ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
TAAR1-Mediated Pathways Regulating Nigrostriatal Function and the Discovery and Pharmacological Characterization of a Novel TAAR1 Agonist, Selutaront
Provisionally accepted
- 1Yantai University, Yantai, China
- 2State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai 264003, China., Yantai, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Schizophrenia is a severe neurodevelopmental mental disorder with unknown etiology. Current atypical antipsychotics improve positive symptoms but have limited efficacy on negative symptoms and cognitive impairment, necessitating new drug development. Trace amine-associated receptor 1 (TAAR1) agonists have emerged as a promising therapeutic strategy for schizophrenia. However, the specific signaling pathways mediating their effects remain incompletely understood, and the development of highly selective agonists is an active area of research. To elucidate the mechanisms, this study focused on the substantia nigra and striatum, brain regions critically im-plicated in schizophrenia pathogenesis. We found that TAAR1 regulates the functional integrity of the nigrostriatal circuit primarily through the cAMP/ protein kinase A (PKA)/ cAMP Response Element-Binding Protein (CREB) and Dopamine-and cAMP-regulated neuronal phosphoprotein 32kDa (DARPP32) signaling axes. Furthermore, we developed a novel TAAR1 agonist, Selutaront, which acts as a potent and selective agonist by forming critical interactions with residues Asp103, Phe267, and Ser107 within the TAAR1 binding pocket. In vivo, Selutaront dose-dependently attenuated MK-801-induced schizophrenia-like behaviors in mice, counteracted the downregulation of the PKA/CREB pathway, and demonstrated favorable pharmacokinetic properties. Collectively, our results indicate that TAAR1 activation primarily exerts its antipsychotic effects via the PKA/CREB pathway. This study not only elucidates a key mechanistic pathway but also provides a promising candidate molecule for the development of novel antipsychotic therapeutics with a potentially improved safety profile.
Keywords: agonist, anti-schizophrenia, Biological Evaluation, regulatory network, Trace amine-associated receptor 1
Received: 03 Dec 2025; Accepted: 11 Feb 2026.
Copyright: © 2026 Zhang, Deng, Lv, Lu, Wang, Wang, Lei, Yunjie and Tian. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wang Yunjie
Jingwei Tian
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.