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-Gs/Gq dual-pathway activation property, being different from that
of the clinical drug candidate SEP-363856 with only TAAR1-Gs pathway activation. In rodent models, 6e significantly
alleviated MK-801-induced schizophrenia-like cognitive phenotypes
without inducing catalepsy. Furthermore, 6e·HCl exhibited
favorable pharmacokinetic (T1/2 = 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.