Effect of IVT administration of various non-peptide B1- and B2-receptor antagonists on Dutch-belt rabbit IOP

Table 2: Effect of IVT administration of various non-peptide B1- and B2-receptor antagonists on Dutch-belt rabbit IOP

Time Post-Dosing (Hours)	Change in IOP (% relative to baseline) by Compound (50μg [0.16%] IVT)
	(S)-WIN-64338	FR-165649	FR-173657	LF23-1591
	(B₂-selective)	(B₂-selective)	(B₂-selective)	(B₁-selective)
4	-4.1 ± 1.7%	-0.2 ± 1.8%	-22.9 ± 4.5%	2.9 ± 5.1%
5	-7.4 ± 2.3%	0.6 ± 1.4%	nd	5.4 ± 4.2%
6	-7.7 ± 3.8%	-1.0 ± 2.0%	-7.6 ± 3.2%	9.6 ± 4.0%
8	-15.9 ± 4.9%^*	-4.2 ± 1.2%	-15.9 ± 4.9%	5.4 ± 2.8%
24	-35.3 ± 4.0%^**	-6.5 ± 2.5%	-13.2 ± 4.2%	1.3 ± 3.0%
30	-45.6 ± 2.9%^**	-9.4 ± 4.0%	-12.7 ± 2.8%	4.3 ± 3.3%
48	-43.2 ± 4.0%^**	-10.8 ± 3.4%	-9.2 ± 2.9%	-13.8 ± 5.6%
72	-47.4 ± 2.9%^**	nd	nd	nd
168	-16.2 ± 2.3%^*	nd	nd	nd

Receptor Antagonist Potencies (IC₅₀s)	298 ± 81 nM (n=3)	195 ± 80 nM (n=6)	323 ± 150 nM (n=6)	nd

Data are mean ± SEM from 7-10 rabbits per group. The mean baseline IOP of these animals ranged from 27.5 ± 0.4 to 28.4 ± 0.4mmHg during the course of these studies. The vehicle had minimal effect on IOP as shown in Figure 2. No effects on IOP of (S)-WIN-64338 ivt were observed in the contralateral eyes. The receptor antagonist potencies refer to the non-equilibrium blocking effects of the antagonists of BK-induced [Ca²⁺]i mobilization in isolated primary h-TM, h-CM and ih-NPE cells to illustrate the differences in relative affinities of the compounds for their respective BK-receptor sub-type(s), primarily the B2-receptor. ^*p<0.01; ^**p<0.001 relative to vehicle baseline IOP or relative to IOP at 4 h post-dose. nd denotes not determined. IOP-lowering data for 10μMg (0.033%) ivt injection of (S)-WIN-64338 are shown in the Results section.