Studies on the Ocular Hypotensive Effects of Prostaglandin F2α Ester Prodrugs and Receptor Selective Prostaglandin Analogs
| Autor: | L. S. Williams, C.E. Fairbairn, A. Cheng-Bennett, Ming Fai Chan, Todd S. Gac, L. J. Kaplan, George Sachs, Charles Gluchowski, James A. Burke, R. A. Lawrence, Tanwir Shan, D.F. Woodward, G. Chen, M.E. Garst, Larry A. Wheeler, Michael B. Roof |
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| Rok vydání: | 1994 |
| Předmět: |
Male
genetic structures Prostaglandin f2 alpha Receptors Prostaglandin Ocular Hypotension Pharmacology Dinoprost Mice Dogs Prostaglandins Synthetic Animals Prodrugs Pharmacology (medical) Receptor Cells Cultured Intraocular Pressure Chemistry Cell Membrane Uterus Esters 3T3 Cells Prodrug eye diseases Rats Macaca fascicularis Ophthalmology Prostaglandin analog Biochemistry Myometrium cardiovascular system Female lipids (amino acids peptides and proteins) Rabbits sense organs |
| Zdroj: | Journal of Ocular Pharmacology and Therapeutics. 10:177-193 |
| ISSN: | 1557-7732 1080-7683 |
| Popis: | The use of natural prostaglandins (PG), such as PGD2, PGE2, PGF2 alpha, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation of ocular hypotensive activity from side effects is to employ ester prodrugs. From a novel series of 11- and 15-mono and 11,15-diacyl esters of PGF2 alpha we identified prodrugs where PGF2 alpha formation rates in the iris-ciliary body exceeded those in the conjunctiva, sclera, and corneal endothelium. Compared to PGF2 alpha-1-isopropyl ester the ocular tissue hydrolysis rates of the 11-monopivaloyl, the 11,15-dipivaloyl ester and the 1,11-lactone were up to 1000 fold less. Despite this large disparity in hydrolysis rates, the pivaloyl esters and the 1,11-lactone were potent ocular hypotensives in our animal models. In studying prostaglandin analogs, we found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys. These included DP-, EP1-, EP2-, EP3-, and FP-receptor selective compounds. These findings were surprising and prompted us to re-examine the receptor selectivity of these agonists by radioligand binding studies. Using radiolabelled PGE2, 17-phenyl PGF2 alpha, and sulprostone we were able to confirm the selectivity of the agonists currently used for receptor characterization directly by radioligand binding competition studies. It appears that multiple prostanoid receptor subtypes may be involved in regulating intraocular pressure. |
| Databáze: | OpenAIRE |
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