Several N-benzylpiperazino derivatives of [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-one and its 5-methyl homologue have been prepared and evaluated for H1-antihistamine activity on guinea pig ileum. The most potent compounds were also evaluated for their ability to stabilize mast cells in the rat passive peritoneal anaphylaxis (PPA) system and were shown to inhibit histamine release at concentrations below those required to inhibit extravasation, suggesting that this might be relevant to their antianaphylactic activity in this system. The compound tested with the most potent H1-antihistamine activity was 6-[3-[4-(4-chlorobenzyl)-1-piperazinyl]propoxy][1]benzopyrano[2,3- d]-1,2,3-triazol-9(1H)-one, 28, which had a pA2 of 9.1 against histamine on guinea pig ileum, comparable to that of mepyramine, and inhibited histamine release in the rat PPA system with an IC50 value of 5.4 X 10(-6) M.

Mammalian angiotensin-converting enzyme (ACE ; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC &! of 0.47 µM, whereas TAPI-2 was slightly less potent (IC &! 18 µM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2h substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is related to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively

1 The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2 When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and lOmgkg-1) inhibited 5-hydroxytryptamine (5-HT)induced bronchospasm for at least 60min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84jigkg '. Nifedipine failed to show any protective effect up to lOO1gkg 1, i.v. and was lethal at higher dose levels. 3 Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4 Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (SOmg kg-', p.o.) was ineffective. 5 Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10-3M), of 1.1 x 10-6M and 8.9 x 10-7M, respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (-)-enantiomer.6 Nifedipine (2 x 10-SM) achieved only 49% of the relaxant effect of 10 -3M isoprenaline in isolated tracheal spirals. Addition of cromakalim (10-5 M) at the end of the nifedipine concentrationresponse experiment caused further relaxation to 94% of the effect of isoprenaline.7 It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.

A series of readily prepared monocyclic N-(4-methoxybenzyl)-v-triazoles (1 ) have been converted into their N-unsubstituted derivatives (2) by treatment with trifluoroacetic acid at 65 'C. The procedure allows the synthesis of a range of N-unsubstituted v-triazoles. Its applicability to multicyclic systems is demonstrated by the synthesis of 3,9-dihydro-9-oxobenzopyrano[2,3-d] -v-triazole (5b), one of a series of compounds of interest as potential sciences Research Centre,

The synthesis and biological activity of a number of 4-hydroxy-3-nitro-2-quinolones are discussed and compared with their related hydroaromatic analogs. Antiallergic activity has been assessed by their ability to inhibit the homocytotropic antibody-antigen induced passive cutaneous anaphylaxis reaction in the rat.