Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia
Aim： To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. Methods： A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein- coupled receptors. [35S]GTPyS-binding assays and...
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| Veröffentlicht in: | Acta pharmacologica Sinica 2016-03, Vol.37 (3), p.322-333 |
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| creator | Sun, Xue Gou, Hong-yan Li, Fei Lu, Guan-yi Song, Rui Yang, Ri-fang Wu, Ning Su, Rui-bin Cong, Bin Li, Jin |
| description | Aim： To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. Methods： A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein- coupled receptors. [35S]GTPyS-binding assays and Ca2＋ imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. Results： In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT＋ receptor partial agonist and （xlA adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors （100-fold lower than for the D3 receptor）. In vivo, Y-QA31 （10-40 mg/kg, po） significantly inhibited MK-8Ol-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose （1 mg,/kg, po）. Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. Conclusion： Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects. |
| doi_str_mv | 10.1038/aps.2015.105 |
| format | Article |
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Methods： A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein- coupled receptors. [35S]GTPyS-binding assays and Ca2＋ imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. Results： In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT＋ receptor partial agonist and （xlA adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors （100-fold lower than for the D3 receptor）. In vivo, Y-QA31 （10-40 mg/kg, po） significantly inhibited MK-8Ol-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose （1 mg,/kg, po）. Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. Conclusion： Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/aps.2015.105</identifier><identifier>PMID: 26775662</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Antipsychotic Agents - chemistry ; Antipsychotic Agents - therapeutic use ; Benzothiazoles - chemistry ; Benzothiazoles - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Immunology ; Internal Medicine ; Locomotion - drug effects ; Male ; Medical Microbiology ; Mice ; Models, Animal ; Original ; original-article ; Pharmacology/Toxicology ; Piperazines - chemistry ; Piperazines - therapeutic use ; Receptor, Serotonin, 5-HT1A - metabolism ; Receptors, Dopamine D3 - antagonists & inhibitors ; Receptors, Dopamine D3 - metabolism ; Schizophrenia - drug therapy ; Schizophrenia - metabolism ; Schizophrenia - physiopathology ; Serotonin 5-HT1 Receptor Agonists - chemistry ; Serotonin 5-HT1 Receptor Agonists - therapeutic use ; Vaccine ; 动物模型 ; 受体拮抗剂 ; 多巴胺 ; 性质 ; 抗精神病药 ; 甲基苯丙胺 ; 精神分裂症 ; 药物</subject><ispartof>Acta pharmacologica Sinica, 2016-03, Vol.37 (3), p.322-333</ispartof><rights>CPS and SIMM 2016</rights><rights>Copyright Nature Publishing Group Mar 2016</rights><rights>Copyright © 2016 CPS and SIMM 2016 CPS and SIMM</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3925-baf173876447a3827a95ffbb7329ef3381a3a95979a176f20467466d520894c13</citedby><cites>FETCH-LOGICAL-c3925-baf173876447a3827a95ffbb7329ef3381a3a95979a176f20467466d520894c13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://image.cqvip.com/vip1000/qk/95561A/95561A.jpg</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775839/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775839/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26775662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Xue</creatorcontrib><creatorcontrib>Gou, Hong-yan</creatorcontrib><creatorcontrib>Li, Fei</creatorcontrib><creatorcontrib>Lu, Guan-yi</creatorcontrib><creatorcontrib>Song, Rui</creatorcontrib><creatorcontrib>Yang, Ri-fang</creatorcontrib><creatorcontrib>Wu, Ning</creatorcontrib><creatorcontrib>Su, Rui-bin</creatorcontrib><creatorcontrib>Cong, Bin</creatorcontrib><creatorcontrib>Li, Jin</creatorcontrib><title>Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacologica Sinica</addtitle><description>Aim： To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. Methods： A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein- coupled receptors. [35S]GTPyS-binding assays and Ca2＋ imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. Results： In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT＋ receptor partial agonist and （xlA adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors （100-fold lower than for the D3 receptor）. In vivo, Y-QA31 （10-40 mg/kg, po） significantly inhibited MK-8Ol-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose （1 mg,/kg, po）. Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. Conclusion： Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.