Antagonistic Activity of Y-25130 on 5-HT3 Receptors

This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in...

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Veröffentlicht in:Japanese journal of pharmacology 1992, Vol.59(4), pp.443-448
Hauptverfasser: Sato, Noriko, Sakamori, Masamitsu, Haga, Keiichiro, Takehara, Shuzo, Setoguchi, Michihide
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container_end_page 448
container_issue 4
container_start_page 443
container_title Japanese journal of pharmacology
container_volume 59
creator Sato, Noriko
Sakamori, Masamitsu
Haga, Keiichiro
Takehara, Shuzo
Setoguchi, Michihide
description This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 μΜ) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, α1-adrenoceptor, α2-adrenoceptor, muscarine and benzodiazepine) even at a 10 μM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.
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In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 μΜ) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, α1-adrenoceptor, α2-adrenoceptor, muscarine and benzodiazepine) even at a 10 μM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.</description><identifier>ISSN: 0021-5198</identifier><identifier>EISSN: 1347-3506</identifier><identifier>DOI: 10.1254/jjp.59.443</identifier><identifier>PMID: 1331590</identifier><identifier>CODEN: JJPAAZ</identifier><language>eng</language><publisher>Kyoto: The Japanese Pharmacological Society</publisher><subject>5-HT3 receptor ; Acetylcholine - metabolism ; Animals ; Antiemetics - metabolism ; Antiemetics - pharmacology ; Biological and medical sciences ; Bridged Bicyclo Compounds - metabolism ; Bridged Bicyclo Compounds - pharmacology ; Bridged Bicyclo Compounds, Heterocyclic ; Cardiotonic Agents - pharmacology ; Cerebral Cortex - drug effects ; Cerebral Cortex - metabolism ; Cerebral Cortex - ultrastructure ; Guinea Pigs ; Heart (isolated) ; Heart - drug effects ; Heart - physiology ; Ileum (isolated) ; Ileum - drug effects ; Ileum - metabolism ; Ileum - ultrastructure ; In Vitro Techniques ; Kinetics ; Male ; Medical sciences ; Muscle Contraction - drug effects ; Myocardial Contraction - drug effects ; Myocardium - metabolism ; Myocardium - ultrastructure ; Nerve Fibers - drug effects ; Nerve Fibers - metabolism ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Norepinephrine - metabolism ; Oxazines - metabolism ; Oxazines - pharmacology ; Pharmacology. Drug treatments ; Rabbits ; Radioligand Assay ; Receptors, Neurotransmitter - metabolism ; Receptors, Serotonin - drug effects ; Receptors, Serotonin - metabolism ; Serotonin Antagonists ; Serotoninergic system ; Stimulation, Chemical ; Sympathetic Nervous System - drug effects ; Sympathetic Nervous System - metabolism ; Y-25130</subject><ispartof>The Japanese Journal of Pharmacology, 1992, Vol.59(4), pp.443-448</ispartof><rights>1992 Elsevier B.V.</rights><rights>The Japanese PharmacologicalSociety</rights><rights>1993 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-eb0f55c76322b01c75e91e688ccd9a74530ac0fd90f414833785d9ae9919bd403</citedby><cites>FETCH-LOGICAL-c620t-eb0f55c76322b01c75e91e688ccd9a74530ac0fd90f414833785d9ae9919bd403</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,1883,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=4378208$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1331590$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sato, Noriko</creatorcontrib><creatorcontrib>Sakamori, Masamitsu</creatorcontrib><creatorcontrib>Haga, Keiichiro</creatorcontrib><creatorcontrib>Takehara, Shuzo</creatorcontrib><creatorcontrib>Setoguchi, Michihide</creatorcontrib><title>Antagonistic Activity of Y-25130 on 5-HT3 Receptors</title><title>Japanese journal of pharmacology</title><addtitle>Jpn.J.Pharmacol.</addtitle><description>This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 μΜ) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, α1-adrenoceptor, α2-adrenoceptor, muscarine and benzodiazepine) even at a 10 μM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.