Structure based discovery of antipsychotic-like TAAR1 agonists

Abstract Schizophrenia is a severe mental illness whose current treatments primarily target dopamine and serotonin receptors. These drugs often cause side effects and vary in effectiveness across patients. The trace amine-associated receptor 1 (TAAR1), which modulates monoamine signaling, has emerged as a promising alternative target. To discover previously unexplored TAAR1 ligands, we computationally dock 65 million molecules against the active state of TAAR1 and experimentally test 55 of those highly ranked. Fourteen TAAR1 agonists emerge with potencies ranging from mid-nanomolar to micromolar. This high functional selectivity may reflect the compact conformation adopted by the activated TAAR1 orthosteric site. While this is favorable for agonist prioritization, simulations suggest that it can be over-optimized for initial hit rates at the expense of subsequent affinity maturation. Hit optimization yields nanomolar agonists whose docking-predicted poses are confirmed by cryo-EM. Three agonists have high brain exposure and potencies, with one compound showing potency comparable to the investigational drug ulotaront and two compounds exhibiting even greater potency, at levels sufficient for behavioral studies. All three potently normalize amphetamine-induced pre-pulse inhibition in mice, a model for schizophrenia, without catalepsy, a common side effect of traditional antipsychotics.