Structure-Based Design of Novel G-Protein-Coupled Receptor TAAR1 Agonists as Potential Antipsychotic Drug Candidates

The existing available antipsychotics have failed to manage the cognitive impairment of schizophrenia and induced a number of seriously undesirable effects. Trace amine-associated receptor 1 (TAAR1) has emerged as an ideal target for the design of antischizophrenia drugs, with the ability to mediate multiple psychological functions by sensing endogenous amine-containing metabolites without the side effects of catalepsy. In this work, a series of novel TAAR1 agonists were designed based on the structural analysis of the TAAR1 activation pocket. Among them, 6e displayed a potent TAAR1-G_s/G_q dual-pathway activation property, being different from that of the clinical drug candidate SEP-363856 with only TAAR1-G_s pathway activation. In rodent models, 6e significantly alleviated MK-801-induced schizophrenia-like cognitive phenotypes without inducing catalepsy. Furthermore, 6e·HCl exhibited favorable pharmacokinetic (T_1/2 = 2.31 h, F = 39%) and safety properties. All these demonstrated that 6e·HCl may be used as a novel drug candidate for schizophrenia treatment.