Abstract | BACKGROUND AND PURPOSE:
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. EXPERIMENTAL APPROACH:
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. KEY RESULTS:
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. CONCLUSIONS AND IMPLICATIONS:
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.
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Authors | K A Maubach, R J Davis, D E Clark, G Fenton, P M Lockey, K L Clark, A W Oxford, R M Hagan, C Routledge, R A Coleman |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 156
Issue 2
Pg. 316-27
(Jan 2009)
ISSN: 1476-5381 [Electronic] England |
PMID | 19154437
(Publication Type: Journal Article)
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Chemical References |
- N-(4-(4-(5-methoxypyridin-2-yl)phenoxymethyl)-5-methylfuran-2-carbonyl)-2-methylbenzenesulfonamide
- PTGER4 protein, human
- Pyridines
- Receptors, Prostaglandin E
- Receptors, Prostaglandin E, EP4 Subtype
- Recombinant Proteins
- Sulfonamides
- Vasodilator Agents
- Dinoprostone
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Topics |
- Adult
- Aged
- Animals
- Carotid Artery, Common
(drug effects, physiology)
- Cell Line
- Cerebral Arteries
(drug effects, physiology)
- Dinoprostone
(pharmacology)
- Dogs
- Dose-Response Relationship, Drug
- Female
- Humans
- In Vitro Techniques
- Male
- Meningeal Arteries
(drug effects, physiology)
- Middle Aged
- Migraine Disorders
(drug therapy)
- Muscle, Smooth, Vascular
(drug effects, physiology)
- Pyridines
(adverse effects, pharmacology, therapeutic use)
- Radioligand Assay
- Receptors, Prostaglandin E
(antagonists & inhibitors)
- Receptors, Prostaglandin E, EP4 Subtype
- Recombinant Proteins
(antagonists & inhibitors)
- Sulfonamides
(adverse effects, pharmacology, therapeutic use)
- Vasoconstriction
(drug effects)
- Vasodilator Agents
(adverse effects, pharmacology, therapeutic use)
- Young Adult
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