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

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...

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Veröffentlicht in:The Journal of pharmacology and experimental therapeutics 2014-09, Vol.350 (3), p.589-604
Hauptverfasser: Maeda, Kenji, Sugino, Haruhiko, Akazawa, Hitomi, Amada, Naoki, Shimada, Jun, Futamura, Takashi, Yamashita, Hiroshi, Ito, Nobuaki, McQuade, Robert D, Mørk, Arne, Pehrson, Alan L, Hentzer, Morten, Nielsen, Vibeke, Bundgaard, Christoffer, Arnt, Jørn, Stensbøl, Tine Bryan, Kikuchi, Tetsuro
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container_issue 3
container_start_page 589
container_title The Journal of pharmacology and experimental therapeutics
container_volume 350
creator Maeda, Kenji
Sugino, Haruhiko
Akazawa, Hitomi
Amada, Naoki
Shimada, Jun
Futamura, Takashi
Yamashita, Hiroshi
Ito, Nobuaki
McQuade, Robert D
Mørk, Arne
Pehrson, Alan L
Hentzer, Morten
Nielsen, Vibeke
Bundgaard, Christoffer
Arnt, Jørn
Stensbøl, Tine Bryan
Kikuchi, Tetsuro
description 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.
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In particular, it bound with high affinity (Ki &lt; 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 &lt; 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 &gt; 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. 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ispartof The Journal of pharmacology and experimental therapeutics, 2014-09, Vol.350 (3), p.589-604
issn 0022-3565
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subjects Animals
Cell Line, Tumor
CHO Cells
Cricetinae
Cricetulus
Dopamine - metabolism
Dopamine Agents - chemistry
Dopamine Agents - metabolism
Dopamine D2 Receptor Antagonists
Dose-Response Relationship, Drug
Humans
Male
Protein Binding - physiology
Quinolones - chemistry
Quinolones - metabolism
Quinolones - pharmacology
Rats
Rats, Wistar
Receptor, Serotonin, 5-HT1A - metabolism
Receptors, Dopamine D2 - agonists
Receptors, Dopamine D2 - metabolism
Serotonin - metabolism
Serotonin Agents - chemistry
Serotonin Agents - metabolism
Thiophenes - chemistry
Thiophenes - metabolism
Thiophenes - pharmacology
title Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator
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