title: Pharmacological profile of UK-74,505, a novel and selective PAF antagonist with potent and prolonged oral activity.
abstract: UK-74505, a novel 1,4-dihydropyridine PAF antagonist, exhibited highly selective, time-dependent inhibition of PAF-induced aggregation of rabbit washed platelets (IC50 = 26.3 +/- 0.88 and 1.12 +/- 0.04 nM after 0.25 and 60 min preincubation, respectively), which became irreversible within 15 min, whereas inhibition by WEB-2086 was both independent of preincubation time (IC50 = 145.7 +/- 24.7 nM) and competitive (KI = 27.5 +/- 7.7 nM; Schild slope = 0.98 +/- 0.04). The selective inhibition of specific [3H]PAF binding by UK-74,505 exhibited a slower onset, the IC50 obtained without preincubation (14.7 +/- 2.6 nM) decreasing 2-fold at 45 min. UK-74,505 was 450-fold weaker as an antagonist of [3H]nitrendipine binding to bovine brain membranes and KCl-induced contraction 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 (ED50 = 35 +/- 5.8 micrograms/kg, i.v.), cutaneous vascular permeability in guinea pigs (ED50 = 0.37 +/- 0.08 mg/kg, p.o.) and lethality in mice, with oral ED50 values of 0.26 +/- 0.03 and 1.33 +/- 0.19 mg/kg at 2 and 8 h, respectively. These data demonstrate that UK-74,505 is a potent, selective, long-acting irreversible PAF antagonist.
authors: Pfizer Central Research, Sandwich, Kent, UK.
authors: M J
authors: MJ
authors: Parry
authors: V A
authors: VA
authors: Alabaster
authors: H E
authors: HE
authors: Cheeseman
authors: K
authors: K
authors: Cooper
authors: R N
authors: RN
authors: deSouza
authors: R F
authors: RF
authors: Keir
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001381:Azepines / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D020746:Calcium Channels, L-Type; D002199:Capillary Permeability / Q000187:drug effects; D002417:Cattle; D004095:Dihydropyridines / Q000494:pharmacology*; D004110:Diltiazem / Q000378:metabolism; D005711:Gallopamil / Q000378:metabolism; D006168:Guinea Pigs; D007022:Hypotension / Q000139:chemically induced / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000378:metabolism; D009568:Nitrendipine / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply; D014230:Triazoles / Q000494:pharmacology; D014316:Tritium
chemical_list: D001381:Azepines; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D007093:Imidazoles; D009124:Muscle Proteins; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; D014316:Tritium; C052518:WEB 2086; C073027:modipafant; D005711:Gallopamil; D011189:Potassium Chloride; D009568:Nitrendipine; D004110:Diltiazem