Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia.

Abstract

AIM:

To investigate the potential effects of Y-QA31, a novel dopamine D3 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 D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT1A receptor partial agonist and α1A adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors (100-fold lower than for the D3 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 D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.

• Authors: Xue Sun, Hong-yan Gou, Fei Li, Guan-yi Lu, Rui Song, Ri-fang Yang, Ning Wu, Rui-bin Su, Bin Cong, Jin Li
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 37 Issue 3 Pg. 322-33 (Mar 2016) ISSN: 1745-7254 [Electronic] United States
• PMID: 26775662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antipsychotic Agents
• Benzothiazoles
• Piperazines
• Receptors, Dopamine D3
• Serotonin 5-HT1 Receptor Agonists
• Y-QA31
• Receptor, Serotonin, 5-HT1A

Topics

• Animals
• Antipsychotic Agents (chemistry, therapeutic use)
• Benzothiazoles (chemistry, therapeutic use)
• Locomotion (drug effects)
• Male
• Mice
• Models, Animal
• Piperazines (chemistry, therapeutic use)
• Receptor, Serotonin, 5-HT1A (metabolism)
• Receptors, Dopamine D3 (antagonists & inhibitors, metabolism)
• Schizophrenia (drug therapy, metabolism, physiopathology)
• Serotonin 5-HT1 Receptor Agonists (chemistry, therapeutic use)