BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache
Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmaco...
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| Veröffentlicht in: | British journal of pharmacology 2009-01, Vol.156 (2), p.316 |
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| creator | Maubach, K A Davis, R J Clark, D E Fenton, G Lockey, P M Clark, K L Oxford, A W Hagan, R M Routledge, C Coleman, R A |
| description | Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist.
BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.
BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.
BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache. |
| doi_str_mv | 10.1111/j.1476-5381.2009.00027.x |
| format | Article |
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BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.
BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.
BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.</description><identifier>EISSN: 1476-5381</identifier><identifier>DOI: 10.1111/j.1476-5381.2009.00027.x</identifier><identifier>PMID: 19154437</identifier><language>eng</language><publisher>England</publisher><subject>Adult ; Aged ; Animals ; Carotid Artery, Common - drug effects ; Carotid Artery, Common - physiology ; Cell Line ; Cerebral Arteries - drug effects ; Cerebral Arteries - physiology ; Dinoprostone - pharmacology ; Dogs ; Dose-Response Relationship, Drug ; Female ; Humans ; In Vitro Techniques ; Male ; Meningeal Arteries - drug effects ; Meningeal Arteries - physiology ; Middle Aged ; Migraine Disorders - drug therapy ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - physiology ; Pyridines - adverse effects ; Pyridines - pharmacology ; Pyridines - therapeutic use ; Radioligand Assay ; Receptors, Prostaglandin E - antagonists & inhibitors ; Receptors, Prostaglandin E, EP4 Subtype ; Recombinant Proteins - antagonists & inhibitors ; Sulfonamides - adverse effects ; Sulfonamides - pharmacology ; Sulfonamides - therapeutic use ; Vasoconstriction - drug effects ; Vasodilator Agents - adverse effects ; Vasodilator Agents - pharmacology ; Vasodilator Agents - therapeutic use ; Young Adult</subject><ispartof>British journal of pharmacology, 2009-01, Vol.156 (2), p.316</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19154437$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maubach, K A</creatorcontrib><creatorcontrib>Davis, R J</creatorcontrib><creatorcontrib>Clark, D E</creatorcontrib><creatorcontrib>Fenton, G</creatorcontrib><creatorcontrib>Lockey, P M</creatorcontrib><creatorcontrib>Clark, K L</creatorcontrib><creatorcontrib>Oxford, A W</creatorcontrib><creatorcontrib>Hagan, R M</creatorcontrib><creatorcontrib>Routledge, C</creatorcontrib><creatorcontrib>Coleman, R A</creatorcontrib><title>BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache</title><title>British journal of pharmacology</title><addtitle>Br J Pharmacol</addtitle><description>Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist.
BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.
BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.
BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Carotid Artery, Common - drug effects</subject><subject>Carotid Artery, Common - physiology</subject><subject>Cell Line</subject><subject>Cerebral Arteries - drug effects</subject><subject>Cerebral Arteries - physiology</subject><subject>Dinoprostone - pharmacology</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Meningeal Arteries - drug effects</subject><subject>Meningeal Arteries - physiology</subject><subject>Middle Aged</subject><subject>Migraine Disorders - drug therapy</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - physiology</subject><subject>Pyridines - adverse effects</subject><subject>Pyridines - pharmacology</subject><subject>Pyridines - therapeutic use</subject><subject>Radioligand Assay</subject><subject>Receptors, Prostaglandin E - antagonists & inhibitors</subject><subject>Receptors, Prostaglandin E, EP4 Subtype</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Sulfonamides - adverse effects</subject><subject>Sulfonamides - pharmacology</subject><subject>Sulfonamides - therapeutic use</subject><subject>Vasoconstriction - drug effects</subject><subject>Vasodilator Agents - adverse effects</subject><subject>Vasodilator Agents - pharmacology</subject><subject>Vasodilator Agents - therapeutic use</subject><subject>Young Adult</subject><issn>1476-5381</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRS0kREvhF5A_oAl2YmdidlC1BakSLLqvJvakTdU4UeIWED9PeM7mSvcencUwxqWI5XC3-1gqyCKd5jJOhDCxECKB-O2Mjf-HEbvs-70QQwH6go2kkVqpFMbs42E5S0QkdSqnHLlvTnSY8rYJ5ANH73hPB7KhOhFvu6YP6JvK8fkL78hSG5pugAJuG1_14W4QtMeA37SnVx46wlB_mcoBrKtth5UnviN0aHd0xc5LPPR0_ZsTtl7M17PHaPW8fJrdr6ItGIhyWzqZOasKApXoAg1AqTWSS4TFPM1yyCUUaIsyLwDAKKlMojLtyKgE0nTCbn607bGoyW3arqqxe9_8PSH9BPdaXqE</recordid><startdate>200901</startdate><enddate>200901</enddate><creator>Maubach, K