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

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.