ABSTRACT
microdant stress is involved in the events that accompany endothelial cell expression of adhesion molecules and leukocyte adherence in many disease states, including atherosclerosis. A recently discovered benzo(b)pyran-4-one derivative, S17834 (10 to 50 micromol/L), reduced tumor necrosis factor-stimulated vascular cell adhesion molecule-1 (VCAM) mRNA accumulation and protein expression in human umbilical vein endothelial cells. Intercellular cell adhesion molecule-1 and E-selectin were also inhibited by S17834, but platelet endothelial cell adhesion molecule-1 was not. Adherence of U937 monocytic cells to the endothelial cells as well as to plastic plates coated with soluble VCAM, intercellular cell adhesion molecule-1, P-selectin, and E-selectin was also decreased. Consistent with an antioxidant mechanism of action, S17834 (10 to 50 micromol/L) inhibited tumor necrosis factor-stimulated release of superoxide from endothelial cells measured by cytochrome c reduction. S17834 had no effect on superoxide produced by xanthine oxidase, indicating that rather than by acting as a scavenger of superoxide anion, the drug acts by inhibiting the production of free radicals. Indeed, S17834 inhibited NADPH oxidase activity of endothelial cell membranes. The ability to inhibit superoxide anion production appears to be key in the effect of S17834 on superoxide anion production and VCAM expression, because these actions were mimicked by adenovirus-mediated overexpression of superoxide dismutase. Furthermore, these actions may be relevant in vivo, because S17834 reduced aortic superoxide anion levels by 40% and aortic atherosclerotic lesions by 60% in apolipoprotein E-deficient mice. These results indicate that S17834 inhibits adhesion molecule expression and adherence of leukocytes to endothelial cells as well as aortic atherogenesis and that perhaps these effects can be explained by its ability to inhibit endogenous superoxide anion production.
Subject(s)
Arteriosclerosis/drug therapy , Cell Adhesion/drug effects , Endothelium, Vascular/metabolism , Enzyme Inhibitors/pharmacology , NADPH Oxidases/antagonists & inhibitors , Animals , Aortic Diseases/drug therapy , Aortic Diseases/metabolism , Aortic Diseases/pathology , Apolipoproteins E/genetics , Arteriosclerosis/metabolism , Arteriosclerosis/pathology , Benzopyrans/pharmacology , Catalase/genetics , Catalase/physiology , Cell Adhesion Molecules/biosynthesis , Cell Adhesion Molecules/genetics , Cells, Cultured , Endothelium, Vascular/drug effects , Endothelium, Vascular/immunology , Humans , Leukocytes/immunology , Mice , Mice, Knockout , RNA, Messenger/biosynthesis , Superoxide Dismutase/genetics , Superoxide Dismutase/physiology , Superoxides/metabolism , Tumor Necrosis Factor-alpha/pharmacology , U937 CellsABSTRACT
Obesity affects a large population of industrialised countries in which occurrence may reach 20%. The multifactorial aspect of the pathology prompted us to develop new entities associating favourable effects on both eating behaviour and metabolic parameters. The 2-trifluoromethyl-benzocyloheptene moiety has been combined with an imidazoline ring for synthesising a new anti-obesity agent. Preparation of the already known 2-trifluoromethyl-5-H-6,7,8,9-tetrahydro-benzocyclohepten-7-one as a key intermediate has been significantly improved, and an enantioselective procedure has been developed for imidazoline construction. The syntheses and pharmacological profiles of the compounds are presented here, particularly the effects on eating behaviour and body weight, and the putative involvement of the L-enantiomer in the treatment of metabolic diseases.
Subject(s)
Anti-Obesity Agents/chemical synthesis , Animals , Anti-Obesity Agents/pharmacology , Appetite Depressants/chemical synthesis , Appetite Depressants/pharmacology , Biogenic Monoamines/metabolism , Blood Pressure/drug effects , Brain Chemistry/drug effects , Eating/drug effects , Fluorobenzenes/chemical synthesis , Fluorobenzenes/pharmacology , In Vitro Techniques , Male , Obesity/drug therapy , Rats , Rats, Sprague-Dawley , Rats, Wistar , Rats, Zucker , Receptors, Drug/drug effects , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , StereoisomerismABSTRACT
Metabolism of arachidonic acid through the 5-lipoxygenase (LO) pathway generates compounds that stimulate osteoclastic bone resorption; since LO metabolites might play a role in bone loss due to excessive resorption it was tried to develop a series of antiresorptive agents starting from an already known LO inhibitor. Of the 35 compounds synthesized, 11 strongly inhibited (10 mumol/l) retinoic acid-induced bone resorption in cultured mouse calvariae; they were also tested for their effect on LO activity using rat peritoneal neutrophils, but no correlation could be drawn between inhibition of LO and bone resorption. Other pathways, still to be identified, must therefore be targeted by these compounds even though LO inhibition might contribute to their effects on bone. Two compounds selected for further studies were found active on parathyroid hormone-induced osteolysis, while they had no effect on basal resorption; they must, therefore, act at some key point in the process of activation of osteoclastic resorption. This series of compounds may represent a new way for the treatment of bone loss due to excessive resorption.
