title: Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.|Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Hong-yan
authors.initials: HY
authors.lastname: Gou
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Guan-yi
authors.initials: GY
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Ri-fang
authors.initials: RF
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Rui-bin
authors.initials: RB
authors.lastname: Su
authors.affiliation: Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical University, Shijiazhuang 050017, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Cong
authors.affiliation: State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000737:chemistry / Q000627:therapeutic use*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D023421:Models, Animal; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use*; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D014150:Antipsychotic Agents; D052160:Benzothiazoles; D010879:Piperazines; D050637:Receptors, Dopamine D3; D058825:Serotonin 5-HT1 Receptor Agonists; C000613308:Y-QA31; D044282:Receptor, Serotonin, 5-HT1A