Identification of a Potent Human Trace Amine-Associated Receptor1 Antagonist

Human trace amine-associated receptor subtype 1 (hTAAR1) is a G protein-coupled receptor that has therapeutic potential for multiple diseases, including schizophrenia, drug addiction, and Parkinson's disease (PD). Although several potent agonists have been identified and have shown positive results in various clinical trials for schizophrenia, the discovery of potenthTAAR1 antagonists remains elusive. Herein, we report the results of structure-activity relationship studies that have led to the discovery of a potent hTAAR1 antagonist (RTI-7470-44,34). RTI-7470-44 exhibited an IC50of 8.4 nM in anin vitrocAMP functional assay, aKiof 0.3 nMin a radioligand binding assay, and showed species selectivity for hTAAR1 over the rat and mouseorthologues. RTI-7470-44 displayed good blood-brain barrier permeability, moderate metabolicstability, and a favorable preliminary off-target profile. Finally, RTI-7470-44 increased the spontaneousfiring rate of mouse VTA dopaminergic neurons and blocked the effects of the known TAAR1 agonist RO5166017.Collectively, this work provides a promising hTAAR1 antagonist probe that can be used to study TAAR1 pharmacology and the potential therapeutic role in hypodopaminergic diseases such as PD

Automated summary

The article reports the discovery of a hTAAR1 antagonist with potential for disease treatment, showing good pharmacological effects and mechanisms.