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BGC20‐1531, a novel, potent and selective prostanoid EP 4 receptor antagonist: a putative new treatment for migraine headache

2009; Wiley; Volume: 156; Issue: 2 Linguagem: Inglês

10.1111/j.1476-5381.2009.00027.x

1476-5381

KA Maubach, R E Davis, D.E. Clark, George W. Fenton, PM Lockey, KL Clark, AW Oxford, RM Hagan, Carol Routledge, R A Coleman,

Neuroscience of respiration and sleep

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.