Molecular pharmacology of the DP/EP2 class prostaglandin AL-6598 and quantitative autoradiographic visualization of DP and EP2 receptor sites in human eyes.

Abstract

DP-class prostaglandins and prostaglandin analogs (collectively, prostaglandins or PGs) such as PGD2, BW245C, ZK110841, and ZK118182, lower intraocular pressure (IOP) in animal models of ocular hypertension. A new analog of ZK118182 (AL-6556; 13,14-dihydro-ZK118182) was synthesized, and the isopropyl ester of AL-6556 (AL-6598) was shown recently to lower IOP in the ocular hypertensive cynomolgus monkey model of glaucoma and in human subjects. AL-6556 and AL-6598 had an affinity (Ki) of 2.66-4.43 microM for DP receptors but a much lower affinity (K(i)s = 38-103 microM) for EP3, FP, IP, and TP receptors (n = 3-5). In addition, AL-6556 and AL-6598 exhibited K(i)s > 100 microM for 19 nonprostanoid receptors. Both PGs stimulated cAMP production (EC50 = 1.07 +/- 0.1 microM and EC50 = 2.64 +/- 0.84 microM; n = 3) by way of DP receptors in embryonic bovine tracheal fibroblasts. While AL-6556 and AL-6598 were partial agonists (EC(50)s = 0.47-0.69 microM; E(max) = 35%-46%) at EP2 receptors in human nonpigmented epithelial cells, neither had any agonist activity at EP4, IP, or FP receptors. The DP antagonist, BWA868C, effectively antagonized the effects of AL-6556 with a high potency (IC50 = 22.8 +/- 3.9 nM; n = 3). DP receptors radiolabeled with [3H]BWA868C on human eye sections by quantitative autoradiography were highly concentrated in the ciliary process (CP), longitudinal (LCM) and circular (CCM) ciliary muscles, and iris with much lower specific binding in the cornea (CN), lens (LNS), and retina (RET). EP2 receptors labeled with [3H]PGE2 were concentrated in the LCM, CM, RET, and iris. In conclusion, AL-6598 and AL-6556 are relatively DP-receptor-selective PGs with full agonist activity at the DP and partial agonist activity at the EP2 receptor. The IOP-lowering activities of these compounds may involve both the inflow and outflow mechanisms, as DP and EP2 receptors were visualized in human ocular tissues involved in such aqueous humor dynamics.

• Authors: Naj A Sharif, Gary W Williams, Julie Y Crider, Shouxi X Xu, Terry L Davis
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 20 Issue 6 Pg. 489-508 (Dec 2004) ISSN: 1080-7683 [Print] United States
• PMID: 15684809 (Publication Type: Journal Article)

Chemical References

• 9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid
• AL 6598
• PTGER2 protein, human
• Ptger2 protein, mouse
• Receptors, Immunologic
• Receptors, Prostaglandin
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP2 Subtype
• ZK 118182
• Dinoprost
• Cyclic AMP
• prostaglandin D2 receptor

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Autoradiography (methods)
• Binding, Competitive
• Blood Platelets (drug effects, metabolism)
• Cattle
• Cell Line
• Cyclic AMP (biosynthesis)
• Dinoprost (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Eye (drug effects, metabolism)
• Female
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Intraocular Pressure (drug effects)
• Male
• Mice
• Middle Aged
• Radioligand Assay (methods)
• Receptors, Immunologic (metabolism)
• Receptors, Prostaglandin (metabolism)
• Receptors, Prostaglandin E (metabolism)
• Receptors, Prostaglandin E, EP2 Subtype
• Swiss 3T3 Cells