Attentuation of some effects of anaphylaxis by 1,18-diamino-6,13-diaza-9,10-dithiaoctadecane tetrahydrochloride (WR 149,024).

Abstract

S-[2 - (5-Aminopentyl) aminoethyl] -phosphorothioic acid (WR 2823) has been shown to be an alpha-adrenergic blocking agent (1, 2). This compound prevents mortality from hemorrhagic shock in dogs (3) and other species (4); it also prevents mortality and some of the cardiovascular effects of endotoxin in dogs (5, 6). We have speculated that the active form of WR 2823 is the symmetrical disulfide of the hydrolysis product of WR 2823 (2) —1, 18-diamino-6,13-diaza-9,10-dithiaoctadecane (WR 149,024). A small quantity of this compound was synthesized for biological testing. We have verified the alpha-adrenergic blocking properties of WR 149,024 (7). An anaphylactic shock model in mice was developed to test for efficacy of the compound in that type of cardiovascular crisis. The results of these studies show that pre-treatment of sensitized mice with WR 149, 024 can reduce the severity of the effects of anaphylaxis. Methods and Materials. WR 149,024 used in these experiments was synthesized by hydrolysis and oxidation of WR 2823 by Dr. D. L. Klayman, Department of Organic Chemistry, Division of Medicinal Chemistry, Walter Reed Army Institute of Research. This material occurred as a white, granular powder, very soluble in water. The chemical was dissolved in normal saline so that the volume of the injection was always 10 μl/g of body weight. All doses of WR 149,024 are expressed as the base. Random bred male ICR mice from the Walter Reed Colony were sensitized by the intraperitoneal injection of a 7.6% solution of egg white in saline (10 μl/g) on days 1, 3, and 5. On day 8, the challenge dose of egg albumin (760 mg/kg, ip) was given. The egg albumin solution was made daily from material purchased from Fisher Scientific Co.