Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies.
The receptors involved in the ocular hypotensive activity of prostaglandins (PG) E2 and F2 alpha in dogs and monkeys was investigated by examining the effects of putative receptor selective agonists on intraocular pressure. A diverse variety of receptor selective agonists lowered intraocular pressure in these species. Thus, FP-receptor agonists (17-phenyl PGF2 alpha, fluprostenol), agonists with potent activity at the EP3 receptor (MB 28767, sulprostone) and a prostanoid with activity at the EP2 receptor (11-deoxy PGE1) were all potent ocular hypotensives when administered as a single dose to dogs and monkeys or b.i.d. for 5 days in monkeys. These findings were regarded as surprising and prompted us to re-examine some aspects of the current classification for prostanoid receptors. At present certain receptor subtypes, notably EP2, EP3 and FP receptors, are defined only according to the potency rank order for agonists. In these studies, we employed radioligand binding studies to determine the degree of competition between prostanoid agonists claimed to be selective on the basis of functional assays. Competition studies with a diverse variety of prostanoids at the binding site for PGE2 and sulprostone on the myometrial plasma membrane prepared from the rat uterus were consistent with the presence of an EP3 receptor. Thus, EP3-receptor agonists (MB 28767 and sulprostone) potently inhibited PGE2 and sulprostone binding, whereas FP agonists (17-phenyl PGF2 alpha, fluprostenol), a DP agonist (BW 245C), an EP1 antagonist (AH 6809), an EP2 agonist (AH 13205) and TP-receptor ligands (BM 13505, I-BOP) afforded little or no inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Woodward
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DF
Allergan, Inc., Department of Biological Sciences, Irvine, CA 92713-9534.
Lawrence
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RA
Fairbairn
C E
CE
Shan
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Williams
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LS
D000818:Animals; D001667:Binding, Competitive; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D007429:Intraocular Pressure / Q000187:drug effects* / Q000502:physiology; D008252:Macaca fascicularis; D008297:Male; D011465:Prostaglandins, Synthetic / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D011982:Receptors, Prostaglandin / Q000145:classification / Q000187:drug effects* / Q000502:physiology
D011465:Prostaglandins, Synthetic; D011982:Receptors, Prostaglandin