In Vitro Comparison of Ulotaront (SEP-363856) and Ralmitaront (RO6889450): Two TAAR1 Agonist Candidate Antipsychotics.

IF 4.5 2区医学 Q1 CLINICAL NEUROLOGY

International Journal of Neuropsychopharmacology Pub Date : 2023-09-25 DOI:10.1093/ijnp/pyad049

Richard Ågren, Nibal Betari, Marcus Saarinen, Hugo Zeberg, Per Svenningsson, Kristoffer Sahlholm

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引用次数: 1

Abstract

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 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.

Methods: 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.

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 dopamine D2.

Conclusions: 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.

Abstract Image

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

背景：微量胺相关受体-1（TAAR1）激动剂已被认为是潜在的抗精神病药物，ulotaront和ralmitront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，但对拉米他滨的一项相应研究未能表明其作为单一疗法或非典型抗精神病药物的辅助疗法的疗效。除了TAAR1激动剂外，ulotaront还是血清素1A受体（5-HT1AR）的部分激动剂。然而，人们对ralmitfront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G蛋白偶联的内向整流钾通道激活分析，比较了ulotaront和ralmitront在TAAR1、5-HT1AR和多巴胺D2方面的作用。结果：Ralmitront在G蛋白募集、cAMP积累和GIRK激活测定中对TAAR1的疗效较低。此外，雷米他滨对5-HT1AR和多巴胺D2缺乏可检测的活性。这些数据可能与理解这两种化合物的临床特征的差异有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal of Neuropsychopharmacology 医学-精神病学

CiteScore

8.40

自引率

2.10%

发文量

230

审稿时长

4-8 weeks

期刊介绍： The central focus of the journal is on research that advances understanding of existing and new neuropsychopharmacological agents including their mode of action and clinical application or provides insights into the biological basis of psychiatric disorders and thereby advances their pharmacological treatment. Such research may derive from the full spectrum of biological and psychological fields of inquiry encompassing classical and novel techniques in neuropsychopharmacology as well as strategies such as neuroimaging, genetics, psychoneuroendocrinology and neuropsychology.