Background 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. In addition to TAAR1 agonism, ulotaront is a partial agonist at the serotonin 1A receptor (5-HT1AR). However, little is publicly known about ralmitaront. Methods We compared ulotaront and ralmitaront at TAAR1, 5-HT1AR, and D2R using luciferase complementation-based G protein recruitment, cAMP accumulation, and GIRK channel activation assays. Results 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 D2R. Conclusions Compared to 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 two compounds.

中文翻译：

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Ulotaront (SEP-363856) 和 Ralmitaront (RO6889450) 的体外比较 - 两种 TAAR1 激动剂候选抗精神病药

背景 痕量胺相关受体 1 (TAAR1) 激动剂已被提议作为潜在的抗精神病药，其中 ulotaront 和拉米塔隆已进入临床试验。虽然 ulotaront 在最近的一项 II 期试验中证明了疗效，但拉米塔隆的相应研究未能显示出作为单一疗法的疗效。除了 TAAR1 激动剂外，ulotaront 还是 5-羟色胺 1A 受体 (5-HT1AR) 的部分激动剂。然而，公众对拉米塔隆知之甚少。方法 我们使用基于荧光素酶互补的 G 蛋白募集、cAMP 积累和 GIRK 通道激活测定来比较 ulotaront 和拉米塔隆在 TAAR1、5-HT1AR 和 D2R 上的情况。结果 雷米塔隆在 G 蛋白募集、cAMP 积累和 GIRK 激活测定中显示 TAAR1 的功效较低。此外，拉米塔隆缺乏可检测到的 5-HT1AR 和 D2R 活性。结论 与 ulotaront 相比，拉米塔隆对 TAAR1 的疗效较低且动力学较慢，并且对 5-HT1AR 缺乏疗效。这些数据可能有助于理解这两种化合物临床特征的差异。