TY - JOUR
T1 - Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold
T2 - Design, Synthesis, and Biological Study
AU - Chiellini, Grazia
AU - Nesi, Giulia
AU - Sestito, Simona
AU - Chiarugi, Sara
AU - Runfola, Massimiliano
AU - Espinoza, Stefano
AU - Sabatini, Martina
AU - Bellusci, Lorenza
AU - Laurino, Annunziatina
AU - Cichero, Elena
AU - Gainetdinov, Raul R.
AU - Fossa, Paola
AU - Raimondi, Laura
AU - Zucchi, Riccardo
AU - Rapposelli, Simona
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/11/10
Y1 - 2016/11/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84994850895&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b01092
DO - 10.1021/acs.jmedchem.6b01092
M3 - Article
SN - 0022-2623
VL - 59
SP - 9825
EP - 9836
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -