AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties
The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic...
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| Veröffentlicht in: | Journal of ocular pharmacology and therapeutics 1995, Vol.11 (3), p.203-212 |
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| creator | KRAUSS, A. H.-P WOODWARD, D. F CHEN, J GIBSON, L. L LAI, R. K PROTZMAN, C. E SHAN, T WILLIAMS, L. S GAC, T. S BURK, R. M |
| description | The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activity was determined in vitro using different smooth muscle assays and platelets. Intraocular pressure was measured tonometrically in ocular normotensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascular permeability was determined in guinea pigs. Despite closely resembling U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 did not lower IOP in either species. The ocular hypotensive effect of AGN 191976 in dogs was attenuated by pretreatment with the TP receptor antagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA2-mimetics caused plasma leakage in the guinea pig conjunctiva. The disparate activities of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye. |
| doi_str_mv | 10.1089/jop.1995.11.203 |
| format | Article |
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H.-P ; WOODWARD, D. F ; CHEN, J ; GIBSON, L. L ; LAI, R. K ; PROTZMAN, C. E ; SHAN, T ; WILLIAMS, L. S ; GAC, T. S ; BURK, R. M</creator><creatorcontrib>KRAUSS, A. H.-P ; WOODWARD, D. F ; CHEN, J ; GIBSON, L. L ; LAI, R. K ; PROTZMAN, C. E ; SHAN, T ; WILLIAMS, L. S ; GAC, T. S ; BURK, R. M</creatorcontrib><description>The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activity was determined in vitro using different smooth muscle assays and platelets. Intraocular pressure was measured tonometrically in ocular normotensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascular permeability was determined in guinea pigs. Despite closely resembling U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 did not lower IOP in either species. The ocular hypotensive effect of AGN 191976 in dogs was attenuated by pretreatment with the TP receptor antagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA2-mimetics caused plasma leakage in the guinea pig conjunctiva. The disparate activities of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye.</description><identifier>ISSN: 1080-7683</identifier><identifier>EISSN: 1557-7732</identifier><identifier>DOI: 10.1089/jop.1995.11.203</identifier><identifier>PMID: 8590251</identifier><language>eng</language><publisher>Larchmont, NY: Liebert</publisher><subject>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid ; Aged ; Animals ; Antihypertensive Agents - pharmacology ; Biological and medical sciences ; Blood Platelets - drug effects ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Capillary Permeability - drug effects ; Conjunctiva - blood supply ; Dogs ; Eye ; Female ; Guinea Pigs ; Humans ; Hydrazines - pharmacology ; Intraocular Pressure - drug effects ; Macaca fascicularis ; Male ; Medical sciences ; Muscle, Smooth - drug effects ; Ocular Hypertension - chemically induced ; Ophthalmic Solutions ; Pharmacology. Drug treatments ; Platelet Aggregation - drug effects ; Prostaglandin Endoperoxides, Synthetic - pharmacology ; Pupil - drug effects ; Receptors, Thromboxane - antagonists & inhibitors ; Receptors, Thromboxane - metabolism ; Thromboxane A2 - analogs & derivatives ; Thromboxane A2 - metabolism ; Thromboxane A2 - pharmacology ; Tonometry, Ocular ; Vasoconstrictor Agents - pharmacology</subject><ispartof>Journal of ocular pharmacology and therapeutics, 1995, Vol.11 (3), p.203-212</ispartof><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>309,310,314,780,784,789,790,4050,4051,23930,23931,25140,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3709205$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8590251$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KRAUSS, A. H.