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M.J. Ogidigben, T. Yamakawa, S. Yufu, L.A. O'Neill–Davis, L.A. Hettrick; Subtype Selective Muscarinic Receptor Agonist With Ocular Hypotensive Properties . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2949.
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The objectives of this study were: 1) to determine, in vitro, the muscarinic receptor subtype selectivity of 1–[1'–(2–Tolyl)–1,4'–bipiperidin–4–yl]–1,3–dihydro–2H–benzimidazol–2–one (TBPB): and 2) to examine, in vivo, its effect on ocular hypotension and miosis.
Chinese hamster ovary (CHO) cells transfected with plasmid expressing human m1, m3, m4, and m5 were used to determine receptor selectivity of TBPB in a fluorometric imaging plate reader (FLPR) assay. Normotensive Dutch Belted rabbits were used to examine the effects of TBPB on intraocular pressure (IOP) and pupillary size upon topical application. In other studies, rabbits were dosed topically with TBPB in the absence and presence of pirenzepine, AF–DX 116 and 4–DAMP, M1, M2, and M3 receptor selective antagonists, respectively, to confirm the predominant muscarinic receptor subtype responsible for the ocular action of TBPB.
TBPB selectively activated m1 receptors with E–max of 91% compared to carbachol (100%) but no significant activation at other receptor subtypes were seen in this study. In contrast, pilocarpine did not show the selectivity exhibited by TBPB. Single, unilateral topical application of TBPB (25, 75, and 250 µg) elicited dose–dependent IOP reduction of 4.8, 6.3, and 7.0 mmHg, respectively, without change in pupillary size in Dutch Belted rabbits. The ocular hypotensive effect of TBPB (75 µg) was significantly antagonized (from 6.3 to 1.6 mmHg) by bilateral pretreatment with pirenzepine (750 µg), but not AF–DX 116 or 4–DAMP, suggesting predominant involvement of M1 receptors.
The in vitro and in vivo data demonstrated that TBPB is a selective M1 agonist that lowers IOP in rabbits without eliciting miosis.
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