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.
Footnotes
- Received February 7, 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 at the following conferences: Kikuchi T, Maeda K, Sugino H, Akazawa H, Amada N, Jordan S, Shimada J, Yamashita H, Ito N, Forbes RA, and McQuade RD (2011) 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; Amada N, Maeda K, Akazawa H, Sugino H, Stensbøl TB, and 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; and Lerdrup L, Plath N, Nielsen V, Pedersen CS, Bundgaard C, Maeda K, Kikuchi T, and Stensbøl TB (2014) Procognitive effect of brexpiprazole in the subchronic phencyclidine rat model. 69th Annual Meeting of the Society of Biological Psychiatry; 2014 May 8–10; New York, NY.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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