi ; Stefano Alcaro ; Sabatino Maione ; Vincenzo Di Marzo ; Federico Corelli ; Antonella Brizzi
- 刊名：ACS Chemical Neuroscience
- 出版年：2016
- 出版时间：June 15, 2016
- 年：2016
- 卷：7
- 期：6
- 页码：737-748
- 全文大小：553K
- 年卷期：0
- ISSN：1948-7193
文摘
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.