Shajan Britto, Bastiampillai Tarun, Hellyer Shane D, Nair Pramod C
Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
Department of Psychiatry, Monash University, Parkville, Melbourne, VIC, Australia.
Front Psychiatry. 2024 Oct 31;15:1464550. doi: 10.3389/fpsyt.2024.1464550. eCollection 2024.
For over seven decades, dopamine receptor 2 (D receptor) antagonists remained the mainstay treatment for neuropsychiatric disorders. Although it is effective for treating hyperdopaminergic symptoms, it is often ineffective for treating negative and cognitive deficits. Trace amine-associated receptor 1 (TAAR1) is a novel, pharmacological target in the treatment of schizophrenia and other neuropsychiatric conditions. Several TAAR1 agonists are currently being developed and are in various stages of clinical and preclinical development. Previous efforts to identify TAAR1 agonists have been hampered by challenges in pharmacological characterisation, the absence of experimentally determined structures, and species-specific preferences in ligand binding and recognition. Further, poor insights into the functional selectivity of the receptor led to the characterisation of ligands with analogous signalling mechanisms. Such approaches limited the understanding of divergent receptor signalling and their potential clinical utility. Recent cryogenic electron microscopic (cryo-EM) structures of human and mouse TAAR1 (hTAAR1 and mTAAR1, respectively) in complex with agonists and G proteins have revealed detailed atomic insights into the binding pockets, binding interactions and binding modes of several agonists including endogenous trace amines (β-phenylethylamine, 3-Iodothyronamine), psychostimulants (amphetamine, methamphetamine), clinical compounds (ulotaront, ralmitaront) and repurposed drugs (fenoldopam). The screening of drug libraries has also led to the discovery of novel TAAR1 agonists (asenapine, guanabenz, guanfacine) which can be used in clinical trials or further developed to treat different neuropsychiatric conditions. Furthermore, an understanding of unappreciated signalling mechanisms (Gq, Gs/Gq) by TAAR1 agonists has come to light with the discovery of selective compounds to treat schizophrenia-like phenotypes. In this review, we discuss the emergence of structure-based approaches in the discovery of novel TAAR1 agonists through drug repurposing strategies and structure-guided designs. Additionally, we discuss the functional selectivity of TAAR1 signalling, which provides important clues for developing disorder-specific compounds.
七十多年来，多巴胺受体2（D2受体）拮抗剂一直是神经精神疾病的主要治疗药物。尽管它对治疗多巴胺能亢进症状有效，但对治疗阴性症状和认知缺陷往往无效。痕量胺相关受体1（TAAR1）是治疗精神分裂症和其他神经精神疾病的一个新的药理学靶点。目前正在开发几种TAAR1激动剂，它们处于临床和临床前开发的不同阶段。先前鉴定TAAR1激动剂的努力受到了药理学表征方面的挑战、缺乏实验确定的结构以及配体结合和识别中的物种特异性偏好的阻碍。此外，对该受体功能选择性的了解不足导致了具有类似信号传导机制的配体的表征。这些方法限制了对不同受体信号传导及其潜在临床应用的理解。最近，人类和小鼠TAAR1（分别为hTAAR1和mTAAR1）与激动剂和G蛋白复合物的低温电子显微镜（cryo-EM）结构揭示了对几种激动剂（包括内源性痕量胺（β-苯乙胺、3-碘甲状腺原氨酸）、精神兴奋剂（苯丙胺、甲基苯丙胺）、临床化合物（乌洛托隆、ralmitaront）和重新利用的药物（非诺多泮））的结合口袋、结合相互作用和结合模式的详细原子见解。药物库的筛选还导致发现了新型TAAR1激动剂（阿塞那平、胍那苄、胍法辛），可用于临床试验或进一步开发以治疗不同的神经精神疾病。此外，随着治疗精神分裂症样表型的选择性化合物的发现，对TAAR1激动剂未被认识的信号传导机制（Gq、Gs/Gq）有了新的认识。在这篇综述中，我们讨论了通过药物重新利用策略和结构导向设计发现新型TAAR1激动剂的基于结构方法的出现。此外，我们还讨论了TAAR1信号传导的功能选择性，这为开发针对特定疾病的化合物提供了重要线索。
