The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the Prostaglandin E2 human model of headache

Maria Antonova,Jes Olesen,Troels Wienecke,Messoud Ashina,Karen Maubach,Emma Thomas

doi:10.1007/s10194-011-0358-9

Abstract

Using a human Prostaglandin E2 (PGE2) model of headache, we examined whether a novel potent and selective EP4 receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy volunteers were randomly allocated to receive 200 and 400 mg BGC20-1531 and placebo, followed by a 25-min infusion of PGE2. We recorded headache intensity on a verbal rating scale, MCA blood flow velocity and STA diameter. There was no difference in headache response or prevention of the dilation of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE2 induced headache and dilatation in normal subjects.

Highlights

The arachidonic acid metabolite prostaglandin E2 (PGE2) plays an important physiological role in the human body including the regulation of vascular tone [1] and modulation of pain [2]
Using a human Prostaglandin E2 (PGE2) model of headache, we examined whether a novel potent and selective EP4 receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA)
There were no differences in baseline velocity in the middle cerebral artery (VMCA) between the left and the right side on all three study days

Summary

Introduction

The arachidonic acid metabolite prostaglandin E2 (PGE2) plays an important physiological role in the human body including the regulation of vascular tone [1] and modulation of pain [2]. Once activated by PGE2, EP1 and EP3 receptors mediate Ca2? PGE2, as a principal pro-inflammatory prostanoid, plays a role in nociceptive processing [7]. It has both direct activating and sensitizing effects on sensory neurones [8]. Increased levels of PGE2 caused up-regulation of the EP4 receptor subtype in rat sensory dorsal root ganglion (DRG) neurons, but not EP1 and EP3 receptor subtypes [9]. Given that sensitization of the sensory neurons mediated mainly through the EP4 receptors [10] it has been suggested that the prostanoid EP4 receptor may be a potential target for the treatment of pain [11]

Objectives

Methods

Results

Conclusion