Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist

Abstract

Human trace amine-associated receptor subtype 1 (hTAAR1) is a G proteincoupled 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 potent hTAAR1 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 IC 50 of 8.4 nM in an in vitro cAMP functional assay, a K i of 0.3 nM in a radioligand binding assay, and showed species selectivity for hTAAR1 over the rat and mouse orthologues. RTI-7470-44 displayed good blood−brain barrier permeability, moderate metabolic stability, and a favorable preliminary off-target profile. Finally, RTI-7470-44 increased the spontaneous firing 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.

Collective and Coordinated Conformational Changes Determine Agonism or Antagonism at the Human Trace Amine-Associated Receptor 1

“…The energy distribution associated with the hTAAR1/ p -TA system demonstrates a free energy of −4.42 kcal/mol, for the hTAAR1/EPPTB system, it is −12.39 kcal/mol, and for the hTAAR1/RTI system, it is −17.84 kcal/mol (Figure B,C). Interestingly, these results align with experimental findings, where RTI exhibits a greater affinity for hTAAR1 compared to EPPTB …”

“…Interestingly, these results align with experimental findings, where RTI exhibits a greater affinity for hTAAR1 compared to EPPTB. 16 The per-residue energy decomposition studies indicate that the free energy variation of hTAAR1 residues for EPPTB and RTI is significantly lower in magnitude than that of p-TA (Figure 4B−D). Based on the chemical structures at physiological pH, p-TA is protonated, creating a distinct difference between the agonist and antagonists under evaluation.…”

“…Because the crystal structure of hTAAR1 is not available, a computational model was generated based on the , a more recent antagonist having higher affinity for hTAAR1. 16 The receptor−ligand complexes were submitted to molecular dynamics, and a detailed analysis of their conformational movements was performed using distance correlation maps. Our findings suggest a coordinated movement based on the presence of an agonist involving the second extracellular loop, transmembrane domain 5, and the third intracellular domains of hTAAR1.…”

Protein Metabolism Changes and Alterations in Behavior of Trace Amine-Associated Receptor 1 Knockout Mice Fed a High-Fructose Diet

“…There is now a significant amount of scientific information relating to the influence of dopamine systems on behavioral and metabolic disorders, which has made it possible to partially discover some of the mechanisms involved in the development of the above pathological conditions, including interaction with reward systems, dopamine signal reception, mood regulation, and metabolic changes [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The connection of the trace amine system with dopamine and other monoamine systems of the brain has been established, but these studies only began around 20 years ago, i.e., when the discovery of the first trace amine receptor, TAAR1, and other TAARs (TAAR2-TAAR9) was made [ 2 , 5 , 27 ].…”

“…TAAR1 is being studied as a potential therapeutic target in the treatment of various mental disorders, such as schizophrenia [ 2 , 27 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Ulotaront (SEP-363856) is a TAAR1 agonist with 5-HT1A receptor agonist activity, currently being tested in phase III clinical development, with very promising results from the phase II trials, which led to the FDA designation as a breakthrough therapy for the treatment of schizophrenia [ 26 , 27 , 28 , 29 , 30 , 40 , 47 , 48 , 49 , 50 , 51 , 52 ].…”