Sunovion Pharmaceuticals, Marlborough, MA 01752, USA.
Department of Pathology, University of Pisa, via Savi 10, 56126 Pisa, Italy.
Int J Mol Sci. 2021 Dec 7;22(24):13185. doi: 10.3390/ijms222413185.
Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.
痕量胺相关受体 1（TAAR1）因其能够调节单胺能和谷氨酸能神经传递而成为神经精神疾病有前途的治疗靶点。特别是，由于 TAAR1 介导的多巴胺能张力调节，激动剂化合物作为治疗精神分裂症和其他精神病的潜在治疗方法引起了人们的兴趣。在这里，我们回顾了精神分裂症的未满足需求、TAAR1 回路生物学和神经药理学的当前知识状态，包括与精神病、阴性和认知症状的病理生理学相关的谷氨酸能、多巴胺能和遗传模型的临床前行为、成像和细胞证据。审查了 TAAR1 候选药物的临床试验数据，并与抗精神病药进行了对比。内源性 TAAR1 配体的鉴定及其随后开发的小分子激动剂揭示了 TAAR1 激活在啮齿动物和非人类灵长类动物中的抗精神病、抗焦虑和抗抑郁特性，以及促认知和 REM 睡眠抑制作用。Ulotaront 是第一个进入随机对照临床试验的 TAAR1 激动剂，已证明在治疗精神分裂症方面有效，而另一种 ralmitaront 目前正在精神分裂症的临床试验中进行评估。结合临床前研究结果，这为进一步研究和开发这种用于治疗精神分裂症和其他精神疾病的新型药理学类别提供了依据。