-P</creatorcontrib><creatorcontrib>WOODWARD, D. F</creatorcontrib><creatorcontrib>CHEN, J</creatorcontrib><creatorcontrib>GIBSON, L. L</creatorcontrib><creatorcontrib>LAI, R. K</creatorcontrib><creatorcontrib>PROTZMAN, C. E</creatorcontrib><creatorcontrib>SHAN, T</creatorcontrib><creatorcontrib>WILLIAMS, L. S</creatorcontrib><creatorcontrib>GAC, T. S</creatorcontrib><creatorcontrib>BURK, R. M</creatorcontrib><title>AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties</title><title>Journal of ocular pharmacology and therapeutics</title><addtitle>J Ocul Pharmacol Ther</addtitle><description>The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activity was determined in vitro using different smooth muscle assays and platelets. Intraocular pressure was measured tonometrically in ocular normotensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascular permeability was determined in guinea pigs. Despite closely resembling U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 did not lower IOP in either species. The ocular hypotensive effect of AGN 191976 in dogs was attenuated by pretreatment with the TP receptor antagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA2-mimetics caused plasma leakage in the guinea pig conjunctiva. The disparate activities of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye.</description><subject>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid</subject><subject>Aged</subject><subject>Animals</subject><subject>Antihypertensive Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Blood Platelets - drug effects</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Capillary Permeability - drug effects</subject><subject>Conjunctiva - blood supply</subject><subject>Dogs</subject><subject>Eye</subject><subject>Female</subject><subject>Guinea Pigs</subject><subject>Humans</subject><subject>Hydrazines - pharmacology</subject><subject>Intraocular Pressure - drug effects</subject><subject>Macaca fascicularis</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Muscle, Smooth - drug effects</subject><subject>Ocular Hypertension - chemically induced</subject><subject>Ophthalmic Solutions</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Aggregation - drug effects</subject><subject>Prostaglandin Endoperoxides, Synthetic - pharmacology</subject><subject>Pupil - drug effects</subject><subject>Receptors, Thromboxane - antagonists & inhibitors</subject><subject>Receptors, Thromboxane - metabolism</subject><subject>Thromboxane A2 - analogs & derivatives</subject><subject>Thromboxane A2 - metabolism</subject><subject>Thromboxane A2 - pharmacology</subject><subject>Tonometry, Ocular</subject><subject>Vasoconstrictor Agents - pharmacology</subject><issn>1080-7683</issn><issn>1557-7732</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9j8FLwzAYxYMoc07PnoQcvLZ-SZqm8TaGTmHqRc_ja5OyjLYJSTfdf-_A4ek9-P148Ai5ZZAzqPTD1oecaS1zxnIO4oxMmZQqU0rw82OHCjJVVuKSXKW0BWACSjYhk0pq4JJNydt8-U6ZZlqVjxTp4Pe2o-Mm-r72PzhYOudZ73o7uoZ-u3FDfbPrMNLNIfjRDsntLQ3RBxtHZ9M1uWixS_bmlDPy9fz0uXjJVh_L18V8lQUmYcyYFrzgqJDzRhoudKmKAupaSwU1csEsoq2gMYURlYZCcKWNbk2tTNUqhWJG7v52w67urVmH6HqMh_Xp1pHfnzimBrs24tC49K8JBZqDFL8b51p3</recordid><startdate>1995</startdate><enddate>1995</enddate><creator>KRAUSS, A. H.-P</creator><creator>WOODWARD, D. F</creator><creator>CHEN, J</creator><creator>GIBSON, L. L</creator><creator>LAI, R. K</creator><creator>PROTZMAN, C. E</creator><creator>SHAN, T</creator><creator>WILLIAMS, L. S</creator><creator>GAC, T. S</creator><creator>BURK, R. M</creator><general>Liebert</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>1995</creationdate><title>AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties</title><author>KRAUSS, A. H.-P ; WOODWARD, D. F ; CHEN, J ; GIBSON, L. L ; LAI, R. K ; PROTZMAN, C. E ; SHAN, T ; WILLIAMS, L. S ; GAC, T. S ; BURK, R. M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p150t-193242a7a22c5d23967440bb9570ba231eaae80cd4d389043279d9fdb7d8f77a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid</topic><topic>Aged</topic><topic>Animals</topic><topic>Antihypertensive Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Blood Platelets - drug effects</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Capillary Permeability - drug effects</topic><topic>Conjunctiva - blood supply</topic><topic>Dogs</topic><topic>Eye</topic><topic>Female</topic><topic>Guinea Pigs</topic><topic>Humans</topic><topic>Hydrazines - pharmacology</topic><topic>Intraocular Pressure - drug effects</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Muscle, Smooth - drug effects</topic><topic>Ocular Hypertension - chemically induced</topic><topic>Ophthalmic Solutions</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation - drug effects</topic><topic>Prostaglandin Endoperoxides, Synthetic - pharmacology</topic><topic>Pupil - drug effects</topic><topic>Receptors, Thromboxane - antagonists & inhibitors</topic><topic>Receptors, Thromboxane - metabolism</topic><topic>Thromboxane A2 - analogs & derivatives</topic><topic>Thromboxane A2 - metabolism</topic><topic>Thromboxane A2 - pharmacology</topic><topic>Tonometry, Ocular</topic><topic>Vasoconstrictor Agents - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KRAUSS, A. H.