Currently existing antipsychotics mainly focus on positive symptoms of schizophreniatarget dopamine system, especially D2 receptors (D2R). Unfortunately, the use of antipsychotics may moreless result in many unwanted adverse effects. D2R binds with A2A adenosine receptor (A2AR)these two receptors antagonistically regulate each other upon activation. Activation of A2AR can suppress hyperfunction of D2R in schizophrenia. J4 is an orally active adenosine analogue that simultaneously modulates adenosine transportersA2A adenosine receptors. Our findings indicate J4 can alleviate schizophrenia-related phenotypes in mouse models of schizophreniahas potential to become a first-in-class non-dopamine antipsychotic drug.

Our team developedsynthesized J4, an orally active adenosine analogue. J4 simultaneously modulates equilibrative nucleoside transporter 1 (ENT1)A2A adenosine receptors (A2AR). Oralintraperitoneal administration of J4 increases synaptic adenosine concentrationactivates A2ARs in the brain. Through functional antagonistic interactions between dopamine D2 receptorsA2ARs, J4 can suppress hyperdopaminergic activityalleviate the methamphetamine-induced behavioralneurochemical abnormalities in mouse models of schizophrenia. J4 has potential to be a first-in-class non-dopamine antipsychotic drug for the treatment of schizophrenia without dopamine-related bothersome side effects.

The prevalence of schizophrenia approaches 1 percent worldwidethe incidence is about 1.5 per 10,000 people. It is very costly for familiessociety. However, currently existing antipsychotics mainly target dopamine D2 receptorsmoreless result in many unwanted adverse effects. Our team developed J4, a novel adenosine analogue. Our preclinical data revealed that J4 can suppress hyperdopaminergic activityalleviate methamphetamine-induced psychosis in mice. Our results open a new avenue for the development of a first-in-class non-dopamine antipsychotic drug. Our findings will be applied to translational researchpatent application along the way. A provisional application for U.S. patent is in progress.