Prostaglandin E2 is a lipid mediator that contributes to inflammatory pain. Selective inhibitors of microsomal PGE synthase-1 and subtype-selective antagonists of PGE2 receptors, particularly EP1 and EP4, may be useful as analgesics with minimized side-effects. Additionally, protein kinase C and PKA downstream of EP1 and EP4, respectively, sensitize/activate multiple molecules including transient receptor potential vanilloid-1 (TRPV1) channels, purinergic P2X3 receptors, and voltage-gated calcium or sodium channels in nociceptors, leading to hyperalgesia. PGE2 is also implicated in neuropathic and visceral pain and in migraine. Thus, PGE2 has a great impact on pain signals, and pharmacological intervention in upstream and downstream signals of PGE2 may serve as novel therapeutic strategies for the treatment of intractable pain.
Notably, Healy et al identified a novel EP4 receptor partial agonist GSK726701A. It has high selectivity against a set of other prostaglandin receptors, such as EP1-3, DP1, FP, IP, TP. It has no significant activity against a wider panel of targets.
This compound demonstrates EP4 agonist activity with similar potency and intrinsic activity in a human whole blood assay on the inhibition of LPS-mediated TNFα induction. This supports the potent anti-inflammatory potential of EP4 agonists. They also examined GSK726701A in the chronic constriction injury (CCI) model of neuropathic pain. At 3mg/kg, twice daily for 8 days, animal model demonstrated a time-dependant, full reversal of CCI-induced mechanical allodynia . This is equivalent to the clinical gold standard gabapentin (30mg/kg). Moreover, GSK726701A demonstrates robust activity in a range of pre-clinical models of pain. The data shows this mechanism has the potential to offer an alternative therapeutic approach in the treatment of pain and inflammatory conditions.