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, 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.