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 |
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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. |
doi_str_mv | 10.1124/jpet.114.213793 |
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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.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.114.213793</identifier><identifier>PMID: 24947465</identifier><language>eng</language><publisher>United States</publisher><subject>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</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2014-09, Vol.350 (3), p.589-604</ispartof><rights>Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c363t-89b85d7976702681d304e3004de1b2b07db7a068892329acfec9e45a7840f373</citedby><cites>FETCH-LOGICAL-c363t-89b85d7976702681d304e3004de1b2b07db7a068892329acfec9e45a7840f373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24947465$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maeda, Kenji</creatorcontrib><creatorcontrib>Sugino, Haruhiko</creatorcontrib><creatorcontrib>Akazawa, Hitomi</creatorcontrib><creatorcontrib>Amada, Naoki</creatorcontrib><creatorcontrib>Shimada, Jun</creatorcontrib><creatorcontrib>Futamura, Takashi</creatorcontrib><creatorcontrib>Yamashita, Hiroshi</creatorcontrib><creatorcontrib>Ito, Nobuaki</creatorcontrib><creatorcontrib>McQuade, Robert D</creatorcontrib><creatorcontrib>Mørk, Arne</creatorcontrib><creatorcontrib>Pehrson, Alan L</creatorcontrib><creatorcontrib>Hentzer, Morten</creatorcontrib><creatorcontrib>Nielsen, Vibeke</creatorcontrib><creatorcontrib>Bundgaard, Christoffer</creatorcontrib><creatorcontrib>Arnt, Jørn</creatorcontrib><creatorcontrib>Stensbøl, Tine Bryan</creatorcontrib><creatorcontrib>Kikuchi, Tetsuro</creatorcontrib><title>Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><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.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Agents - chemistry</subject><subject>Dopamine Agents - metabolism</subject><subject>Dopamine D2 Receptor Antagonists</subject><subject>Dose-Response Relationship, Drug</subject><subject>Humans</subject><subject>Male</subject><subject>Protein Binding - physiology</subject><subject>Quinolones - chemistry</subject><subject>Quinolones - metabolism</subject><subject>Quinolones - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptor, Serotonin, 5-HT1A - metabolism</subject><subject>Receptors, Dopamine D2 - agonists</subject><subject>Receptors, Dopamine D2 - metabolism</subject><subject>Serotonin - metabolism</subject><subject>Serotonin Agents - chemistry</subject><subject>Serotonin Agents - metabolism</subject><subject>Thiophenes - chemistry</subject><subject>Thiophenes - metabolism</subject><subject>Thiophenes - pharmacology</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kDtPwzAUhS0EoqUwsyGPLGn9ShyzQcWjUiWW7pGT3ICrxA62U9H-elIVmO650nfO8CF0S8mcUiYW2x7imMScUS4VP0NTmjKaEEr4OZoSwljC0yydoKsQtoRQITJ-iSZMKCFFlk7Rx5OH7970Xh9cC3j1gI3FOxO9w9rWp2fncPWpva4ieHPQ0TiLXYM1tm4HLQ7gXXTW2KR2ve6MBTyiZhzZ487VQ6uj89footFtgJvfO0Obl-fN8i1Zv7-ulo_rpOIZj0muyjytpZKZJCzLac2JAE6IqIGWrCSyLqUmWZ4rxpnSVQOVApFqmQvScMln6P4023v3NUCIRWdCBW2rLbghFDQVOVWc8HxEFye08i4ED03Re9Npvy8oKY5yi6PcMYniJHds3P2OD2UH9T__Z5P_AEMAdos</recordid><startdate>20140901</startdate><enddate>20140901</enddate><creator>Maeda, Kenji</creator><creator>Sugino, Haruhiko</creator><creator>Akazawa, Hitomi</creator><creator>Amada, Naoki</creator><creator>Shimada, Jun</creator><creator>Futamura, Takashi</creator><creator>Yamashita, Hiroshi</creator><creator>Ito, Nobuaki</creator><creator>McQuade, Robert D</creator><creator>Mørk, Arne</creator><creator>Pehrson, Alan L</creator><creator>Hentzer, Morten</creator><creator>Nielsen, Vibeke</creator><creator>Bundgaard, Christoffer</creator><creator>Arnt, Jørn</creator><creator>Stensbøl, Tine Bryan</creator><creator>Kikuchi, Tetsuro</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20140901</creationdate><title>Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c363t-89b85d7976702681d304e3004de1b2b07db7a068892329acfec9e45a7840f373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Dopamine - metabolism</topic><topic>Dopamine Agents - chemistry</topic><topic>Dopamine Agents - metabolism</topic><topic>Dopamine D2 Receptor Antagonists</topic><topic>Dose-Response Relationship, Drug</topic><topic>Humans</topic><topic>Male</topic><topic>Protein Binding - physiology</topic><topic>Quinolones - chemistry</topic><topic>Quinolones - metabolism</topic><topic>Quinolones - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptor, Serotonin, 5-HT1A - metabolism</topic><topic>Receptors, Dopamine D2 - agonists</topic><topic>Receptors, Dopamine D2 - metabolism</topic><topic>Serotonin - metabolism</topic><topic>Serotonin Agents - chemistry</topic><topic>Serotonin Agents - metabolism</topic><topic>Thiophenes - chemistry</topic><topic>Thiophenes - metabolism</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maeda, Kenji</creatorcontrib><creatorcontrib>Sugino, Haruhiko</creatorcontrib><creatorcontrib>Akazawa, Hitomi</creatorcontrib><creatorcontrib>Amada, Naoki</creatorcontrib><creatorcontrib>Shimada, Jun</creatorcontrib><creatorcontrib>Futamura, Takashi</creatorcontrib><creatorcontrib>Yamashita, Hiroshi</creatorcontrib><creatorcontrib>Ito, Nobuaki</creatorcontrib><creatorcontrib>McQuade, Robert D</creatorcontrib><creatorcontrib>Mørk, Arne</creatorcontrib><creatorcontrib>Pehrson, Alan L</creatorcontrib><creatorcontrib>Hentzer, Morten</creatorcontrib><creatorcontrib>Nielsen, Vibeke</creatorcontrib><creatorcontrib>Bundgaard, Christoffer</creatorcontrib><creatorcontrib>Arnt, Jørn</creatorcontrib><creatorcontrib>Stensbøl, Tine Bryan</creatorcontrib><creatorcontrib>Kikuchi, Tetsuro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maeda, Kenji</au><au>Sugino, Haruhiko</au><au>Akazawa, Hitomi</au><au>Amada, Naoki</au><au>Shimada, Jun</au><au>Futamura, Takashi</au><au>Yamashita, Hiroshi</au><au>Ito, Nobuaki</au><au>McQuade, Robert D</au><au>Mørk, Arne</au><au>Pehrson, Alan L</au><au>Hentzer, Morten</au><au>Nielsen, Vibeke</au><au>Bundgaard, Christoffer</au><au>Arnt, Jørn</au><au>Stensbøl, Tine Bryan</au><au>Kikuchi, Tetsuro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Brexpiprazole I: in vitro and in vivo characterization of a novel serotonin-dopamine activity modulator</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2014-09-01</date><risdate>2014</risdate><volume>350</volume><issue>3</issue><spage>589</spage><epage>604</epage><pages>589-604</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><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.</abstract><cop>United States</cop><pmid>24947465</pmid><doi>10.1124/jpet.114.213793</doi><tpages>16</tpages></addata></record> |
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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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