Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model
The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK 3 receptors were found in the rat bladder, the empha...
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| Veröffentlicht in: | Pharmacology 2002-05, Vol.65 (2), p.96-102 |
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| creator | Choppin, Agnes Groke, Gretchen Bringas, Analyn Stepan, George Dillon, Michael P. |
| description | The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK 3 receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK 2 (pK i = 9.94 ± 0.03) and NK 1 (pK i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK 1 (pK i = 8.08 ± 0.07) and NK 2 (pK i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK 2 receptor agonist, [βAla 8 ]neurokinin A (4–10) (10 µg·kg –1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg –1 ) of YM-44781 and YM-44778 (IC 50 = 27 ± 8 and 100 ± 44 µg· kg –1 , respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC 50 = 11 ± 7 µg·kg –1 ) of the contraction of the rat urinary bladder induced by challenge with the NK 1 -selective receptor agonist [Sar 9 ,Met(O 2 ) 11 ]substance P sulphone (0.3 µg·kg –1 ). YM-44781 and YM-44778 did not produce major inhibition of [Sar 9 ,Met(O 2 ) 11 ]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK 2 and NK 1 receptor antagonists, respectively, whereas YM-44778 is a nonselective NK 2 /NK 1 receptor antagonist in the drug-induced bladder contraction model. |
| doi_str_mv | 10.1159/000056193 |
| format | Article |
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Since no functional NK 3 receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK 2 (pK i = 9.94 ± 0.03) and NK 1 (pK i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK 1 (pK i = 8.08 ± 0.07) and NK 2 (pK i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK 2 receptor agonist, [βAla 8 ]neurokinin A (4–10) (10 µg·kg –1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg –1 ) of YM-44781 and YM-44778 (IC 50 = 27 ± 8 and 100 ± 44 µg· kg –1 , respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC 50 = 11 ± 7 µg·kg –1 ) of the contraction of the rat urinary bladder induced by challenge with the NK 1 -selective receptor agonist [Sar 9 ,Met(O 2 ) 11 ]substance P sulphone (0.3 µg·kg –1 ). YM-44781 and YM-44778 did not produce major inhibition of [Sar 9 ,Met(O 2 ) 11 ]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK 2 and NK 1 receptor antagonists, respectively, whereas YM-44778 is a nonselective NK 2 /NK 1 receptor antagonist in the drug-induced bladder contraction model.</description><identifier>ISSN: 0031-7012</identifier><identifier>EISSN: 1423-0313</identifier><identifier>DOI: 10.1159/000056193</identifier><identifier>PMID: 11937780</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Animals ; Binding, Competitive ; CHO Cells ; Cricetinae ; Dipeptides - metabolism ; Dipeptides - pharmacology ; Female ; Indoles - metabolism ; Indoles - pharmacology ; Muscle Contraction - drug effects ; Neurokinin A - analogs & derivatives ; Neurokinin A - pharmacology ; Neurokinin-1 Receptor Antagonists ; Original Paper ; Peptide Fragments - pharmacology ; Piperidines - metabolism ; Piperidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Neurokinin-1 - genetics ; Receptors, Neurokinin-1 - metabolism ; Receptors, Neurokinin-2 - antagonists & inhibitors ; Receptors, Neurokinin-2 - genetics ; Receptors, Neurokinin-2 - metabolism ; Receptors, Neurokinin-3 - antagonists & inhibitors ; Receptors, Neurokinin-3 - genetics ; Receptors, Neurokinin-3 - metabolism ; Receptors, Tachykinin - antagonists & inhibitors ; Receptors, Tachykinin - metabolism ; Spiro Compounds - metabolism ; Spiro Compounds - pharmacology ; Transfection ; Urinary Bladder - drug effects ; Urinary Bladder - physiology</subject><ispartof>Pharmacology, 2002-05, Vol.65 (2), p.96-102</ispartof><rights>2002 S. Karger AG, Basel</rights><rights>Copyright 2002 S. Karger AG, Basel</rights><rights>Copyright (c) 2002 S. Karger AG, Basel</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c329t-78cdcbdcff48b0cfc64afba75b7e70fc8c2852e684e5097d0e23ad6dd184e8253</citedby><cites>FETCH-LOGICAL-c329t-78cdcbdcff48b0cfc64afba75b7e70fc8c2852e684e5097d0e23ad6dd184e8253</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,2429,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11937780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choppin, Agnes</creatorcontrib><creatorcontrib>Groke, Gretchen</creatorcontrib><creatorcontrib>Bringas, Analyn</creatorcontrib><creatorcontrib>Stepan, George</creatorcontrib><creatorcontrib>Dillon, Michael P.