In Silico Discovery of Novel Potent Trace Amine-Associated Receptor TAAR1 Agonists as Promising Drug Candidates for the Treatment of Schizophrenia

All currently available antipsychotics act primarily
as dopamine
D2 receptor blockers, demonstrating established efficacy for positive
symptoms but showing limited effectiveness against negative symptoms
and cognitive impairment, coupled with significant side effects. The
latest studies have demonstrated that the coupling of trace amine-associated
receptor 1 (TAAR1) with Gs or Gq proteins has a synergistic effect
on addressing these schizophrenia symptoms. Inspired by this, we propose
an innovative concept of designing dual-pathway TAAR1-Gs/Gq agonists
for schizophrenia treatment. Through structure-based multilevel virtual
screening and rational optimization, we identified a novel compound
ZH8965 with excellent Gs/Gq activation potency. Subsequent molecular
modeling studies explained its unique mechanism of action. Oral treatment
with ZH8965 significantly alleviated the antipsychotic-like phenotypes
and cognitive impairment without inducing catalepsy like haloperidol
in the MK-801-induced mice. Moreover, ZH8965 demonstrated favorable
PK and safety profiles. Considering these results, ZH8965 represents
a promising non-D2 receptor-targeting therapeutic candidate for schizophrenia.