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Shinsaku Yamane, Satoshi Nakayama, Tomohiro Karakawa, Shintaro Nakao, Tsutomu Shiroya, Yutaka Shichino; Agonist activity and binding affinity of ONO-9054 to EP3 and FP Receptors. Invest. Ophthalmol. Vis. Sci. 2013;54(15):766.
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© ARVO (1962-2015); The Authors (2016-present)
ONO-9054 (Ono Pharmaceuticals, Osaka Japan) is a novel prodrug compound. ONO-9054 is an isopropyl ester derivative of the free acid ONO-AG-367. The purpose of this study was to investigate the agonist activity and binding affinity of ONO-9054 and ONO-AG-367 to the prostaglandin receptors. To investigate the potential off-target effects of ONO-9054 and ONO-AG-367, the binding affinity for 66 receptors and transporters were studied.
The binding affinity of ONO-9054 and ONO-AG-367 to prostaglandin receptors (EP1, EP2, EP3, EP4, FP, IP, TP, and DP receptors) was assessed with cells over expressing each prostaglandin receptor. The agonist activities of ONO-9054 and ONO-AG-367 were examined using the intracellular calcium signaling response in EP3 or FP receptor-expressing cells. The binding affinity of ONO-9054 and ONO-AG-367 on 66 additional receptors and transporters were also assessed.
ONO-9054 exhibited high affinity for the FP receptor only and no affinity for any other prostaglandin receptors. ONO-AG-367 exhibited high affinity for both the EP3 and FP receptors. ONO-AG-367 exhibited potent agonist activity with EC50 values of 14.8 nmol/L for the EP3 receptor and 11.1 nmol/L for the FP receptor, respectively. ONO-9054 exhibited a low potency agonist effect on these receptors. ONO-9054 and ONO-AG-367 at 10 μmol/L did not produce greater than 35% inhibition of binding at any of the 66 other targets examined.
ONO-AG-367, the biologically active free acid of ONO-9054, is a highly selective and potent prostaglandin FP and EP3 receptor agonist. The agonist activity of ONO-AG-367 to FP receptor was similar to previously reported values of FP agonists such as latanoprost acid, bimatoprost acid, and travoprost acid. On the other hand, the agonist activity of ONO-AG-367 to EP3 receptor was more potent than these FP agonists.
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