Aryl-heteroaryl derivatives as novel wake-promoting agents.

In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.

Wake-promoting agents: search for next generation modafinil: part IV.

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.

Wake promoting agents: search for next generation modafinil, lessons learned: part III.

In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).

Synthesis and evaluation of pyridazinone-phenethylamine derivatives as selective and orally bioavailable histamine H3 receptor antagonists with robust wake-promoting activity.

A series of pyridazinone-phenethylamine derivatives with moderate to low nanomolar affinity for rat and human H(3)R are described. These analogs exhibited excellent selectivity and metabolic stability, with acceptable rat pharmacokinetic properties. In vivo, 7 and 11 demonstrated potent H(3)R functional antagonism in the rat dipsogenia model and robust wake-promoting activity in the rat electroencephalogram/electromyography (EEG/EMG) model.

Identification of pyridazin-3-one derivatives as potent, selective histamine H₃ receptor inverse agonists with robust wake activity.

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

The roles of dopamine transport inhibition and dopamine release facilitation in wake enhancement and rebound hypersomnolence induced by dopaminergic agents.

Study Objective: Rebound hypersomnolence (RHS: increased sleep following increased wake) is a limiting side-effect of many wake-promoting agents. In particular, RHS in the first few hours following wake appears to be associated with dopamine (DA)-releasing agents, e.g.

Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus.

The 5-HT(6) receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT(6) receptor improve cognitive performance in a number of preclinical models and have recently been found to be effective in Alzheimer's disease patients. Systemic administration of 5-HT(6) antagonists increases the release of acetylcholine and glutamate in the frontal cortex and dorsal hippocampus.

Activation of p38MAPK in microglia after ischemia.

p38MAPK has been implicated in the regulation of proinflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia.

Prolonged calpain-mediated spectrin breakdown occurs regionally following experimental brain injury in the rat.

Calpain, a calcium-activated neutral protease family, has been implicated in the neuropathologic sequelae accompanying various neurological disorders. We have characterized the distribution and time course of calpain activation following brain injury in the rat, using a monoclonal antibody that recognizes calpain-generated breakdown products (BDPs) of spectrin. Adult male Sprague-Dawley rats received lateral fluid percussion brain injury of moderate severity (2.

Increased expression of IL-1beta converting enzyme in hippocampus after ischemia: selective localization in microglia.

Although the interleukin-1beta converting enzyme (ICE)/CED-3 family of proteases has been implicated recently in neuronal cell death in vitro and in ovo, the role of specific genes belonging to this family in cell death in the nervous system remains unknown. To address this question, we examined the in vivo expression of one of these genes, Ice, after global forebrain ischemia in gerbils. Using RT-PCR and Western immunoblot techniques, we detected an increase in the mRNA and protein expression of ICE in hippocampus during a period of 4 d after ischemia.

Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain.

Transient ischemia-induced perturbations in calcium homeostasis have been proposed to lead to pathological activation of the cysteine protease calpain I and subsequent delayed neuronal death in the CA1 region of hippocampus. We report here on the design and characterization of antibodies selective for calpain-generated fragments of brain spectrin, and their use for immunoblot and immunohistochemical analyses of calpain activation following cerebral ischemia in the gerbil. Although spectrin was susceptible to degradation in vitro by many mammalian proteases, only calpain degraded spectrin to generate fragments immunoreactive with the antibodies.

Aurintricarboxylic acid protects hippocampal neurons from NMDA- and ischemia-induced toxicity in vivo.

The polymeric dye aurintricarboxylic acid (ATA) has been shown to protect various cell types from apoptotic cell death, reportedly through inhibition of a calcium-dependent endonuclease activity. Recent studies have indicated that there may be some commonalities among apoptosis, programmed cell death, and certain other forms of neuronal death. To begin to explore the possibility of common biochemical mechanisms underlying ischemia- or excitotoxin-induced neuronal death and apoptosis in vivo, gerbils or rats subjected to transient global ischemia or NMDA microinjection, respectively, received a simultaneous intracerebral infusion of ATA or vehicle.

NADH fluorescence and regional energy metabolites during focal ischemia and reperfusion of rat brain.

Transient focal ischemia was produced in rat brain using simultaneous, reversible occlusion of the middle cerebral artery (MCA) and both carotid arteries. NADH tissue fluorescence and regional levels of ATP and lactate were measured after occlusion for 1 or 2.5 h and after reperfusion for 1 or 24 h following a 2.

Correlation between cerebral blood flow and ATP content following tourniquet-induced ischemia in cat brain.

Cerebral ischemia was produced in anesthetized cats using a neck tourniquet, which diminished cortical blood flow to less than 2 ml/100 g/min and depleted levels of ATP throughout the brain. Following a 30-min insult, cortical flow measured with H2 electrodes returned nearly to control, but subsequently decreased to 14-47% of control values. Despite this secondary hypoperfusion, ATP levels adjacent to the H2 electrode were restored to 75% of normal during the 2-h recirculation period.

Factors limiting regeneration of ATP following temporary ischemia in cat brain.

Cerebral ischemia was induced in cats using bilateral carotid artery occlusion coupled with hemorrhagic hypotension. Thirty minutes of ischemia, which depleted levels of ATP and phosphocreatine throughout the cerebral cortex, was followed by 2-4 hours of recirculation. During the recovery period, cortical perfusion and NADH fluorescence were monitored through a cranial window.

Echocardiographic features of atrioventricular and ventriculoatrial conduction.

The potential application of diagnostic ultrasound to understanding of the hemodynamic effects of various rhythm and conduction disturbances has not been fully explored. To investigate the change in cardiac function associated with various atrioventricular (A-V) sequencing intervals during cardiac pacing, simultaneous M mode and two dimensional echocardigraphic and hemodynamic studies were performed in 23 dogs. One to one A-V and ventriculoatrial (V-A) sequential pacing at cycle lengths of 400 and 300 ms revealed a stepwise reduction in left ventricular pressure and cardiac output as the A-V interval was changed from +100 to -100 ms.