</description><subject>5-HT3 receptor</subject><subject>Acetylcholine - metabolism</subject><subject>Animals</subject><subject>Antiemetics - metabolism</subject><subject>Antiemetics - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Bridged Bicyclo Compounds - metabolism</subject><subject>Bridged Bicyclo Compounds - pharmacology</subject><subject>Bridged Bicyclo Compounds, Heterocyclic</subject><subject>Cardiotonic Agents - pharmacology</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Cerebral Cortex - ultrastructure</subject><subject>Guinea Pigs</subject><subject>Heart (isolated)</subject><subject>Heart - drug effects</subject><subject>Heart - physiology</subject><subject>Ileum (isolated)</subject><subject>Ileum - drug effects</subject><subject>Ileum - metabolism</subject><subject>Ileum - ultrastructure</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Muscle Contraction - drug effects</subject><subject>Myocardial Contraction - drug effects</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - ultrastructure</subject><subject>Nerve Fibers - drug effects</subject><subject>Nerve Fibers - metabolism</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Norepinephrine - metabolism</subject><subject>Oxazines - metabolism</subject><subject>Oxazines - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Rabbits</subject><subject>Radioligand Assay</subject><subject>Receptors, Neurotransmitter - metabolism</subject><subject>Receptors, Serotonin - drug effects</subject><subject>Receptors, Serotonin - metabolism</subject><subject>Serotonin Antagonists</subject><subject>Serotoninergic system</subject><subject>Stimulation, Chemical</subject><subject>Sympathetic Nervous System - drug effects</subject><subject>Sympathetic Nervous System - metabolism</subject><subject>Y-25130</subject><issn>0021-5198</issn><issn>1347-3506</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1LxDAQhoMoun5cvAs9iAeh66RJts1x8RsEQfTgKWSnU03ptjXpCv57o13Wi5eE8D68k3kYO-Yw5ZmSF3XdT5WeSim22IQLmadCwWybTQAyniquiz22H0IdnwVwuct2uRBcaZgwMW8H-9a1LgwOkzkO7tMNX0lXJa9ppriApGsTld49i-SJkPqh8-GQ7VS2CXS0vg_Yy8318-Vd-vB4e385f0hxlsGQ0gIqpTCfiSxbAMdckeY0KwrEUttcKgEWoSo1VJLLQoi8UDEgrblelBLEATsbe3vffawoDGbpAlLT2Ja6VTB5XEJkICJ4PoLouxA8Vab3bmn9l-FgfgyZaMgobaKhCJ-sW1eLJZV_6Kgk5qfr3Aa0TeVtiy5sMBm_mUERsasRq0MUSJvc-iiyIVP374FrxX_Hjkecvonx3XpDbayRYw1FkZ-OvAnoqEUqnSccTNm5_5b4Bo2OlJ4</recordid><startdate>1992</startdate><enddate>1992</enddate><creator>Sato, Noriko</creator><creator>Sakamori, Masamitsu</creator><creator>Haga, Keiichiro</creator><creator>Takehara, Shuzo</creator><creator>Setoguchi, Michihide</creator><general>The Japanese Pharmacological Society</general><general>Japanese Pharmacological Society</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><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>1992</creationdate><title>Antagonistic Activity of Y-25130 on 5-HT3 Receptors</title><author>Sato, Noriko ; Sakamori, Masamitsu ; Haga, Keiichiro ; Takehara, Shuzo ; Setoguchi, Michihide</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-eb0f55c76322b01c75e91e688ccd9a74530ac0fd90f414833785d9ae9919bd403</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>5-HT3 receptor</topic><topic>Acetylcholine - metabolism</topic><topic>Animals</topic><topic>Antiemetics - metabolism</topic><topic>Antiemetics - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Bridged Bicyclo Compounds - metabolism</topic><topic>Bridged Bicyclo Compounds - pharmacology</topic><topic>Bridged Bicyclo Compounds, Heterocyclic</topic><topic>Cardiotonic Agents - pharmacology</topic><topic>Cerebral Cortex - drug effects</topic><topic>Cerebral Cortex - metabolism</topic><topic>Cerebral Cortex - ultrastructure</topic><topic>Guinea Pigs</topic><topic>Heart (isolated)</topic><topic>Heart - drug effects</topic><topic>Heart - physiology</topic><topic>Ileum (isolated)</topic><topic>Ileum - drug effects</topic><topic>Ileum - metabolism</topic><topic>Ileum - ultrastructure</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Muscle Contraction - drug effects</topic><topic>Myocardial Contraction - drug effects</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - ultrastructure</topic><topic>Nerve Fibers - drug effects</topic><topic>Nerve Fibers - metabolism</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Norepinephrine - metabolism</topic><topic>Oxazines - metabolism</topic><topic>Oxazines - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Rabbits</topic><topic>Radioligand Assay</topic><topic>Receptors, Neurotransmitter - metabolism</topic><topic>Receptors, Serotonin - drug