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

Acta Pharmacologica Sinica
Xue SunJin Li

Abstract

To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. 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. 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 al...Continue Reading

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Citations

May 3, 2016·Expert Opinion on Drug Discovery·Antoni CortésVicent Casadó
Nov 13, 2017·Pharmacological Reports : PR·Hong-Yan GouJin Li
Oct 20, 2017·Frontiers in Pharmacology·Sebastiano Alfio TorrisiGian Marco Leggio
Sep 8, 2016·The European Journal of Neuroscience·Pierre Sokoloff, Bernard Le Foll
Oct 23, 2018·ACS Medicinal Chemistry Letters·Satishkumar GadhiyaWayne W Harding
Oct 17, 2020·European Journal of Pharmacology·Cristina CosiSilvia Gatti-McArthur

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