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Brexpiprazole II: Antipsychotic-Like and Procognitive Effects of a Novel Serotonin-Dopamine Activity Modulator

2014; American Society for Pharmacology and Experimental Therapeutics; Volume: 350; Issue: 3 Linguagem: Inglês

10.1124/jpet.114.213819

1521-0103

Kenji Maeda, Linda Lerdrup, Haruhiko Sugino, Hitomi Akazawa, Naoki Amada, Robert D. McQuade, Tine B. Stensbøl, Christoffer Bundgaard, Jørn Arnt, Tetsuro Kikuchi,

Treatment of Major Depression

Brexpiprazole (OPC-34712, 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1 H )-one) is a novel serotonin-dopamine activity modulator with partial agonist activity at serotonin 1A (5-HT 1A ) and D 2/3 receptors, combined with potent antagonist effects on 5-HT 2A , α 1B -, and α 2C -adrenergic receptors. Brexpiprazole inhibited conditioned avoidance response (ED 50 = 6.0 mg/kg), apomorphine- or d-amphetamine-induced hyperactivity (ED 50 = 2.3 and 0.90, respectively), and apomorphine-induced stereotypy (ED 50 = 2.9) in rats at clinically relevant D 2 receptor occupancies. Brexpiprazole also potently inhibited apomorphine-induced eye blinking in monkeys. The results suggest that brexpiprazole has antipsychotic potential. Brexpiprazole induced catalepsy (ED 50 = 20) well above clinically relevant D 2 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 D 2 occupancies. In the NOR test, the 5-HT 1A agonist buspirone and the 5-HT 2A 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-HT 1A 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-HT 1A, D 2 , and 5-HT 2A receptors, with possible modulating activity through additional monoamine receptors.