Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.
Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
Int J Neuropsychopharmacol. 2023 Sep 25;26(9):599-606. doi: 10.1093/ijnp/pyad049.
Trace amine-associated receptor-1 (TAAR1) agonists have been proposed as potential antipsychotics, with ulotaront and ralmitaront having reached clinical trials. While ulotaront demonstrated efficacy in a recent Phase II trial, a corresponding study studies of ralmitaront failed to show efficacy as a monotherapy or as an adjunct to atypical antipsychotics. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is known about ralmitaront.
We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and dopamine D2 using luciferase complementation-based G protein recruitment, cAMP accumulation, and G protein-coupled inward rectifier potassium channel activation assays.
Ralmitaront showed lower efficacy at TAAR1 in G protein recruitment, cAMP accumulation, and GIRK activation assays. Moreover, ralmitaront lacked detectable activity at 5-HT1AR and dopamine D2.
Compared with ulotaront, ralmitaront shows lower efficacy and slower kinetics at TAAR1 and lacks efficacy at 5-HT1AR. These data may be relevant to understanding differences in clinical profiles of these 2 compounds.
痕量胺相关受体-1（TAAR1）激动剂被认为是有潜力的抗精神病药物，其中乌洛托隆和拉米托隆已经进入临床试验。虽然乌洛托隆在最近的一项 II 期试验中显示出疗效，但相应的拉米托隆研究未能显示出作为单一疗法或作为非典型抗精神病药物的辅助疗法的疗效。除了 TAAR1 激动作用外，乌洛托隆还是 5-羟色胺 1A 受体（5-HT1AR）的部分激动剂。然而，对于拉米托隆知之甚少。
我们比较了乌洛托隆和拉米托隆在 TAAR1、5-HT1AR 和多巴胺 D2 上的作用，使用基于荧光素酶互补的 G 蛋白募集、cAMP 积累和 G 蛋白偶联内向整流钾通道激活测定法。
拉米托隆在 G 蛋白募集、cAMP 积累和 GIRK 激活测定中对 TAAR1 的作用效果较低。此外，拉米托隆在 5-HT1AR 和多巴胺 D2 上缺乏可检测的活性。
与乌洛托隆相比，拉米托隆在 TAAR1 上的疗效较低，动力学较慢，并且在 5-HT1AR 上缺乏疗效。这些数据可能与理解这两种化合物的临床特征差异有关。
