metiamide and oxmetidine

Suspensions of rat liver hepatocytes exposed to oxmetidine rapidly lose viability, an event preceded by a marked and rapid inhibition of cell respiration and depletion of ATP. In isolated rat liver mitochondria (RLM), oxmetidine inhibits pyruvate/malate- but not succinate-supported, ADP-stimulated oxygen consumption (state 3). The purpose of this investigation was to determine the exact molecular site of oxmetidine-induced inhibition of RLM electron transport. Oxmetidine did not significantly inhibit succinate-supported, ADP-stimulated state 3 oxygen consumption in isolated RLM at concentrations up to 0.5 mM. In contrast, oxmetidine significantly inhibited beta-hydroxybutyrate- or isocitrate-supported mitochondrial state 3 oxygen consumption at concentrations above 10 microM and 25 microM, respectively. In RLM electron transport particles (ETP), oxmetidine inhibited NADH-oxidase and NADH-CoQ reductase activity (IC50 of 3.4 microM and 2.6 microM, respectively). However, oxmetidine did not significantly affect NADH-Fe3(CN)6 reductase activity (at concentrations up to 200 microM). SK&F 92058, a thiourea analog of oxmetidine approximately 24-fold less toxic to hepatocytes, produced a similar pattern of inhibition of respiration, although far less potent (IC50 of 0.8 mM and 0.6 mM for NADH-oxidase and NADH-CoQ reductase, respectively). SK&F 92058 did not significantly inhibit NADH-Fe3(CN)6 reductase activity at concentrations up to 3.0 mM. Studies with [14C]oxmetidine failed to show any specific, saturable binding to rat liver ETP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Electron Transport; Histamine H2 Antagonists; Imidazoles; Metiamide; Mitochondria, Liver; Oxidation-Reduction; Oxygen Consumption; Rats

Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity. Six histamine receptor H2-antagonists were tested. The minimum drug concentrations that caused 100% cell death (leakage of intracellular lactate dehydrogenase and loss of intracellular potassium) ranged from 0.87 to 22.50 mM for the analogs tested. At toxic concentrations, two of the least potent analogs, SK&F 92909 and SK&F 9205A both caused a rapid decrease in hepatocyte O2 consumption and ATP content which occurred before any evidence of cell injury. The potency of these molecules as cytotoxicants to isolated hepatocytes did not correlate with their potency as histamine H2-receptor antagonists whereas there was a significant correlation between increasing potency and increasing octanol/water partition coefficients. These data suggest that lipid solubility may be a key factor in the cytotoxicity of this class of drugs to isolated rat hepatocytes.

Topics: Animals; Dose-Response Relationship, Drug; Histamine H2 Antagonists; Imidazoles; L-Lactate Dehydrogenase; Liver; Male; Metiamide; Pyrimidinones; Rats; Rats, Inbred Strains; Structure-Activity Relationship

The effects on prolactin secretion of histamine H2-receptor antagonists infused intracerebroventricularly were studied in urethane anaesthetized male rats. A dose of 1.6 mumol cimetidine stimulated basal prolactin secretion and did not affect the histamine-induced release, whereas 0.4 mumol cimetidine inhibited basal and histamine-stimulated prolactin secretion. 0.1 mumol cimetidine had no effect. The more potent H2-receptor antagonist ranitidine at doses of 0.1, 0.4, 1.6 mumol had no effect on basal prolactin secretion, whereas 0.4 and 1.6 mumol inhibited the histamine-stimulated secretion completely. SKF-92408, a compound resembling cimetidine in chemical structure but devoid of H2-receptor antagonist activity, stimulated basal prolactin secretion at a dose of 1.6 mumol, but had no effect on the histamine-induced release or at a dose of 0.4 mumol. The H2-receptor antagonists metiamide and oxmetidine (1.6 mumol) stimulated basal prolactin secretion and did not prevent the response to histamine. A dose of 0.4 or 1.6 mumol imidazole (the ring structure contained in cimetidine, SKF-92408, metiamide, and oxmetidine) had no effect on basal or histamine-stimulated prolactin secretion. The findings indicate that cimetidine stimulates prolactin secretion by a non-specific action when infused centrally at high doses. In contrast, when infused at lower doses cimetidine inhibits the basal and histamine-stimulated secretion by blockade of H2-receptors. The prolactin-stimulatory action of cimetidine was not due to an H2-agonist effect, since ranitidine did not prevent the response. Cimetidine did not stimulate prolactin secretion via an effect on the dopaminergic system, since the drug had no effect on the dopamine concentration in hypophysial portal blood or in hypothalamic tissue and since inhibition of the dopamine synthesis by alpha-methyl-p-tyrosine did not prevent the cimetidine-induced prolactin release.

Topics: Animals; Cimetidine; Dopamine; Dose-Response Relationship, Drug; Guanidines; Histamine H2 Antagonists; Imidazoles; Injections, Intraventricular; Male; Metiamide; Prolactin; Ranitidine; Rats; Rats, Inbred Strains

The in vivo and in vitro effects on the aggregatory response of human platelets to ADP and collagen of a series of imidazole and non-imidazole histamine H2 receptor antagonists, and imidazole derivatives, have been studied. Bolus i.v. administration of the antagonists cimetidine and oxmetidine was without effect. However, inhibition of platelet aggregation was observed in vitro with oxmetidine, metiamide and to a lesser extent burimamide, but not with cimetidine or the non-imidazole antagonist ranitidine. Of the imidazole derivatives only imidazole and its 1-methyl analogue significantly affected platelet aggregation. The relationship between potency as a histamine H2 receptor antagonist, the presence of an imidazole ring structure and the antiaggregatory effectiveness of these compounds is discussed. Although certain antagonists clearly inhibit platelet aggregation in vitro, effects are only seen at drug concentrations exceeding those achieved under normal therapeutic conditions; thus the clinical significance of these observations remains to be determined.

Topics: Burimamide; Cimetidine; Dose-Response Relationship, Drug; Furans; Histamine H2 Antagonists; Humans; Imidazoles; Male; Metiamide; Platelet Aggregation; Ranitidine

Applications of physical organic chemistry and dynamic structure--activity analysis are illustrated by studies made during the development of specific drugs acting as antagonists of histamine at H2 receptors. Imidazolylalkylguanidines, isothioureas, and carboxamidines were found to be partial agonists, and attempts were made to remove the agonist component by lengthening the side chain and replacing the strongly basic group in these molecules by nonbasic groups. This approach furnished thioureas and cyanoguanidines as competitive antagonist, e.g., burimamide and cimetidine. Thoughts about molecular interactions led to the discovery of other nonbasic chemical groups for antagonist structures, in particular 1,1-diamino-2-nitroethenes and 2-amino-pyrimidine-4-ones (isocytosines). Such moieties are incorporated, respectively, in the recently described antagonist drugs ranitidine and oxmetidine.

Topics: Animals; Awards and Prizes; Burimamide; Chemistry, Clinical; Furans; Histamine H2 Antagonists; Humans; Imidazoles; Isothiuronium; Metiamide; Molecular Conformation; Ranitidine; Structure-Activity Relationship