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, the 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 analogs, namely 1 and 2, showed potent functional activity in in vitro and in vivo models.

Hit-to-lead optimization of mouse Trace Amine Associated Receptor 1 (mTAAR1) agonists with a diphenylmethane-scaffold: Design, Synthesis, and biological study.

CHIELLINI, GRAZIA
Primo
;
NESI, GIULIA;SESTITO, SIMONA;ZUCCHI, RICCARDO;RAPPOSELLI, SIMONA
Ultimo
2016-01-01

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, the 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 analogs, namely 1 and 2, showed potent functional activity in in vitro and in vivo models.
2016
Chiellini, Grazia; Nesi, Giulia; Sestito, Simona; Chiarugi, S; Runfola, M; Espinoza, S; Sabatini, Martina; Bellusci, L; Laurino, A; Cichero, E; Gainetdinov, Rr; Fossa, P; Raimondi, L; Zucchi, Riccardo; Rapposelli, Simona
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/810510
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