Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study

Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena Cichero, Raul R. Gainetdinov, Paola Fossa, Laura Raimondi, Riccardo Zucchi, Simona Rapposelli

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

The trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides trace amines (TAs), including thyroid hormone-derivatives like 3-iodothyronamine (T1AM), catechol-O-methyltransferase products like 3-methoxytyramine, and amphetamine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronamine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1-16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2, showed potent functional activity in in vitro and in vivo models.

Lingua originaleInglese
pagine (da-a)9825-9836
Numero di pagine12
RivistaJournal of Medicinal Chemistry
Volume59
Numero di pubblicazione21
DOI
Stato di pubblicazionePubblicato - 10 nov 2016
Pubblicato esternamente

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