Mj. Parry et al., PHARMACOLOGICAL PROFILE OF UK-74,505, A NOVEL AND SELECTIVE PAF ANTAGONIST WITH POTENT AND PROLONGED ORAL ACTIVITY, Journal of lipid mediators and cell signalling, 10(3), 1994, pp. 251-268
UK-74505, a novel 1,4-dihydropyridine PAF antagonist, exhibited highly
selective, time-dependent inhibition of PAF-induced aggregation of ra
bbit washed platelets (IC50 = 26.3 +/- 0.88 and 1.12 +/- 0.04 nM after
0.25 and 60 min preincubation, respectively), which became irreversib
le within 15 min, whereas inhibition by WEB-2086 was both independent
of preincubation time (IC50 = 145.7 +/- 24.7 nM) and competitive (K-I
= 27.5 +/- 7.7 nM; Schild slope = 0.98 +/- 0.04). The selective inhibi
tion of specific [H-3]PAF binding by UK-74,505 exhibited a slower onse
t, the IC50 obtained without preincubation (14.7 +/- 2.6 nM) decreasin
g 2-fold at 45 min. UK-74,505 was 450-fold weaker as an antagonist of
[H-3]nitrendipine binding to bovine brain membranes and KCl-induced co
ntraction of rat aorta. UK-74,505 was 10-30-fold more potent than WEB-
2086 in vivo as an inhibitor of PAF-induced hypotension in rats (ED(50
) = 35 +/- 5.8 mu g/kg, i.v.), cutaneous vascular permeability in guin
ea pigs (ED(50) = 0.37 +/- 0.08 mg/kg, p.o.) and lethality in mice, wi
th oral ED(50) values of 0.26 +/- 0.03 and 1.33 +/- 0.19 mg/kg at 2 an
d 8 h, respectively. These data demonstrate that UK-74,505 is a potent
, selective, long-acting irreversible PAF antagonist.