AL-8810: A novel prostaglandin F-2 alpha analog with selective antagonist effects at the prostaglandin F-2 alpha (FP) receptor

A novel analog of prostaglandin F-2 alpha [AL-88101 (5Z, 13E)-(9S,11S,15R)- 9,15-dihydroxy-11-fluoro-15-(2-indanyl)-16,17, 18,19,20-pentanor-5,13-prost adienoic acid] has been discovered with uniquely low efficacy (E-max) at th e endogenous prostaglandin F-2 alpha receptors (FP receptors) of A7r5 rat t horacic aorta smooth muscle cells and Swiss mouse 3T3 fibroblasts, as assay ed by stimulation of phospholipase C activity. AL-8810 has weak agonist pot ency (EC50) of 261 +/- 44 nM (n = 3) and E-max = 19% (relative to the full FP receptor agonist cloprostenol) in A7r5 cells and EC50 of 186 +/- 63 nM ( n = 3) and E-max = 23% in3T3 fibroblasts. AL-8810 exhibited properties of a n apparent competitive antagonist, i.e., produced parallel dextral shifts o f the agonist concentration-response curves and no significant suppression of the maximal agonist-induced response, when the potent, selective FP rece ptor agonist fluprostenol was used. The inhibition parameters of AL-8810 we re: pA(2) = 6.68 +/- 0.23 and 6.34 +/- 0.09 (n = 3-4) for A7r5 cells and 3T 3 cells, respectively, with Schild slopes ranging from 0.80 to 0.92. AL-881 0 concentration-dependently antagonized the response to 100 nM fluprostenol (K-i = 426 +/- 63 nM; n = 5) in A7r5 cells. However, even at 10 mu M conce ntration, AL-8810 did not significantly inhibit functional responses of TP, DP, EP2, EP4, receptor subtypes in various cell lines. AL-8810 also did no t antagonize the phospholipase C-coupled V-1-vasopressin receptor in A7r5 c ells. These results suggest that AL-8810 is a unique, selective antagonist at the FP receptor, a heretofore unavailable pharmacological tool that shou ld be valuable for studying FP receptor-mediated functional responses in co mplex biological systems.