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A series of phenyl-substituted analogues of prostaglandin F2 alpha (PGF2 alpha) were prepared and evaluated for ocular hypotensive effect and side effects in different animal models. In addition, the activity of the analogues on FP receptors was studied in vitro. The results were compared with those of PGF2 alpha and its isopropyl ester. The phenyl-substituted PGF2 alpha analogues exhibited good intraocular pressure reducing effect, were more selective, and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its isopropyl ester. The analogues exhibited high activity on FP receptors in a stereoselective manner for the 15 alpha-hydroxyl group.

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The vascular effects of PGE2, PGF2alpha and latanoprost acid on isolated bovine long posterior ciliary arteries and episcleral veins have been investigated using a small vessel myograph. PGE2 caused vasorelaxation both in the ciliary artery and episcleral vein (EC50: 7.9x10(-9) M and 2.1x10(-8) M respectively). Blockade of thromboxane receptors with GR 32191B, a TP receptor antagonist, shifted the concentration-response curves to the left in both preparations, probably indicating a slight co-stimulation of TP receptors in these vessels. Blockade of tachykinin NK-1 receptors had no effect on the PGE2 concentration-response curve. PGF2alpha caused a concentration dependent contraction in half of the ciliary arteries examined and relaxation in the other half. In the presence of the thromboxane receptor antagonist (GR 3211B) PGF2alpha always induced relaxation of the ciliary artery (EC50:1.3x10[-5] M). At higher concentrations PGF2alpha tended to slightly constrict the episcleral veins, but in the presence of the TP receptor antagonist (GR 32191B) only relaxation was observed. Latanoprost acid contracted the ciliary artery at concentrations above 10(-6) M. This effect was completely abolished by the TP receptor antagonist (GR 32191B). In the episcleral vein latanoprost acid induced a slight relaxation but in the presence of the TP receptor antagonist (GR 32191B) no effect was observed. These results indicate that PGE2 invariably induces vasorelaxation of bovine ciliary arteries and episcleral veins, whereas both PGF2alpha and latanoprost acid at high concentrations can cause vasoconstriction probably by stimulating TP receptors. PGF2alpha causes marked relaxation of both ciliary arteries and episcleral veins in the presence of the TP blocker which seems unlikely to be mediated by FP receptors.