Structure based discovery of antipsychotic-like TAAR1 agonists

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 new TAAR1 ligands, we computationally docked 65 million molecules against the active state of TAAR1 and experimentally tested 55 of those highly ranked. Fourteen molecules active against TAAR1 with potencies ranging from mid-nanomolar to micromolar, all as agonists. This high functional selectivity may reflect the compact conformation adopted by the activated TAAR1 orthosteric site. While this was favorable for agonist prioritization, simulations suggest that it can be over-optimized for initial hit rates at the expense of subsequent affinity maturation. Here, hit optimization yielded nanomolar agonists whose docking-predicted poses were confirmed by cryo-EM. Three agonists had high brain exposure and potencies apparently better than the investigational drug ulotaront and sufficient for behavioral studies. All three potently normalized amphetamine-induced pre-pulse inhibition in mice, a model for schizophrenia, without catalepsy, a common side effect of traditional antipsychotics.