Center for Drug Discovery, RTI International, Research Triangle Park, North Carolina 27709, United States.
Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N4N1, Canada.
ACS Chem Neurosci. 2022 Apr 6;13(7):1082-1095. doi: 10.1021/acschemneuro.2c00086. Epub 2022 Mar 24.
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 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, ). RTI-7470-44 exhibited an IC of 8.4 nM in an cAMP functional assay, a 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.
人源痕迹胺相关受体亚型 1（hTAAR1）是一种 G 蛋白偶联受体，在多种疾病（包括精神分裂症、药物成瘾和帕金森病）的治疗中具有潜在作用。虽然已经发现了几种有效的激动剂，并且在各种精神分裂症临床试验中取得了积极的结果，但强效 hTAAR1 拮抗剂的发现仍然难以捉摸。在此，我们报告了结构-活性关系研究的结果，这些研究导致了一种有效的 hTAAR1 拮抗剂（RTI-7470-44，）的发现。RTI-7470-44 在 cAMP 功能测定中表现出 8.4 nM 的 IC，在放射性配体结合测定中表现出 0.3 nM 的 Ki，对 hTAAR1 具有种属选择性，而对大鼠和小鼠同源物则没有。RTI-7470-44 显示出良好的血脑屏障通透性、中等的代谢稳定性和有利的初步非靶标特征。最后，RTI-7470-44 增加了小鼠 VTA 多巴胺能神经元的自发放电率，并阻断了已知 TAAR1 激动剂 RO5166017 的作用。总之，这项工作提供了一种有前途的 hTAAR1 拮抗剂探针，可用于研究 TAAR1 药理学以及在低多巴胺能疾病（如帕金森病）中的潜在治疗作用。
