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The orexin system plays a major role in the integration of metabolic and circadian influences that drive wakefulness. This paper describes initial Phase I trials of a novel dual orexin receptor antagonist SB-649868 that has demonstrated preclinical potential for treatment of sleep disorders. The trial designs included a single ascending dose escalation(More)
Central sensitization is a condition of enhanced excitability of spinal cord neurons that contributes to the exaggerated pain sensation associated with chronic tissue or nerve injury. N-methyl-D-aspartate (NMDA) receptors are thought to play a key role in central sensitization. We have tested this hypothesis by characterizing in vitro and in vivo a novel(More)
STUDY OBJECTIVES To assess the acute effects of SB-649868 in male subjects with Primary Insomnia with regard to (1) objective and subjective sleep parameters, (2) safety and tolerability, (3) next-day residual effects. DESIGN Multicenter, randomized, double-blind, placebo-controlled crossover study using a complete set of Williams orthogonal Latin Squares(More)
Lacidipine, a new, long-acting antihypertensive dihydropyridine calcium antagonist was tested for potential antioxidant effect in a series of tests that consider specific radical species. A direct quenching of several radical species could be measured. Moreover, in biological membranes deriving from rat brain tissue, lacidipine showed an activity comparable(More)
BACKGROUND Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a nonhuman primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys. METHODS Eight rhesus monkeys were(More)
Gavestinel [GV150526A; ( E)-3[(phenylcarbamoil)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt] is a selective antagonist at the strychnine-insensitive glycine site of the -methyl-D-aspartate (NMDA) receptor. It was tested for its ability to substitute for phencyclidine (PCP) in rats and rhesus monkeys trained to discriminate PCP from saline,(More)
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic(More)
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the(More)
Clinical study results for neurokinin (NK) receptor antagonists in the treatment of depression have been mixed, with Phase III studies failing to fulfill the early promise demonstrated in Phase II studies. Casopitant, a selective NK1 antagonist that achieves nearly complete receptor occupancy was studied in 2 randomized, placebo-controlled, double-blind,(More)
The metabotropic glutamate receptors (mGluRs) form a family of G-protein-coupled receptors which consists of at least seven members termed mGluR1-mGluR7. These members are classified into subfamilies according to their sequence similarities, signal transduction mechanisms and agonist selectivities. mGluR1 and mGluR5 are coupled to the phosphoinositide(More)