Potent Histamine H2-receptor Agonist Research Articles

Imidazolylpropylguanidines as histamine H2 receptor agonists: 3D-QSAR of a large series

Imidazolylpropylguanidines are potent histamine H2 receptor agonists and act as inotropic vasodilators. A large series of 141 derivatives was tested in the isolated guinea pig atrium and submitted to CoMFA. Since all compounds are full agonists, pD2 values reflect H2 receptor binding. Hydrophobicity was considered as Σf of the variable structural moiety, calculated by the Leo–Hansch method. Preliminary Hansch analysis with Σf, (Σf)2 and indicator variables showed that pD2 additively depends on contributions of certain substructures and has a hydrophobic optimum. For CoMFA, all 3D structures were optimized and aligned. Partial Least Squares analysis of pD2 as function of steric and electrostatic field variables and of Σf and (Σf)2 led to models with r2 of 0.78 with and 0.93 without hydrophobicity. Results indicate a parabolic dependence of pD2 on hydrophobic effects. The 3D distribution of field influences on pD2 suggests a model (shape and electrostatic potential) of the binding site. The role of branching and different substituent effects of a first and a second ring indicate that adequately branched structures induce a conformational change of the binding site enabling a favourable accommodation of the second ring with various substituents.

Hypothalamo‐preoptic Histaminergic Projections in Sleep‐Wake Control in the Cat

Cats were chronically implanted with electrodes for polygraphic recordings and cannulae for intracerebral microinjections in order to study the functional role of histaminergic innervation of the preoptic-anterior hypothalamus in sleep-wake control. alpha-Fluoromethylhistidine (alpha FMH, 50 micrograms in 1 microliter), a specific inhibitor of the histamine-synthesizing enzyme, when injected bilaterally into the preoptic area, where numerous histaminergic fibres and terminal-like structures are present, caused a significant increase in deep slow wave sleep (S2) and paradoxical sleep (PS) and a decrease in wakefulness. In contrast, microinjections of histamine (5 or 30 micrograms in 1 microliter) in the same area dose-relatedly increased wakefulness and decreased both slow wave sleep and paradoxical sleep. The effects of histamine were reduced by pretreatment with mepyramine (1 mg/kg i.p.), a well known histamine H1 receptor antagonist, and were mimicked by a local injection of impromidine (1 microgram in 1 microliter), a potent histamine H2 receptor agonist. Microinjections of mepyramine alone (120 micrograms in 1 microliter) caused an increase in slow wave sleep. These results suggest that preoptic histaminergic innervation is involved in sleep-wake control and that the action might be mediated via both H1 and H2 receptors.

Short‐term toxicological studies with impromidine (SK&F 92676): A specific histamine H2‐receptor agonist

Impromidine is a specific, potent histamine H2-receptor agonist. The present paper describes the results of acute and short-term repeated-dose toxicity studies with impromidine in rodents and dogs. The intravenous LD50 was 9.6 mg kg-1 in male mice, 12.7 mg kg-1 in female mice and 25.5 mg kg-1 in rats. The minimum lethal dose in dogs after 30 min intravenous infusion was 27.7 mg kg-1 during the infusion and 4 mg kg-1 within 14 days. In 12- or 14-day tests in rats by the intravenous (maximum dose 3.24 mg per kg per day) and subcutaneous (maximum dose 20 mg per kg per day) routes, impromidine had no serious toxicological effects. In 12- or 14-day studies in dogs by the i.v. (maximum dose 0.259 mg per kg per day) and intramuscular (maximum dose 0.5 mg per kg per day) routes, impromidine caused vasodilation, tachycardia and vomiting. In a few dogs, at the highest dose levels, there was erosion and irritation of the gastrointestinal tract and myocardial damage. Other minor pathological changes were seen in the liver, kidneys and pancreas. No changes were seen other than those to be expected from the pharmacological actions of impromidine as an H2-receptor agonist. Studies in anaesthetized rats, either spontaneously respiring or sustained by artificial respiration, indicate that, at acute doses, impromidine causes death by respiratory failure.

Impromidine-induced hypothermia in rats: effect of cimetidine and mianserine.

Impromidine, a highly potent histamine H2-receptor agonist, given i.v. at doses of 3.1-62 nmole, induced a dose-dependent hypothermia in the rat with a maximal effect after 15 min. Cimetidine, an H2-receptor antagonist, having no effect when administered alone, antagonized the hypothermic action of impromidine. Two antiserotoninergic agents, p-chlorophenylalanine and metergoline, and chronic treatment with an antidepressant mianserine reduced the impromidine-induced hypothermia. It is suggested that the impromidine-induced hypothermia is an H2-receptor-mediated phenomenon, and the antagonizing effect of mianserine is related to serotonin receptor blocking activity of the drug rather than to its direct H2-receptor antagonism.