Dual agonism of FP and EP3 receptors by ricinoleic acid: Plausible therapeutic in glaucoma

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Aims/Purpose: Prostaglandin analogues used in glaucoma therapy act on prostaglandin F (FP) receptor to enhance the uveoscleral outflow, however they do not have affinity for prostaglandin E3 (EP3) receptors which are extensively present in iris‐ciliary body‐trabecular meshwork. Ricinoleic acid (RA) derived from the castor oil used as labor inducer as it causes EP3 receptor agonism and release of prostaglandins. This property of dual agonism, makes it an ideal candidate for ocular hypotensive therapy. Therefore, this study was designed to study the interaction RA with FP and EP3 receptor. Methods: The three‐dimensional structure modeling and docking was performed for FP and E3 receptor with ricinoleic acid and their respective positive controls. To study interaction of RA with FP and EP3 receptor, calcium binding and cAMP release assay were performed in ovarian, kidney, corneal epithelial and trabecular meshwork cell lines. The variable concentration of RA were compared to the positive and negative controls. The ovarian and trabecular meshwork cells supernatant were assessed for the levels of PGF2alpha using ELISA. Results: The in‐silico study showed RA higher binding affinity for EP3 receptor as compared to its natural (PGE2) and synthetic ligand (Misoprostol). The RA had comparatively less affinity for FP receptor compared to controls. In calcium release and cAMP assay, RA variable doses (10‐1000nM) were able to increase the release of calcium and decrease the cAMP levels in dose dependent manner. The dose response of RA for the EP3 agonism was significantly higher than latanoprost, and travoprost. The EP3 agonism by RA caused the release of PGF2alpha at lower levels, which plateaued after the 200nM dose. Conclusions: The study shows that at lower doses RA had higher interaction with EP3 but comparable affinity for FP receptors. The release of prostaglandin by EP3 agonism might be responsible for its dual agonism. The compound can be tested further for its hypotensive properties in glaucoma.

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