</description><subject>Animals</subject><subject>Antipsychotic Agents - chemistry</subject><subject>Antipsychotic Agents - therapeutic use</subject><subject>Benzothiazoles - chemistry</subject><subject>Benzothiazoles - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Locomotion - drug effects</subject><subject>Male</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Models, Animal</subject><subject>Original</subject><subject>original-article</subject><subject>Pharmacology/Toxicology</subject><subject>Piperazines - chemistry</subject><subject>Piperazines - therapeutic use</subject><subject>Receptor, Serotonin, 5-HT1A - metabolism</subject><subject>Receptors, Dopamine D3 - 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chemistry</topic><topic>Antipsychotic Agents - therapeutic use</topic><topic>Benzothiazoles - chemistry</topic><topic>Benzothiazoles - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Locomotion - drug effects</topic><topic>Male</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Models, Animal</topic><topic>Original</topic><topic>original-article</topic><topic>Pharmacology/Toxicology</topic><topic>Piperazines - chemistry</topic><topic>Piperazines - therapeutic use</topic><topic>Receptor, Serotonin, 5-HT1A - metabolism</topic><topic>Receptors, Dopamine D3 - antagonists & inhibitors</topic><topic>Receptors, Dopamine D3 - metabolism</topic><topic>Schizophrenia - drug therapy</topic><topic>Schizophrenia - metabolism</topic><topic>Schizophrenia - physiopathology</topic><topic>Serotonin 5-HT1 Receptor Agonists - chemistry</topic><topic>Serotonin 5-HT1 Receptor Agonists - therapeutic use</topic><topic>Vaccine</topic><topic>动物模型</topic><topic>受体拮抗剂</topic><topic>多巴胺</topic><topic>性质</topic><topic>抗精神病药</topic><topic>甲基苯丙胺</topic><topic>精神分裂症</topic><topic>药物</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Xue</creatorcontrib><creatorcontrib>Gou, Hong-yan</creatorcontrib><creatorcontrib>Li, Fei</creatorcontrib><creatorcontrib>Lu, Guan-yi</creatorcontrib><creatorcontrib>Song, Rui</creatorcontrib><creatorcontrib>Yang, Ri-fang</creatorcontrib><creatorcontrib>Wu, Ning</creatorcontrib><creatorcontrib>Su, Rui-bin</creatorcontrib><creatorcontrib>Cong, Bin</creatorcontrib><creatorcontrib>Li, Jin</creatorcontrib><collection>中文科技期刊数据库</collection><collection>中文科技期刊数据库-CALIS站点</collection><collection>中文科技期刊数据库-7.0平台</collection><collection>中文科技期刊数据库-医药卫生</collection><collection>中文科技期刊数据库- 镜像站点</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sun, Xue</au><au>Gou, Hong-yan</au><au>Li, Fei</au><au>Lu, Guan-yi</au><au>Song, Rui</au><au>Yang, Ri-fang</au><au>Wu, Ning</au><au>Su, Rui-bin</au><au>Cong, Bin</au><au>Li, Jin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacologica Sinica</addtitle><date>2016-03-01</date><risdate>2016</risdate><volume>37</volume><issue>3</issue><spage>322</spage><epage>333</epage><pages>322-333</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Aim： To investigate the potential effects of Y-QA31, a novel dopamine D3 receptor antagonist, as an antipsychotic drug. Methods： A panel of radioligand-receptor binding assays was performed to identify the affinities of Y-QA31 for different G protein- coupled receptors. [35S]GTPyS-binding assays and Ca2＋ imaging were used to assess its intrinsic activities. The antipsychotic profile of Y-QA31 was characterized in mouse models for the positive symptoms and cognitive deficits of schizophrenia and extrapyramidal side effects with haloperidol and clozapine as positive controls. Results： In vitro, Y-QA31 is a dopamine D3 receptor antagonist that is 186-fold more potent at the D3 receptor than at the D2 receptor. Y-QA31 also exhibits 5-HT＋ receptor partial agonist and （xlA adrenoceptor antagonist activities with medium affinity, whereas it exhibits very little affinity for other receptors （100-fold lower than for the D3 receptor）. In vivo, Y-QA31 （10-40 mg/kg, po） significantly inhibited MK-8Ol-induced hyperlocomotion and methamphetamine-induced prepulse inhibition disruption in a dose-dependent manner. Y-QA31 also inhibited the avoidance response and methamphetamine-induced hyperlocomotion with potency lower than haloperidol. Y-QA31 was effective in alleviating the MK-801-induced disruption of novel object recognition at a low dose （1 mg,/kg, po）. Moreover, Y-QA31 itself did not affect spontaneous locomotion or induce cataleptic response until its dose reached 120 mg/kg. Conclusion： Y-QA31 is a selective D3R antagonist that exhibits antipsychotic effects in some animal models with positive symptoms and cognitive disorder and less extrapyramidal side effects.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26775662</pmid><doi>10.1038/aps.2015.105</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Acta pharmacologica Sinica, 2016-03, Vol.37 (3), p.322-333 |
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| subjects | Animals Antipsychotic Agents - chemistry Antipsychotic Agents - therapeutic use Benzothiazoles - chemistry Benzothiazoles - therapeutic use Biomedical and Life Sciences Biomedicine Immunology Internal Medicine Locomotion - drug effects Male Medical Microbiology Mice Models, Animal Original original-article Pharmacology/Toxicology Piperazines - chemistry Piperazines - therapeutic use Receptor, Serotonin, 5-HT1A - metabolism Receptors, Dopamine D3 - antagonists & inhibitors Receptors, Dopamine D3 - metabolism Schizophrenia - drug therapy Schizophrenia - metabolism Schizophrenia - physiopathology Serotonin 5-HT1 Receptor Agonists - chemistry Serotonin 5-HT1 Receptor Agonists - therapeutic use Vaccine 动物模型 受体拮抗剂 多巴胺 性质 抗精神病药 甲基苯丙胺 精神分裂症 药物 |
| title | Y-QA31, a novel dopamine D3 receptor antagonist, exhibits antipsychotic-like properties in preclinical animal models of schizophrenia |
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