TAAR1-mediated pathways regulating nigrostriatal function and the discovery and pharmacological characterization of a novel TAAR1 agonist, Selutaront.

Introduction: Schizophrenia is a severe neurodevelopmental disorder with limited treatment options. Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target, yet its downstream signaling mechanisms and the development of highly selective agonists remain incompletely explored. Methods: In this study, we established a TAAR1 knockdown rat model to elucidate its role in movement regulation and downstream signaling. Through molecular docking, site-directed mutagenesis and functional tests, we identified and characterized a novel TAAR1 agonist - Selutaront. We evaluated its antipsychotic-like effects in a mouse model similar to schizophrenia induced by MK-801 and identified its potential mechanism. Finally, we conducted pharmacokinetic analysis, Caco-2 permeability tests and liver microsomal stability tests to assess its drugability. Results: The research results indicate that TAAR1 mainly regulates the functional integrity of the substantia nigra-striatum circuit through the cAMP/PKA/CREB and DARPP32 signaling axes. Selutaront is a highly selective TAAR1 agonist, which forms a crucial interaction with the residues Asp103, Phe267, and Ser107 in the binding pocket. In vivo, Selutaront dose-dependently alleviates the schizophrenia-like behaviors induced by MK-801 in mice and counteracts the downregulation of the PKA/CREB pathway. Moreover, it exhibits excellent pharmacokinetic properties. Conclusion: This study demonstrates that TAAR1 regulates nigrostriatal function primarily via the PKA/CREB/DARPP32 signaling axis. Selutaront, a novel highly selective TAAR1 agonist with favorable drug-like properties, represents a promising candidate for schizophrenia treatment and provides mechanistic insights into TAAR1-targeted therapy.