RT Journal Article
SR Electronic
T1 AL-8810: A Novel Prostaglandin F2α Analog with Selective Antagonist Effects at the Prostaglandin F2α (FP) Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1278
OP 1284
VO 290
IS 3
A1 Brenda W. Griffin
A1 Peter Klimko
A1 Julie Y. Crider
A1 Najam A. Sharif
YR 1999
UL http://jpet.aspetjournals.org/content/290/3/1278.abstract
AB A novel analog of prostaglandin F2α[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 F2α 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) andEmax = 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. The American Society for Pharmacology and Experimental Therapeutics