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.