Lam Vincent M, Mielnik Catharine A, Baimel Corey, Beerepoot Pieter, Espinoza Stefano, Sukhanov Ilya, Horsfall Wendy, Gainetdinov Raul R, Borgland Stephanie L, Ramsey Amy J, Salahpour Ali
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
Front Pharmacol. 2018 Sep 4;9:953. doi: 10.3389/fphar.2018.00953. eCollection 2018.
The trace amine associated receptor 1 (TAAR1) is a G-protein coupled receptor expressed in the monoaminergic regions of the brain, and represents a potential novel therapeutic target for the treatment of neurological disorders. While selective agonists for TAAR1 have been successfully identified, only one high affinity TAAR1 antagonist has been described thus far. We previously identified four potential low potency TAAR1 antagonists through an screen on a TAAR1 homology model. One of the identified antagonists (compound ) was predicted to have favorable physicochemical properties, which would allow the drug to cross the blood brain barrier. studies were therefore carried out and showed that compound potentiates amphetamine- and cocaine-mediated locomotor activity. Furthermore, electrophysiology experiments demonstrated that compound increased firing of dopamine neurons similar to EPPTB, the only known TAAR1 antagonist. In order to assess whether the effects of compound were mediated through TAAR1, experiments were carried out on TAAR1-KO mice. The results showed that compound is able to enhance amphetamine- and cocaine-mediated locomotor activity, even in TAAR1-KO mice, suggesting that the effects of this compound are not mediated by TAAR1. In collaboration with Psychoactive Drug Screening Program, we attempted to determine the targets for compound . Psychoactive Drug Screening Program (PDSP) results suggested several potential targets for compound including, the dopamine, norepinephrine and serotonin transporters; as well as sigma 1 and 2 receptors. Our follow-up studies using heterologous cell systems showed that the dopamine transporter is not a target of compound . Therefore, the biological target of compound mediating its psychoactive effects still remains unknown.
痕量胺相关受体1（TAAR1）是一种在大脑单胺能区域表达的G蛋白偶联受体，是治疗神经疾病的一个潜在新型治疗靶点。虽然已成功鉴定出TAAR1的选择性激动剂，但迄今为止仅描述了一种高亲和力TAAR1拮抗剂。我们之前通过对TAAR1同源模型的筛选鉴定出了四种潜在的低效TAAR1拮抗剂。其中一种鉴定出的拮抗剂（化合物 ）预计具有良好的理化性质，这将使该药物能够穿过血脑屏障。因此进行了 研究，结果表明化合物 增强了苯丙胺和可卡因介导的运动活性。此外，电生理学实验表明，化合物 增加多巴胺神经元的放电，类似于唯一已知的TAAR1拮抗剂EPPTB。为了评估化合物 的作用是否通过TAAR1介导，在TAAR1基因敲除小鼠上进行了实验。结果表明，即使在TAAR1基因敲除小鼠中，化合物 也能够增强苯丙胺和可卡因介导的运动活性，这表明该化合物的 作用不是由TAAR1介导的。与精神活性药物筛选项目合作，我们试图确定化合物 的靶点。精神活性药物筛选项目（PDSP）结果提示了化合物 的几个潜在靶点，包括多巴胺、去甲肾上腺素和5-羟色胺转运体；以及σ1和σ2受体。我们使用异源细胞系统的后续研究表明，多巴胺转运体不是化合物 的靶点。因此，介导其精神活性作用的化合物 的生物学靶点仍然未知。
