Purpose: The aim of this study was to determine selected in vivo ocular properties of
AL-12182 (5,6-dihydro-4,5-didehydro-11-deoxy-11-oxa-16-(3-chlorophenoxy)-ω-tetranor-PGF2α
isopropyl ester) and the in vitro profile of its free acid, AL-12180.
Methods: Previously documented radioligand binding and functional assays involving human
ciliary muscle cells (h-CM), human trabecular meshwork (h-TM) and other cells, and
porcine ocular arteries were utilized. For in vivo procedures, we utilized rabbits, cats, and
nonhuman primates to measure hyperemia, pupil diameter, and intraocular pressure (IOP),
respectively.
Results: AL-12180 exhibited the highest affinity for the FP-receptor (Ki = 143 ± 36 nM) and
much lower affinity for DP-, EP3-, IP-, and TP-receptors, and for several nonprostanoid receptors,
enzymes, neurotransmitter uptake sites, ion channels, and other regulatory sites. AL-
12180 activated phospholipase C-mediated phosphoinositide hydrolysis (potency, EC50 =
13.7–42.7 nM) through the FP-receptor in a variety of cells, such as h-CM, h-TM cells, human
embryonic kidney cells expressing the cloned human ciliary body FP-receptor (HEK-FP),
mouse 3T3 cells, and rat vascular smooth muscle cells. AL-8810, an FP-antagonist, blocked the
effects of AL-12180 in h-CM cells (IC50 = 8.7 µM). AL-12180 also stimulated the mobilization
of intracellular Ca2+ ([Ca2+]i) in h-TM cells (EC50 = 111 ± 36 nM), h-CM cells (EC50 = 11 nM),
and in host cells expressing the cloned human ciliary body FP-receptor (EC50 = 5.9 ± 3.1 nM).
AL-12180 lacked significant agonist activity at DP-, EP2-, EP4-, IP-, and TP-receptors in cellbased
assays. However, AL-12180 contracted porcine central retinal and short posterior ciliary
arteries in vitro with micromolar potencies that appeared to involve TP-receptor activation.
in vivo, AL-12182 elicited dose-related hyperemia in the rabbit eye, miosis in the cat eye, and
ocular hypotension in the nonhuman primate eye.
Conclusions: AL-12180 is a relatively potent and selective FP-receptor agonist whose isopropyl
ester prodrug (AL-12182) lowers IOP by as much as 40% following topical ocular dosing
in a laser-induced nonhuman primate model of ocular hypertension.
