Abstract
Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) is a novel drug candidate in clinical development for psychiatric disorders with high affinity for serotonin, dopamine, and noradrenaline receptors. In particular, it bound with high affinity (Ki < 1 nM) to human serotonin 1A (h5-HT1A)-, h5-HT2A-, long form of human D2 (hD2L)-, hα1B-, and hα2C-adrenergic receptors. It displayed partial agonism at h5-HT1A and hD2 receptors in cloned receptor systems and potent antagonism of h5-HT2A receptors and hα1B/2C-adrenoceptors. Brexpiprazole also had affinity (Ki < 5 nM) for hD3-, h5-HT2B-, h5-HT7-, hα1A-, and hα1D-adrenergic receptors, moderate affinity for hH1 (Ki = 19 nM), and low affinity for hM1 receptors (Ki > 1000 nM). Brexpiprazole potently bound to rat 5-HT2A and D2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT2A antagonism. Furthermore, in vivo D2 partial agonist activity of brexpiprazole was confirmed by its inhibitory effect on reserpine-induced DOPA accumulation in rats. In rat microdialysis studies, brexpiprazole slightly reduced extracellular dopamine in nucleus accumbens but not in prefrontal cortex, whereas moderate increases of the dopamine metabolites, homovanillic acid and DOPAC (3,4-dihydroxy-phenyl-acetic acid), in these areas also suggested in vivo D2 partial agonist activity. In particular, based on a lower intrinsic activity at D2 receptors and higher binding affinities for 5-HT1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D2 receptor agonist- and antagonist-related adverse effects. In conclusion, brexpiprazole is a serotonin-dopamine activity modulator with a unique pharmacology, which may offer novel treatment options across a broad spectrum of central nervous system disorders.
Footnotes
- Received February 5, 2014.
- Accepted June 18, 2014.
This work was funded by Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan) and H. Lundbeck A/S (Valby, Denmark).
This work was previously presented as a poster presentation at the following workshops: Kikuchi T, Maeda K, Sugino H, Akazawa H, Amada N, Jordan S, Shimada J, Yamashita H, Ito N, Forbes RA, McQuade RD (2014) Preclinical pharmacology of OPC-34712: a novel compound with dopamine D2 receptor partial agonist activity. 66th Annual Meeting of the Society of Biological Psychiatry; 2011 May 12–14; San Francisco, CA; Maeda K, Stensbøl TB, Hentzer M, Akazawa H, Sugino H, Shimada J, Futamura T, Kikuchi T (2014) In vitro pharmacological profile of brexpiprazole, a novel serotonin-dopamine activity modulator. 69th Annual Meeting of the Society of Biological Psychiatry; 2014 May 8–10; New York, NY; Mørk A, Nielsen V, Pehrson A, Bundgaard C, Maeda K, Kikuchi T (2014) Effects of brexpiprazole on receptor occupancies and extracellular levels of neurotransmitters in the rat brain. 69th Annual Meeting of the Society of Biological Psychiatry; 2014 May 8–10; New York, NY; and Amada N, Maeda K, Akazawa H, Sugino H, Stensbøl TB, Kikuchi T (2014) Brexpiprazole, a novel serotonin-dopamine activity modulator: in vivo evaluation of its antipsychotic-like profile. 69th Annual Meeting of the Society of Biological Psychiatry; 2014 May 8–10; New York, NY.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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