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. [35S]GTPγS-binding assays and Ca2+ 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.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Seeman P, Van Tol HH . Dopamine receptor pharmacology. Trends Pharmacol Sci 1994; 15: 264–70.
Neve KA, Seamans JK, Trantham-Davidson H . Dopamine receptor signaling. J Recept Signal Transduct Res 2004; 24: 165–205.
Millan MJ, Mannoury la Cour C, Novi F, Maggio R, Audinot V, Newman-Tancredi A, et al. S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: I. Receptor-binding profile and functional actions at G-protein-coupled receptors. J Pharmacol Exp Ther 2008; 324: 587–99.
Tandon R, Fleischhacker WW . Comparative efficacy of antipsychotics in the treatment of schizophrenia: a critical assessment. Schizophr Res 2005; 79: 145–55.
Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006; 5: 25–43.
Schwartz JC, Diaz J, Pilon C, Sokoloff P . Possible implications of the dopamine D3 receptor in schizophrenia and in antipsychotic drug actions. Brain Res Brain Res Rev 2000; 31: 277–87.
Glickstein SB, Desteno DA, Hof PR, Schmauss C . Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb Cortex 2005; 15: 1016–24.
Shaikh S, Collier DA, Sham PC, Ball D, Aitchison K, Vallada H, et al. Allelic association between a Ser-9-Gly polymorphism in the dopamine D3 receptor gene and schizophrenia. Hum Genet 1996; 97: 714–9.
Millan MJ, Gobert A, Newman-Tancredi A, Lejeune F, Cussac D, Rivet JM, et al. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptorial, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293: 1048–62.
Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, et al. Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther 2000; 294: 1154–65.
Millan MJ, Dekeyne A, Rivet JM, Dubuffet T, Lavielle G, Brocco M . S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: II. Functional and behavioral profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293: 1063–73.
Millan MJ, Loiseau F, Dekeyne A, Gobert A, Flik G, Cremers TI, et al. S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent: III. Actions in models of therapeutic activity and induction of side effects. J Pharmacol Exp Ther 2008; 324: 1212–26.
Song R, Yang RF, Wu N, Su RB, Li J, Peng XQ, et al. YQA14: a novel dopamine D3 receptor antagonist that inhibits cocaine self-administration in rats and mice, but not in D3 receptor-knockout mice. Addict Biol 2012; 17: 259–73.
Karasawa J, Hashimoto K, Chaki S . D-Serine and a glycine transporter inhibitor improve MK-801-induced cognitive deficits in a novel object recognition test in rats. Behav Brain Res 2008; 186: 78–83.
Luttgen M, Elvander E, Madjid N, Ogren SO . Analysis of the role of 5-HT1A receptors in spatial and aversive learning in the rat. Neuropharmacology 2005; 48: 830–52.
Newman-Tancredi A, Rivet JM, Cussac D, Touzard M, Chaput C, Marini L, et al. Comparison of hippocampal G protein activation by 5-HT1A receptor agonists and the atypical antipsychotics clozapine and S16924. Naunyn Schmiedebergs Arch Pharmacol 2003; 368: 188–99.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–12.
Ekman A, Nissbrandt H, Heilig M, Dijkstra D, Eriksson E . Central administration of dopamine D3 receptor antisense to rat: effects on locomotion, dopamine release and [3H]spiperone binding. Naunyn Schmiedebergs Arch Pharmacol 1998; 358: 342–50.
Yarkov AV, Der TC, Joyce JN . Locomotor activity induced by MK-801 is enhanced in dopamine D3 receptor knockout mice but suppression by dopamine D3/D2 antagonists does not occur through the dopamine D3 receptor. Eur J Pharmacol 2010; 627: 167–72.
Boulay D, Depoortere R, Perrault G, Borrelli E, Sanger DJ . Dopamine D2 receptor knock-out mice are insensitive to the hypolocomotor and hypothermic effects of dopamine D2/D3 receptor agonists. Neuropharmacology 1999; 38: 1389–96.
Svensson TH . Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 1145–58.
Leriche L, Schwartz JC, Sokoloff P . The dopamine D receptor mediates locomotor hyperactivity induced by NMDA receptor blockade. Neuropharmacology 2003; 45: 174–81.
Sokoloff P, Leriche L, Diaz J, Louvel J, Pumain R . Direct and indirect interactions of the dopamine D3 receptor with glutamate pathways: implications for the treatment of schizophrenia. Naunyn Schmiedebergs Arch Pharmacol 2013; 386: 107–24.
French ED, Levenson S, Ceci A . Characterization of the actions of phencyclidine on midbrain dopamine neurons. NIDA Res Monogr 1989; 95: 255–63.
Adell A, Jimenez-Sanchez L, Lopez-Gil X, Romon T . Is the acute NMDA receptor hypofunction a valid model of schizophrenia? Schizophr Bull 2012; 38: 9–14.
Nakajima S, Gerretsen P, Takeuchi H, Caravaggio F, Chow T, Le Foll B, et al. The potential role of dopamine D3 receptor neurotransmission in cognition. Eur Neuropsychopharmacol 2013; 23: 799–813.
Swerdlow NR, Geyer MA, Braff DL . Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 2001; 156: 194–215.
