Pharmacological profile of UK-74,505, a novel and selective PAF antagonist with potent and prolonged oral activity.

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.

UK-74,505, a novel and selective PAF antagonist, exhibits potent and long lasting activity in vivo.

UK-74,505, a potent and selective PAF antagonist in vitro, has been shown to be extremely active given orally or intravenously to various species. In anaesthetised guinea pigs UK-74,505 at 30 & 100 micrograms/kg i.v. inhibited bronchoconstrictor responses to aerosolised PAF without affecting blood pressure or heart rate. The increased cutaneous vascular permeability to intradermal PAF in rats was inhibited by UK-74,505 with an ED50 of 280 +/- 5 micrograms/kg p.o. In conscious dogs, complete inhibition of PAF-induced whole blood aggregation ex-vivo occurred for at least 14 hours after an oral dose of 75 micrograms/kg. It is concluded that UK-74,505 is an effective, orally active PAF antagonist of long duration with the potential for once daily dosing.

Comparison of potency of alpha 2-adrenoceptor antagonists in vitro: evidence for heterogeneity of alpha 2-adrenoceptors.

A comparison has been made of affinity of alpha-adrenoceptor antagonists for alpha 2 binding sites in radioligand binding assays, and functional antagonist activity at pre- and postjunctional alpha 2-adrenoceptors in various in vitro preparations. The antagonists displaced [3H]-rauwolscine from rat brain and rabbit spleen membranes but there were substantial differences in rank order and absolute potency in the two tissues. pA2 values for yohimbine, phentolamine and Wy26703 against the selective alpha 2 agonist UK-14,304 were determined in the rat left atrium, rat and rabbit vas deferens and rabbit saphenous vein preparations. The pA2 values varied substantially between the tissues, differing by two orders of magnitude in the case of Wy26703. Yohimbine was more potent in rabbit preparations while Wy26703 was markedly more potent in all the rat preparations. Yohimbine and Wy26703 were compared in the dog saphenous vein preparation where pre- and postjunctional alpha 2 antagonist activity can be compared in the same tissue. As in the rabbit preparations, yohimbine was more potent than Wy26703 at both sites but the absolute potencies were different. It is concluded that alpha 2-adrenoceptors are a heterogeneous population, different subgroups being more apparent between species rather than between tissue types or location.

Comparison of activity of alpha-adrenoceptor agonists and antagonists in dog and rabbit saphenous vein.

The alpha adrenoceptors present on the saphenous vein of the dog and rabbit were characterised in vitro using the selective alpha 1 antagonist prazosin and the alpha 2 antagonists rauwolscine and yohimbine. In the dog saphenous vein, prazosin and rauwolscine competitively antagonised contractile responses to phenylephrine and UK-14,304 respectively. Noradrenaline was competitively blocked by prazosin only. In contrast, phenylephrine and methoxamine-induced responses in the rabbit saphenous vein were insensitive to prazosin and corynanthine. Rauwolscine competitively blocked responses to UK-14,304, noradrenaline and phenylephrine and pA2 values were similar against each agonist. Noradrenaline and UK-14,304 were equipotent agonists on the rabbit saphenous vein while in the dog vein noradrenaline has a lower potency than UK-14,304. These results suggest that the dog saphenous vein has a mixed population of alpha adrenoceptors, while the alpha adrenoceptors on the rabbit vein are homogeneous, with characteristics of the alpha 2 subtype.