Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HTReceptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis.

Abstract

The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HTR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named.exhibits submicromolar potency on both TAAR1 and 5-HTR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed thatwas highly efficacious against the positive and negative symptoms of schizophrenia in mice models.also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing ofis exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compoundwarrants further clinical development for the treatment of schizophrenia and AD-related psychosis.