Brexpiprazole I: In vitro and in vivo characterization of a novel serotonin-dopamine activity modulator

Kenji Maeda, Haruhiko Sugino, Hitomi Akazawa, Naoki Amada, Jun Shimada, Takashi Futamura, Hiroshi Yamashita, Nobuaki Ito, Robert D. McQuade, Arne Mørk, Alan L. Pehrson, Morten Hentzer, Vibeke Nielsen, Christoffer Bundgaard, Jørn Arnt, Tine Bryan Stensbøl, Tetsuro Kikuchi

Research output: Contribution to journalArticlepeer-review

250 Scopus citations


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 (K i < 1 nM) to human serotonin 1A (h5-HT 1A )-, h5-HT 2A -, long form of human D 2 (hD 2L )-, hα 1B -, and hα 2C -adrenergic receptors. It displayed partial agonism at h5-HT 1A and hD 2 receptors in cloned receptor systems and potent antagonism of h5-HT 2A receptors and hα 1B/2C -adrenoceptors. Brexpiprazole also had affinity (K i < 5 nM) for hD 3- , h5-HT 2B -, h5-HT 7 -, hα 1A -, and hα 1D -adrenergic receptors, moderate affinity for hH 1 (K i = 19 nM), and low affinity for hM 1 receptors (K i > 1000 nM). Brexpiprazole potently bound to rat 5-HT 2A and D 2 receptors in vivo, and ex vivo binding studies further confirmed high 5-HT 1A receptor binding potency. Brexpiprazole inhibited DOI (2,5-dimethoxy-4-iodoamphetamine)-induced head twitches in rats, suggestive of 5-HT 2A antagonism. Furthermore, in vivo D 2 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 D 2 partial agonist activity. In particular, based on a lower intrinsic activity at D 2 receptors and higher binding affinities for 5-HT 1A/2A receptors than aripiprazole, brexpiprazole would have a favorable antipsychotic potential without D 2 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.

Original languageEnglish
Pages (from-to)589-604
Number of pages16
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Sep 2014


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