title: Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator.
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.
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.) Maeda.Kenji@otsuka.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugino
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Hitomi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Naoki
authors.initials: N
authors.lastname: Amada
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Takashi
authors.initials: T
authors.lastname: Futamura
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Ito
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Robert D
authors.initials: RD
authors.lastname: McQuade
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Arne
authors.initials: A
authors.lastname: Mørk
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Alan L
authors.initials: AL
authors.lastname: Pehrson
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Morten
authors.initials: M
authors.lastname: Hentzer
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Vibeke
authors.initials: V
authors.lastname: Nielsen
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Jørn
authors.initials: J
authors.lastname: Arnt
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Tine Bryan
authors.initials: TB
authors.lastname: Stensbøl
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., J.S., T.F., H.Y., N.I., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (A.M., M.H., V.N., C.B., J.A., T.B.S.); and Lundbeck Research USA, Paramus, New Jersey (A.L.P.).
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000737:chemistry* / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D011485:Protein Binding / Q000502:physiology; D015363:Quinolones / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000737:chemistry* / Q000378:metabolism*; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D015363:Quinolones; D017448:Receptors, Dopamine D2; D018490:Serotonin Agents; D013876:Thiophenes; C113776:dopamine D2L receptor; D044282:Receptor, Serotonin, 5-HT1A; C000591922:brexpiprazole; D012701:Serotonin; D004298:Dopamine