The prostaglandin E₂ EP₄ receptor : the elucidation of agonist mediated receptor regulation and a novel therapeutic role for an EP₄ agonist in allergic lung inflammation

Prostaglandin (PG) E2 is involved in a number of physiological and path op hysiologicaI events in many tissues. PGE2 mediates its actions through interaction with specific plasma-membrane G-protein coupled receptors (GPCR's). There are four subtypes of PGE2 receptors: EP1, EP2, EP3 and EP4, classified by their different pharmacological profiles and signal transduction pathways. EP4 agonists have potential therapeutic benefit in diseases such as osteoporosis (EP4 mediates the bone anabolic actions of PGE 2), but possibly in other areas such as asthma. A characteristic feature of GPCR's is their ability to undergo agonist-induced desensitization and this response may limit the therapeutic utility of agonists due to tachyphylaxis. This thesis outlines [1] the agonist-induced regulation of EP4 by PGE2; [2] the development of a novel selective agonist of EP 4 that also mediates EP4 desensitization; and [3] the discovery of a new role for EP4 in mouse models of allergic lung inflammation by employing this selective agonist. PGE2 challenge of EP 4 in human embryonic kidney cells results in desensitization of intracellular signalling responses (cAMP), phosphorylation independent of protein kinase A and sequestration. These events are mediated by sequences in the carboxyl-terminal tail of EP4. EP4 agonists were discovered by preparing analogues of PGE2 by replacing the hydroxycyclopentanone ring by a lactam. Optimized compound (19a) shows high potency at EP4 and is highly selective over the other seven prostaglandin receptors. In vivo stability was increased further by the addition of a gem di-fluro group on carbon 15 of the molecule. The resulting compound, EP 4_Ags, was employed to selectively elucidate the role of EP4 in mouse models of allergic lung inflammation. The EP4 agonist prevents ovalbumin (OVA)-induced inflammation, airways hyperreactivity (AHR) and T helper (Th) 2 cytokine increases. While interleukin (IL)-13-induced inflammation is not inhibited by the EP4 agonist, AHR is attenuated. These results demonstrate that an EP4 agonist has potent anti-inflammatory activity in a mouse model of allergen-induced lung inflammation. Additionally, EP4 may have effects on AHR independent of its anti-inflammatory activity. Interestingly, the rapid desensitization observed in-vitro did not appear to limit efficacy in-vivo. The role of EP4 in mouse models of allergic lung inflammation is a novel finding and the use of an EP4 agonist may have therapeutic benefit in the treatment of asthma.

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