ICI 207968

Leukotrienes and thromboxane A₂ are autacoids derived from arachidonic acid (5,8,11,14-eicosatretraenoic acid).They are synthesized in cells by 5-lipoxygenase and thromboxane synthase, resp.Leukotrienes are related to inflammatory and allergic diseases, while thromboxane A₂ is a potent platelet aggregating and vasoconstrictor agent involved in cardiovascular pathologies.In this article the authors have calculated partial potential energy surfaces at the AM1 level for some 5-lipoxygenase inhibitors, thromboxane synthase inhibitors, thromboxane A₂ receptor antagonists, and a dual blocker which inhibits thromboxane synthase and antagonizes thromboxane A₂ receptor.The objective was to identify stereoelectronic properties and topog. requirements for these compounds that could be related to their biol. activities.Based on the results and on mol. mechanisms of pharmacol. action, the authors were able to propose new potential 5-lipoxygenase inhibitors and dual blockers derived from pyrazole, pyrrole, 1,2,3-triazole, and 1,2,4-triazole.

1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1β, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa.2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa.3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively.4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 × 10−11 mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media.5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely.6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions. Hence treatment with mepacrine seems a prospect worth pursuing.