Y-QA31, a novel dopamine D 3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia

Aim: To investigate the potential effects of Y-QA31, a novel dopamine D 3 receptor antagonist, as an antipsychotic drug. Methods: A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein-coupled receptors. [ 35 S]GTPγS-binding assays and Ca 2+ imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. Results: In vitro , Y-QA31 is a dopamine D 3 receptor antagonist that is 186-fold more potent at the D 3 receptor than at the D 2 receptor. Y-QA31 also exhibits 5-HT 1A receptor partial agonist and α 1A adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors (100-fold lower than for the D 3 receptor). In vivo , Y-QA31 (10–40 mg/kg, po ) significantly inhibited MK-801-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose (1 mg/kg, po ). Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. Conclusion: Y-QA31 is a selective D 3 R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.