Synthesis of potent non-imidazole histamine H3-receptor antagonists.

Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N alpha-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 microM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (Ki = 0.18 +/- 0.10 microM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki = 39 +/- 11 nM), ED50 = 1.1 +/- 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.

Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients.

Plasma concentrations of the antioxidant vitamin ascorbic acid were measured by high-performance liquid chromatography in critically ill patients in whom the excessive generation of reactive oxygen species could compromise antioxidant defense mechanisms. Median concentrations of both total vitamin C (ascorbic acid and dehydroascorbic acid) and ascorbic acid in these patients were < 25% (P < 0.001) of the values found in healthy control subjects and in subjects in two other disease groups (diabetes, gastritis) in which reactive oxygen species are reported to be increased. The low values could not be explained by age, sex, intake, or treatment differences, but were associated with the severity of the illness and were not prevented by the use of parenteral nutrition containing ascorbic acid. In addition, the vitamin was less stable in blood samples taken from critically ill patients than in similar samples from subjects in the other groups. The findings indicate that antioxidant defenses could be considerably compromised in these very sick patients. If this reduces the patient's capacity to scavenge reactive species, then the potential of these species to damage DNA and lipid membranes could be increased and compromise recovery.

Structure-activity studies with histamine H3-receptor ligands.

Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Some compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side-chain amino group show strong H3-antagonist activity. These have served as leads to provide aryloxyethyl- and aryloxy-propylimidazoles which are potent H3 antagonists of histamine. Structure-activity studies of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea), have explored the the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N'-Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having Ki = 1.5 nM.