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Vol. 290, Issue 3, 1278-1284, September 1999
Analog with
Selective Antagonist Effects at the Prostaglandin
F2 (FP) Receptor
Molecular Pharmacology Unit (B.W.G., J.Y.C., N.A.S.) and Medicinal
Chemistry Unit (P.K.), Alcon Laboratories, Inc., Fort Worth, Texas
A novel analog of prostaglandin F2
[AL-8810; (5Z,
13E)-(9S,11S,15R)-9,15-dihydroxy-11-fluoro-15-(2-indanyl)-16,17,18,19,20-pentanor-5,13-prostadienoic acid] has been discovered with uniquely low efficacy
(Emax) at the endogenous prostaglandin
F2 receptors (FP receptors) of A7r5 rat thoracic aorta
smooth muscle cells and Swiss mouse 3T3 fibroblasts, as assayed by
stimulation of phospholipase C activity. AL-8810 has weak agonist
potency (EC50) of 261 ± 44 nM (n = 3) and Emax = 19% (relative to the
full FP receptor agonist cloprostenol) in A7r5 cells and
EC50 of 186 ± 63 nM (n = 3) and Emax = 23% in 3T3 fibroblasts. AL-8810
exhibited properties of an apparent competitive antagonist, i.e.,
produced parallel dextral shifts of the agonist concentration-response
curves and no significant suppression of the maximal agonist-induced
response, when the potent, selective FP receptor agonist fluprostenol
was used. The inhibition parameters of AL-8810 were:
pA2 = 6.68 ± 0.23 and 6.34 ± 0.09 (n = 3-4) for A7r5 cells and 3T3 cells,
respectively, with Schild slopes ranging from 0.80 to 0.92. AL-8810
concentration-dependently antagonized the response to 100 nM
fluprostenol (Ki = 426 ± 63 nM;
n = 5) in A7r5 cells. However, even at 10 µM
concentration, AL-8810 did not significantly inhibit functional
responses of TP, DP, EP2, EP4, receptor
subtypes in various cell lines. AL-8810 also did not antagonize the
phospholipase C-coupled V1-vasopressin receptor in A7r5
cells. These results suggest that AL-8810 is a unique, selective
antagonist at the FP receptor, a heretofore unavailable pharmacological
tool that should be valuable for studying FP receptor-mediated
functional responses in complex biological systems.
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