</creatorcontrib><title>Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model</title><title>Pharmacology</title><addtitle>Pharmacology</addtitle><description>The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK 3 receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK 2 (pK i = 9.94 ± 0.03) and NK 1 (pK i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK 1 (pK i = 8.08 ± 0.07) and NK 2 (pK i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK 2 receptor agonist, [βAla 8 ]neurokinin A (4–10) (10 µg·kg –1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg –1 ) of YM-44781 and YM-44778 (IC 50 = 27 ± 8 and 100 ± 44 µg· kg –1 , respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC 50 = 11 ± 7 µg·kg –1 ) of the contraction of the rat urinary bladder induced by challenge with the NK 1 -selective receptor agonist [Sar 9 ,Met(O 2 ) 11 ]substance P sulphone (0.3 µg·kg –1 ). YM-44781 and YM-44778 did not produce major inhibition of [Sar 9 ,Met(O 2 ) 11 ]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK 2 and NK 1 receptor antagonists, respectively, whereas YM-44778 is a nonselective NK 2 /NK 1 receptor antagonist in the drug-induced bladder contraction model.</description><subject>Animals</subject><subject>Binding, Competitive</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Dipeptides - metabolism</subject><subject>Dipeptides - pharmacology</subject><subject>Female</subject><subject>Indoles - metabolism</subject><subject>Indoles - pharmacology</subject><subject>Muscle Contraction - drug effects</subject><subject>Neurokinin A - analogs & derivatives</subject><subject>Neurokinin A - pharmacology</subject><subject>Neurokinin-1 Receptor Antagonists</subject><subject>Original Paper</subject><subject>Peptide Fragments - pharmacology</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Neurokinin-1 - genetics</subject><subject>Receptors, Neurokinin-1 - metabolism</subject><subject>Receptors, Neurokinin-2 - antagonists & inhibitors</subject><subject>Receptors, Neurokinin-2 - genetics</subject><subject>Receptors, Neurokinin-2 - metabolism</subject><subject>Receptors, Neurokinin-3 - antagonists & inhibitors</subject><subject>Receptors, Neurokinin-3 - genetics</subject><subject>Receptors, Neurokinin-3 - metabolism</subject><subject>Receptors, Tachykinin - antagonists & inhibitors</subject><subject>Receptors, Tachykinin - metabolism</subject><subject>Spiro Compounds - metabolism</subject><subject>Spiro Compounds - pharmacology</subject><subject>Transfection</subject><subject>Urinary Bladder - drug effects</subject><subject>Urinary Bladder - physiology</subject><issn>0031-7012</issn><issn>1423-0313</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpd0UtLxDAQAOAgiq6Pg2dBAoIgbDWPtkmPur4WfFz04KmkeazVbrImrbD_3qwtK5jLZIZvhpAB4BCjc4yz4gLFk-W4oBtghFNCE0Qx3QQjFGPCECY7YDeEj6hywvg22MHRMsbRCLQ3xmjZQmfg22OSpozj8XBjHAqrfpMiK_gYPrlv3cAXId-Xn7WtLby0rZg5W4c2jGHMBbz23SyZWtVJreBVI5TSHk6cbb2Qbe0sfHRKN_tgy4gm6IMh7oHX25uXyX3y8Hw3nVw-JJKSok0Yl0pWShqT8gpJI_NUmEqwrGKaISO5JDwjOuepzlDBFNKECpUrhWOFk4zugdN-7sK7r06HtpzXQeqmEVa7LpQMZxyniER48g9-uM7b-LYSo7wglLJipc56Jb0LwWtTLnw9F34ZUblaRLleRLTHw8Summv1J4efj-CoB5_Cz7Rfg779BzkPh20</recordid><startdate>20020501</startdate><enddate>20020501</enddate><creator>Choppin, Agnes</creator><creator>Groke, Gretchen</creator><creator>Bringas, Analyn</creator><creator>Stepan, George</creator><creator>Dillon, Michael P.</creator><general>S. Karger AG</general><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>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20020501</creationdate><title>Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model</title><author>Choppin, Agnes ; Groke, Gretchen ; Bringas, Analyn ; Stepan, George ; Dillon, Michael P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c329t-78cdcbdcff48b0cfc64afba75b7e70fc8c2852e684e5097d0e23ad6dd184e8253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Animals</topic><topic>Binding, Competitive</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Dipeptides - metabolism</topic><topic>Dipeptides - pharmacology</topic><topic>Female</topic><topic>Indoles - metabolism</topic><topic>Indoles - pharmacology</topic><topic>Muscle Contraction - drug effects</topic><topic>Neurokinin A - analogs & derivatives</topic><topic>Neurokinin A - pharmacology</topic><topic>Neurokinin-1 Receptor Antagonists</topic><topic>Original Paper</topic><topic>Peptide Fragments - pharmacology</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Neurokinin-1 - genetics</topic><topic>Receptors, Neurokinin-1 - metabolism</topic><topic>Receptors, Neurokinin-2 - antagonists & inhibitors</topic><topic>Receptors, Neurokinin-2 - genetics</topic><topic>Receptors, Neurokinin-2 - metabolism</topic><topic>Receptors, Neurokinin-3 - antagonists & inhibitors</topic><topic>Receptors, Neurokinin-3 - genetics</topic><topic>Receptors, Neurokinin-3 - metabolism</topic><topic>Receptors, Tachykinin - antagonists & inhibitors</topic><topic>Receptors, Tachykinin - metabolism</topic><topic>Spiro Compounds - metabolism</topic><topic>Spiro Compounds - pharmacology</topic><topic>Transfection</topic><topic>Urinary Bladder - drug effects</topic><topic>Urinary Bladder - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choppin, Agnes</creatorcontrib><creatorcontrib>Groke, Gretchen</creatorcontrib><creatorcontrib>Bringas, Analyn</creatorcontrib><creatorcontrib>Stepan, George</creatorcontrib><creatorcontrib>Dillon, Michael P.</creatorcontrib><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>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma 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</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</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>MEDLINE - Academic</collection><jtitle>Pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choppin, Agnes</au><au>Groke, Gretchen</au><au>Bringas, Analyn</au><au>Stepan, George</au><au>Dillon, Michael P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model</atitle><jtitle>Pharmacology</jtitle><addtitle>Pharmacology</addtitle><date>2002-05-01</date><risdate>2002</risdate><volume>65</volume><issue>2</issue><spage>96</spage><epage>102</epage><pages>96-102</pages><issn>0031-7012</issn><eissn>1423-0313</eissn><abstract>The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK 3 receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK 2 (pK i = 9.94 ± 0.03) and NK 1 (pK i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK 1 (pK i = 8.08 ± 0.07) and NK 2 (pK i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK 2 receptor agonist, [βAla 8 ]neurokinin A (4–10) (10 µg·kg –1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg –1 ) of YM-44781 and YM-44778 (IC 50 = 27 ± 8 and 100 ± 44 µg· kg –1 , respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC 50 = 11 ± 7 µg·kg –1 ) of the contraction of the rat urinary bladder induced by challenge with the NK 1 -selective receptor agonist [Sar 9 ,Met(O 2 ) 11 ]substance P sulphone (0.3 µg·kg –1 ). YM-44781 and YM-44778 did not produce major inhibition of [Sar 9 ,Met(O 2 ) 11 ]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK 2 and NK 1 receptor antagonists, respectively, whereas YM-44778 is a nonselective NK 2 /NK 1 receptor antagonist in the drug-induced bladder contraction model.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>11937780</pmid><doi>10.1159/000056193</doi><tpages>7</tpages></addata></record> |
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| subjects | Animals Binding, Competitive CHO Cells Cricetinae Dipeptides - metabolism Dipeptides - pharmacology Female Indoles - metabolism Indoles - pharmacology Muscle Contraction - drug effects Neurokinin A - analogs & derivatives Neurokinin A - pharmacology Neurokinin-1 Receptor Antagonists Original Paper Peptide Fragments - pharmacology Piperidines - metabolism Piperidines - pharmacology Rats Rats, Sprague-Dawley Receptors, Neurokinin-1 - genetics Receptors, Neurokinin-1 - metabolism Receptors, Neurokinin-2 - antagonists & inhibitors Receptors, Neurokinin-2 - genetics Receptors, Neurokinin-2 - metabolism Receptors, Neurokinin-3 - antagonists & inhibitors Receptors, Neurokinin-3 - genetics Receptors, Neurokinin-3 - metabolism Receptors, Tachykinin - antagonists & inhibitors Receptors, Tachykinin - metabolism Spiro Compounds - metabolism Spiro Compounds - pharmacology Transfection Urinary Bladder - drug effects Urinary Bladder - physiology |
| title | Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model |
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