Subject(s)
Bone Resorption/drug therapy , Lipoxygenase Inhibitors/chemical synthesis , Thiophenes/chemical synthesis , Animals , Animals, Newborn , Bone Development/drug effects , Female , In Vitro Techniques , Lipoxygenase/metabolism , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Male , Mice , Neutrophils/drug effects , Neutrophils/enzymology , Peritoneal Cavity/cytology , Rats , Rats, Inbred Lew , Skull/drug effects , Skull/growth & development , Spectrophotometry, Infrared , Structure-Activity Relationship , Thiophenes/chemistryABSTRACT
We have assessed the effect of midazolam on sleep in a model of transient insomnia in healthy adults using polysomnographic recordings. The subjects were randomly assigned to one of three treatment groups (placebo or midazolam 7.5 or 15 mg) and spent a single night in the sleep laboratory. Midazolam or placebo were given double-blind immediately before turning off the lights. Midazolam 15 mg was effective in inducing sleep, while 7.5 mg and 15 mg produced improvement in the maintenance of sleep. Subjectively, sleep latency and the number of awakenings were reduced dose-dependently. Midazolam did not impair psychomotor performance on the morning after administration.
Subject(s)
Midazolam/therapeutic use , Sleep Initiation and Maintenance Disorders/drug therapy , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Male , Midazolam/administration & dosage , Midazolam/pharmacology , Psychomotor Performance/drug effects , Sleep/drug effects , Sleep, REM/drug effects , Time FactorsABSTRACT
The effects of the histamine H3 receptor agonist, (R)-alpha-methylhistamine were compared with those of the histamine H3 antagonist, thioperamide, in rats implanted with electrodes for chronic sleep recordings. (R)-alpha-Methylhistamine (1.0-4.0 micrograms) injected bilaterally into the premammillary area where histamine immunoreactive neurons have been detected increased slow wave sleep, whereas wakefulness and REM sleep were decreased. No significant effects were observed when (R)-alpha-methylhistamine (1.0-8.0 mg/kg) was administered i.p. Thioperamide (1.0-4.0 mg/kg i.p.) increased wakefulness and decreased slow wave sleep and REM sleep. Pretreatment with thioperamide (4.0 mg/kg) prevented the effects of (R)-alpha-methylhistamine (2.0 micrograms) on slow wave sleep and wakefulness. Our results further support an active role for histamine in the control of the waking state.
Subject(s)
Receptors, Histamine/drug effects , Sleep/drug effects , Wakefulness/drug effects , Animals , Drug Interactions , Histamine Antagonists , Injections, Intraperitoneal , Injections, Intraventricular , Male , Mammillary Bodies , Methylhistamines/antagonists & inhibitors , Methylhistamines/pharmacology , Piperidines/pharmacology , Rats , Rats, Inbred Strains , Receptors, Histamine/physiology , Receptors, Histamine H3ABSTRACT
The effects of the H1-receptor antagonist diphenhydramine and the brain-penetrating H2-receptor antagonist zolantidine were studied in rats implanted for chronic sleep recordings. Diphenhydramine (1.0-4.0 mg/kg) significantly increased slow wave sleep and decreased wakefulness. Zolantidine (0.25-8.0 mg/kg) had no significant effects on any of the sleep parameters examined. One possibility is that zolantidine did not enter the brain in sufficient concentration to produce significant changes on sleep and wakefulness. Another possibility is that blockade of H2-receptor involved parts of the brain other than those implicated in the sleep-wake cycle. The feasibility remains that H2-receptors are not involved in sleep regulation. The absence of selective, brain-penetrating H2-receptor agonists precludes a more detailed analysis of the role of this subtype of receptor in the control of sleep and wakefulness.