A</creator><creator>Davis, R J</creator><creator>Clark, D E</creator><creator>Fenton, G</creator><creator>Lockey, P M</creator><creator>Clark, K L</creator><creator>Oxford, A W</creator><creator>Hagan, R M</creator><creator>Routledge, C</creator><creator>Coleman, R A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>200901</creationdate><title>BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache</title><author>Maubach, K A ; Davis, R J ; Clark, D E ; Fenton, G ; Lockey, P M ; Clark, K L ; Oxford, A W ; Hagan, R M ; Routledge, C ; Coleman, R A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g797-8cfd16dc4be7425ba977f55aed20ca83687817bacbf8b777941492465de942733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Carotid Artery, Common - drug effects</topic><topic>Carotid Artery, Common - physiology</topic><topic>Cell Line</topic><topic>Cerebral Arteries - drug effects</topic><topic>Cerebral Arteries - physiology</topic><topic>Dinoprostone - pharmacology</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Meningeal Arteries - drug effects</topic><topic>Meningeal Arteries - physiology</topic><topic>Middle Aged</topic><topic>Migraine Disorders - drug therapy</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - physiology</topic><topic>Pyridines - adverse effects</topic><topic>Pyridines - pharmacology</topic><topic>Pyridines - therapeutic use</topic><topic>Radioligand Assay</topic><topic>Receptors, Prostaglandin E - antagonists & inhibitors</topic><topic>Receptors, Prostaglandin E, EP4 Subtype</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Sulfonamides - adverse effects</topic><topic>Sulfonamides - pharmacology</topic><topic>Sulfonamides - therapeutic use</topic><topic>Vasoconstriction - drug effects</topic><topic>Vasodilator Agents - adverse effects</topic><topic>Vasodilator Agents - pharmacology</topic><topic>Vasodilator Agents - therapeutic use</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maubach, K A</creatorcontrib><creatorcontrib>Davis, R J</creatorcontrib><creatorcontrib>Clark, D E</creatorcontrib><creatorcontrib>Fenton, G</creatorcontrib><creatorcontrib>Lockey, P M</creatorcontrib><creatorcontrib>Clark, K L</creatorcontrib><creatorcontrib>Oxford, A W</creatorcontrib><creatorcontrib>Hagan, R M</creatorcontrib><creatorcontrib>Routledge, C</creatorcontrib><creatorcontrib>Coleman, R A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>British journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maubach, K A</au><au>Davis, R J</au><au>Clark, D E</au><au>Fenton, G</au><au>Lockey, P M</au><au>Clark, K L</au><au>Oxford, A W</au><au>Hagan, R M</au><au>Routledge, C</au><au>Coleman, R A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache</atitle><jtitle>British journal of pharmacology</jtitle><addtitle>Br J Pharmacol</addtitle><date>2009-01</date><risdate>2009</risdate><volume>156</volume><issue>2</issue><spage>316</spage><pages>316-</pages><eissn>1476-5381</eissn><abstract>Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist.
BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.
BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo.
BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.</abstract><cop>England</cop><pmid>19154437</pmid><doi>10.1111/j.1476-5381.2009.00027.x</doi></addata></record> |
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| subjects | Adult Aged Animals Carotid Artery, Common - drug effects Carotid Artery, Common - physiology Cell Line Cerebral Arteries - drug effects Cerebral Arteries - physiology Dinoprostone - pharmacology Dogs Dose-Response Relationship, Drug Female Humans In Vitro Techniques Male Meningeal Arteries - drug effects Meningeal Arteries - physiology Middle Aged Migraine Disorders - drug therapy Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - physiology Pyridines - adverse effects Pyridines - pharmacology Pyridines - therapeutic use Radioligand Assay Receptors, Prostaglandin E - antagonists & inhibitors Receptors, Prostaglandin E, EP4 Subtype Recombinant Proteins - antagonists & inhibitors Sulfonamides - adverse effects Sulfonamides - pharmacology Sulfonamides - therapeutic use Vasoconstriction - drug effects Vasodilator Agents - adverse effects Vasodilator Agents - pharmacology Vasodilator Agents - therapeutic use Young Adult |
| title | BGC20-1531, a novel, potent and selective prostanoid EP receptor antagonist: a putative new treatment for migraine headache |
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