effects</topic><topic>Receptors, Serotonin - metabolism</topic><topic>Serotonin Antagonists</topic><topic>Serotoninergic system</topic><topic>Stimulation, Chemical</topic><topic>Sympathetic Nervous System - drug effects</topic><topic>Sympathetic Nervous System - metabolism</topic><topic>Y-25130</topic><toplevel>online_resources</toplevel><creatorcontrib>Sato, Noriko</creatorcontrib><creatorcontrib>Sakamori, Masamitsu</creatorcontrib><creatorcontrib>Haga, Keiichiro</creatorcontrib><creatorcontrib>Takehara, Shuzo</creatorcontrib><creatorcontrib>Setoguchi, Michihide</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Pascal-Francis</collection><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>Japanese journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sato, Noriko</au><au>Sakamori, Masamitsu</au><au>Haga, Keiichiro</au><au>Takehara, Shuzo</au><au>Setoguchi, Michihide</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antagonistic Activity of Y-25130 on 5-HT3 Receptors</atitle><jtitle>Japanese journal of pharmacology</jtitle><addtitle>Jpn.J.Pharmacol.</addtitle><date>1992</date><risdate>1992</risdate><volume>59</volume><issue>4</issue><spage>443</spage><epage>448</epage><pages>443-448</pages><issn>0021-5198</issn><eissn>1347-3506</eissn><coden>JJPAAZ</coden><abstract>This paper describes the 5-hydroxytryptamine3 (5-HT3) receptor antagonism of Y-25130 ((±)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-l,4-benzoxazine-8-carboxamide monohydrochloride) in the rat cerebral cortex, isolated rabbit heart and isolated guinea pig ileum. In an in vitro binding assay, Y-25130 inhibited the specific binding of [3H]quipazine to 5-HT3 receptors at the synaptic membranes of the rat cerebral cortex with a Ki value of 2.9 nM, the same as that of ondansetron. Metoclopramide, 5-HT and 2-methyl-5-HT also showed an inhibitory effect, but their affinities for 5-HT3 receptors were lower than that of Y-25130. Y-25130 showed low affinity for histamine H1 receptors (IC50 = 4.4 μΜ) but it could not reveal any affinities for the other receptors (5-HT1A, 5-HT2, dopamine D1, dopamine D2, α1-adrenoceptor, α2-adrenoceptor, muscarine and benzodiazepine) even at a 10 μM concentration. In the isolated rabbit heart, Y-25130 antagonized the indirect sympathomimetic responses to 5-HT (pA2 value = 10.06) and this effect was more potent than that of metoclopramide. In the isolated longitudinal smooth muscle of the guinea pig ileum, concentration-contraction effect curves for 5-HT were biphasic in the presence of ketanserin. Y-25130 shifted to the right only in the second phase of concentration-effect curves for 5-HT (pA2 value = 7.04) and its activity was more potent than that of metoclopramide. These results indicate that Y-25130 is a potent and selective 5-HT3 receptor antagonist.</abstract><cop>Kyoto</cop><pub>The Japanese Pharmacological Society</pub><pmid>1331590</pmid><doi>10.1254/jjp.59.443</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; Free Full-Text Journals in Chemistry
subjects 5-HT3 receptor
Acetylcholine - metabolism
Animals
Antiemetics - metabolism
Antiemetics - pharmacology
Biological and medical sciences
Bridged Bicyclo Compounds - metabolism
Bridged Bicyclo Compounds - pharmacology
Bridged Bicyclo Compounds, Heterocyclic
Cardiotonic Agents - pharmacology
Cerebral Cortex - drug effects
Cerebral Cortex - metabolism
Cerebral Cortex - ultrastructure
Guinea Pigs
Heart (isolated)
Heart - drug effects
Heart - physiology
Ileum (isolated)
Ileum - drug effects
Ileum - metabolism
Ileum - ultrastructure
In Vitro Techniques
Kinetics
Male
Medical sciences
Muscle Contraction - drug effects
Myocardial Contraction - drug effects
Myocardium - metabolism
Myocardium - ultrastructure
Nerve Fibers - drug effects
Nerve Fibers - metabolism
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Norepinephrine - metabolism
Oxazines - metabolism
Oxazines - pharmacology
Pharmacology. Drug treatments
Rabbits
Radioligand Assay
Receptors, Neurotransmitter - metabolism
Receptors, Serotonin - drug effects
Receptors, Serotonin - metabolism
Serotonin Antagonists
Serotoninergic system
Stimulation, Chemical
Sympathetic Nervous System - drug effects
Sympathetic Nervous System - metabolism
Y-25130
title Antagonistic Activity of Y-25130 on 5-HT3 Receptors
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