Zhang M, Ballard ME, Kohlhaas KL, Browman KE, Jongen-Relo AL, Unger LV, et al. Effect of dopamine D3 antagonists on PPI in DBA/2J mice or PPI deficit induced by neonatal ventral hippocampal lesions in rats. Neuropsychopharmacology 2006; 31: 1382–92.
Zhang M, Ballard ME, Drescher K, Gross G, Decker MW, LE R . Evaluation of D3 receptor involvement in psychosis: studies in preclinical animal models. 33th Annual Meeting 2003; Society of Neuroscience.
Zhang M, Ballard ME, Unger LV, Haupt A, Gross G, Decker MW, et al. Effects of antipsychotics and selective D3 antagonists on PPI deficits induced by PD 128907 and apomorphine. Behav Brain Res 2007; 182: 1–11.
Ralph RJ, Varty GB, Kelly MA, Wang YM, Caron MG, Rubinstein M, et al. The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice. J Neurosci 1999; 19: 4627–33.
Wedzony K, Mackowiak M, Zajaczkowski W, Fijal K, Chocyk A, Czyrak A . WAY 100135, an antagonist of 5-HT1A serotonin receptors, attenuates psychotomimetic effects of MK-801. Neuropsychopharmacology 2000; 23: 547–59.
Gogos A, Kwek P, Chavez C, van den Buuse M . Estrogen treatment blocks 8-hydroxy-2-dipropylaminotetralin- and apomorphine-induced disruptions of prepulse inhibition: involvement of dopamine D1 or D2 or serotonin 5-HT1A, 5-HT2A, or 5-HT7 receptors. J Pharmacol Exp Ther 2010; 333: 218–27.
Wadenberg ML, Ericson E, Magnusson O, Ahlenius S . Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat. Biol Psychiatry 1990; 28: 297–307.
Wadenberg ML, Soliman A, VanderSpek SC, Kapur S . Dopamine D2 receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology 2001; 25: 633–41.
Wadenberg ML, Hicks PB . The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci Biobehav Rev 1999; 23: 851–62.
Wadenberg ML, Ahlenius S . Antipsychotic-like profile of combined treatment with raclopride and 8-OH-DPAT in the rat: enhancement of antipsychotic-like effects without catalepsy. J Neural Transm Gen Sect 1991; 83: 43–53.
Young ME, Sutherland S . The spatiotemporal distinctiveness of direct causation. Psychon Bull Rev 2009; 16: 729–35.
Grayson B, Idris NF, Neill JC . Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat. Behav Brain Res 2007; 184: 31–8.
Ahlander M, Misane I, Schott PA, Ogren SO . A behavioral analysis of the spatial learning deficit induced by the NMDA receptor antagonist MK-801 (dizocilpine) in the rat. Neuropsychopharmacology 1999; 21: 414–26.
Laszy J, Laszlovszky I, Gyertyan I . Dopamine D3 receptor antagonists improve the learning performance in memory-impaired rats. Psychopharmacology (Berl) 2005; 179: 567–75.
Zimnisky R, Chang G, Gyertyan I, Kiss B, Adham N, Schmauss C . Cariprazine, a dopamine D3-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl) 2013; 226: 91–100.
Micale V, Cristino L, Tamburella A, Petrosino S, Leggio GM, Di Marzo V, et al. Enhanced cognitive performance of dopamine D3 receptor "knock-out" mice in the step-through passive-avoidance test: assessing the role of the endocannabinoid/endovanilloid systems. Pharmacol Res 2010; 61: 531–6.
Watson DJ, Loiseau F, Ingallinesi M, Millan MJ, Marsden CA, Fone KC . Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex. Neuropsychopharmacology 2012; 37: 770–86.
Loiseau F, Millan MJ . Blockade of dopamine D3 receptors in frontal cortex, but not in sub-cortical structures, enhances social recognition in rats: similar actions of D1 receptor agonists, but not of D2 antagonists. Eur Neuropsychopharmacol 2009; 19: 23–33.
Millan MJ, Di Cara B, Dekeyne A, Panayi F, De Groote L, Sicard D, et al. Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis. J Neurochem 2007; 100: 1047–61.
Muller-Spahn F . Current use of atypical antipsychotics. Eur Psychiatry 2002; 17: 377s–84s.
Perrault G, Depoortere R, Morel E, Sanger DJ, Scatton B . Psycho-pharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997; 280: 73–82.
Millan MJ, Gressier H, Brocco M . The dopamine D3 receptor antagonist, (+)-S 14297, blocks the cataleptic properties of haloperidol in rats. Eur J Pharmacol 1997; 321: R7–9.
Gyertyan I, Saghy K . The selective dopamine D3 receptor antagonists, SB 277011-A and S 33084 block haloperidol-induced catalepsy in rats. Eur J Pharmacol 2007; 572: 171–4.
Acknowledgements
This research was supported by grants from the Innovation of Major New Drug Program, National Science and Technology Major Project of China (No 2011ZX09102-005-01 and 2012ZX09301-003).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Sun, X., Gou, Hy., Li, F. et al. Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia. Acta Pharmacol Sin 37, 322–333 (2016). https://doi.org/10.1038/aps.2015.105
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2015.105
