Orexin (hypocretin) neuropeptides have, among others, been implicated in arousal/sleep control, and antagonizing the orexin signaling pathway has been previously demonstrated to promote sleep in animals and humans. This mechanism opens up a new therapeutic approach to curb excessive wakefulness in insomnia disorder rather than to promote sleep-related signaling. Here we describe the preclinical pharmacological in vitro and in silico characterization of lemborexant ((1,2)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)--(5-fluoropyridin-2-yl)cyclopropanecarboxamide)), a dual orexin receptor antagonist (DORA), as a novel experimental therapeutic agent for the symptomatic treatment of insomnia disorder and compare its properties to two other DORAs, almorexant and suvorexant. Lemborexant binds to both orexin receptors and functionally inhibits them in a competitive manner with low nanomolar potency, without any species difference apparent among human, rat, and mouse receptors. Binding and dissociation kinetics on both orexin receptors are rapid. Lemborexant is selective for both orexin receptors over 88 other receptors, transporters, and ion channels of important physiologic function. In silico modeling of lemborexant into the orexin receptors showed that it assumes the same type of conformation within the receptor-binding pocket as suvorexant, the -stacked horseshoe-like conformation.

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Diamond-like carbon with silicon (DLC-Si) coatings formed by plasma-assisted chemical vapor deposition showed low friction coefficients of the order of 0.01 against steel without a lubricant, not only in dry atmosphere but also in humid atmosphere, where conventional DLC coatings showed higher friction coefficients of 0.1-0.2. DLC-Si coatings with 1 fim thickness deposited on steel were slid against steel using a conventional ball-on-disk type of apparatus to compare with a low friction mechanism of DLC-Si in dry and humid atmospheres. Analyses of wear scars indicated that formation and/or transfer of graphite-like carbon including hydrogen that originated in a DLC-Si coating occurred in dry atmosphere, while oxidation of contained silicon with water vapor formed silica-sol by sliding in humid atmosphere. The latter, peculiar to DLC-Si, was considered to cause the low friction coefficient in humid atmosphere through adsorbed water on silica.

Serum mannan-binding protein (S-MBP) comprises a series of homooligomers, and activates complement when it binds to appropriate carbohydrate ligands. In this study, the structural requirements necessary for complement activation were examined for rat, rabbit, and human S-MBPs. On SDS-PAGE under non-reducing conditions, the S-MBPs gave three major bands: large, middle, and small oligomers. Since three subunits (23-25 kDa) form a triple helix (the base structural unit) at the collagen-like domain within the S-MBP molecule, it was estimated that human and rabbit S-MBPs comprise a mixture of pentamers, tetramers, and trimers of the respective structural units. In contrast, rat S-MBP is composed of tetramers, trimers, and dimers. The large and middle oligomers were almost equal in their ability to activate complement, whereas the small oligomers had very low or no activity. Upon digestion with bacterial collagenase, the large and small oligomers were degraded almost completely. In contrast, the middle oligomers remained largely intact, and the surviving middle oligomers retained complete ability to activate complement. The degraded product, trimers of the carbohydrate recognition domain (CRD), did not show any complement activating activity. These data indicate that not only the structural integrity of the S-MBP collagen-like domain and CRD, but also a unique conformational structure present in the middle oligomers are critically important for carbohydrate-mediated complement activation.