title: Brexpiprazole II: antipsychotic-like and procognitive effects 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 serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT1A) and D2/3 receptors, combined with potent antagonist effects on 5-HT2A, α1B-, and α2C-adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED50 = 2.9) in rats at clinically relevant D2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED50 = 20) well above clinically relevant D2 receptor occupancies, suggesting a low risk for extrapyramidal side effects. Subchronic treatment with phencyclidine (PCP) induced cognitive impairment in both novel object recognition (NOR) and attentional set-shifting (ID-ED) tests in rats. Brexpiprazole reversed the PCP-induced cognitive impairment in the NOR test at 1.0 and 3.0 mg/kg, and in the ID-ED test at 1.0 mg/kg. However, aripiprazole (10 mg/kg) was ineffective in both tests, despite achieving relevant D2 occupancies. In the NOR test, the 5-HT1A agonist buspirone and the 5-HT2A antagonist M100907 [(R)-(2,3-dimethoxyphenyl)[1-(4-fluorophenethyl)piperidin-4-yl]methanol] partially but significantly reversed PCP-induced impairment. Furthermore, the effect of brexpiprazole was reversed by cotreatment with the 5-HT1A antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate). The results indicate that brexpiprazole has antipsychotic-like activity and robust efficacy in relevant models of cognitive impairment associated with schizophrenia. The effects of brexpiprazole in the cognitive tests are superior to those of aripiprazole. We propose that the pharmacologic profile of brexpiprazole be based on its balanced effects on 5-HT1A, D2, and 5-HT2A receptors, with possible modulating activity through additional monoamine receptors.
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.) 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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
authors.forename: Linda
authors.initials: L
authors.lastname: Lerdrup
authors.affiliation: Qs' Research Institute, Otsuka Pharmaceutical Co., Ltd. Tokushima, Japan (K.M., H.S., H.A., N.A., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
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., T.K.); Otsuka Pharmaceutical Development & Commercialization, Princeton, New Jersey (R.D.M.); and Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark (L.L., T.B.S., C.B., J.A.).
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kikuchi
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008252:Macaca fascicularis; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology; D012701:Serotonin / Q000502:physiology*; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D004298:Dopamine