EP4 receptor agonists: the most promising novel bronchodilator for several decades

James Buckley1, Mark Birrell1, Sarah Maher1, Anthony Nials2, Deborah Clarke1, Maria Belvisi1. 1Respiratory Pharmacology, Imperial College London, London, SW7 2AZ, United Kingdom, 2GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, SG1 2NY, United Kingdom.

Due to recent safety concerns with beta 2 adrenoceptor agonists (e.g. salbutamol), there has been an ongoing attempt to identify novel bronchodilator agents for use in asthma and COPD. Due to its beneficial action on airway calibre, prostaglandin E2 (PGE2) was previously investigated as a potential therapy, however in addition to bronchodilator activity, in clinical studies PGE2 also produced tussive effects and bronchial irritancy. As PGE2 mediates its actions via a number of different prostanoid receptors, it was hoped that by selectively targeting individual receptors, the beneficial actions could be selected. In a previous study (Nials et al 1993), the EP2 receptor was identified as mediating PGE2-induced relaxation however when tested clinically, an EP2 agonist (AH13205) produced disappointing results.

To investigate the receptor involved in PGE2-induced airway smooth muscle relaxation, isolated tracheal tissue from a number of species (guinea pig, mouse, rat, Cyno monkey, human) was sutured to force-displacement transducers (Grass Instruments, U.S.A.) in 10ml organ baths containing 10µM indomethacin-treated Kreb’s Henseleit solution heated to 37˚C and bubbled with 95% O2/5% CO2. Contractile tone was induced using 1µM carbachol and selective prostanoid receptor agonists and antagonists were evaluated. In addition, the relaxation to PGE2 was investigated in tracheal segments from prostanoid receptor deficient mice.

The data produced showed that in guinea pig, mouse and Cyno monkey tracheal tissue, PGE2-induced relaxation is mediated by EP2 receptors. However in rat and human tissue, the EP4 receptor appears to mediate PGE2 induced relaxation. The two EP2 agonists tested failed to relax human airway samples and 10µM AH6809 (an EP1/EP2/DP selective antagonist) failed to inhibit PGE2-induced relaxation. Conversely, the EP4 agonist ONO-AE1-329 produced substantial relaxation (76.2 ± 8.6% max relaxation to 100µM papaverine) and two structurally different EP4 antagonists GW627368X and ONO-AE3-208 (both 1µM) both inhibited PGE2-induced relaxation.

These results therefore offer a potential explanation for the poor efficacy of the EP2 agonist (AH13205) in human subjects. In contrast to guinea pig tissue (where AH13205 produced the expected relaxant response), the EP4 receptor mediates PGE2-induced relaxation in human airways. Furthermore, as we have recently (Maher et al 2009) identified the EP3 receptor as mediating the tussive actions of PGE2, it appears possible that an EP4 agonist could potentially produce the beneficial actions of PGE2 in the absence of bronchial irritation or tussive effects. If this data is paralleled in clinical studies, targeting the EP4 receptor could produce the most promising novel bronchodilator for several decades.

1. Maher SA et al. Am J Respir Crit Care Med 2009; 180(10): 923-928.

2. Nials AT et al. Cardiovascular Drug Reviews, 1993; 11: 165-179.