-P</creatorcontrib><creatorcontrib>WOODWARD, D. F</creatorcontrib><creatorcontrib>CHEN, J</creatorcontrib><creatorcontrib>GIBSON, L. L</creatorcontrib><creatorcontrib>LAI, R. K</creatorcontrib><creatorcontrib>PROTZMAN, C. E</creatorcontrib><creatorcontrib>SHAN, T</creatorcontrib><creatorcontrib>WILLIAMS, L. S</creatorcontrib><creatorcontrib>GAC, T. S</creatorcontrib><creatorcontrib>BURK, R. M</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of ocular pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KRAUSS, A. H.-P</au><au>WOODWARD, D. F</au><au>CHEN, J</au><au>GIBSON, L. L</au><au>LAI, R. K</au><au>PROTZMAN, C. E</au><au>SHAN, T</au><au>WILLIAMS, L. S</au><au>GAC, T. S</au><au>BURK, R. M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties</atitle><jtitle>Journal of ocular pharmacology and therapeutics</jtitle><addtitle>J Ocul Pharmacol Ther</addtitle><date>1995</date><risdate>1995</risdate><volume>11</volume><issue>3</issue><spage>203</spage><epage>212</epage><pages>203-212</pages><issn>1080-7683</issn><eissn>1557-7732</eissn><abstract>The possible subdivision of thromboxane A2-sensitive (TP) receptors is currently a controversial subject. We report herein on a novel thromboxane A2 mimetic, AGN 191976, which has almost identical pharmacological activity to the well-characterized prostaglandin H2/thromboxane A2 (PGH2/TxA2) mimetic U-46619, but its effects on intraocular pressure are quite distinct from U-46619. Prostanoid receptor activity was determined in vitro using different smooth muscle assays and platelets. Intraocular pressure was measured tonometrically in ocular normotensive Beagle dogs and Cynomolgus monkeys. Conjunctival microvascular permeability was determined in guinea pigs. Despite closely resembling U-46619 as a potent and selective TP receptor agonist, AGN 191976 was a potent ocular hypotensive in dogs and monkeys whereas U-46619 did not lower IOP in either species. The ocular hypotensive effect of AGN 191976 in dogs was attenuated by pretreatment with the TP receptor antagonist SQ 29548. Thus, the ocular hypotensive effects of AGN 191976 are consistent with TP receptor stimulation. Both TxA2-mimetics caused plasma leakage in the guinea pig conjunctiva. The disparate activities of U-46619 and AGN 191976 in our studies suggest the existence of heterogeneous populations of TP-receptors in the eye.</abstract><cop>Larchmont, NY</cop><pub>Liebert</pub><pmid>8590251</pmid><doi>10.1089/jop.1995.11.203</doi><tpages>10</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1080-7683 |
| ispartof | Journal of ocular pharmacology and therapeutics, 1995, Vol.11 (3), p.203-212 |
| issn | 1080-7683 1557-7732 |
| language | eng |
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| source | Mary Ann Liebert Online Subscription; MEDLINE |
| subjects | 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid Aged Animals Antihypertensive Agents - pharmacology Biological and medical sciences Blood Platelets - drug effects Bridged Bicyclo Compounds, Heterocyclic - pharmacology Capillary Permeability - drug effects Conjunctiva - blood supply Dogs Eye Female Guinea Pigs Humans Hydrazines - pharmacology Intraocular Pressure - drug effects Macaca fascicularis Male Medical sciences Muscle, Smooth - drug effects Ocular Hypertension - chemically induced Ophthalmic Solutions Pharmacology. Drug treatments Platelet Aggregation - drug effects Prostaglandin Endoperoxides, Synthetic - pharmacology Pupil - drug effects Receptors, Thromboxane - antagonists & inhibitors Receptors, Thromboxane - metabolism Thromboxane A2 - analogs & derivatives Thromboxane A2 - metabolism Thromboxane A2 - pharmacology Tonometry, Ocular Vasoconstrictor Agents - pharmacology |
| title | AGN 191976: a novel thromboxane A2-mimetic with ocular hypotensive properties |
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