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https://www.readbyqxmd.com/read/28807572/identification-of-highly-selective-and-potent-orexin-receptor-1-antagonists-derived-from-a-dual-orexin-receptor-1-2-antagonist-based-on-the-structural-framework-of-pyrazoylethylbenzamide
#1
Aya Futamura, Dai Nozawa, Yuko Araki, Yunoshin Tamura, Seiken Tokura, Hiroshi Kawamoto, Yuichi Tokumaru, Sora Kakihara, Takeshi Aoki, Norikazu Ohtake
The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28807167/treatment-of-insomnia-with-traditional-chinese-herbal-medicine
#2
Amrinder Singh, Kaicun Zhao
Insomnia is a condition with sleep problems and many people suffered from it. Chronic insomnia can last for long time and it will severely affect people's health and the quality of life. In conventional medicine, the most commonly used the medicine is benzodiazepine. It is effective but also has significant side effects. Patients try to use some kinds of alternative medicines. Chinese medicinal herbs and formulas have been used in the treatment of insomnia for more than 2000 years in China. In recent decades, Chinese herbal medicine has been widely used in the Western countries...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28794459/multiple-excitatory-actions-of-orexins-upon-thalamo-cortical-neurons-in-dorsal-lateral-geniculate-nucleus-implications-for-vision-modulation-by-arousal
#3
Lukasz Chrobok, Katarzyna Palus-Chramiec, Anna Chrzanowska, Mariusz Kepczynski, Marian Henryk Lewandowski
The orexinergic system of the lateral hypothalamus plays a crucial role in maintaining wakefulness and mediating arousal in a circadian time-dependent manner. Due to the extensive connections of orexinergic neurons, both orexins (OXA and OXB) exert mainly excitatory effects upon remote brain areas, including the thalamus. The dorsal lateral geniculate nucleus (DLG) is a relay thalamic centre for the visual system. Its thalamo-cortical (TC) neurons convey photic information from the retina to the primary visual cortex...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28781729/the-modulatory-role-of-orexin-1-receptor-in-ca1-on-orofacial-pain-induced-learning-and-memory-deficits-in-rats
#4
Razieh Kooshki, Mehdi Abbasnejad, Saeed Esmaeili-Mahani, Maryam Raoof
INTRODUCTION: Cognitive impairment is commonly associated with pain. The modulatory role of orexin 1 receptor (OX1R) in pain pathways as well as learning and memory processes is reported in several studies. The current study was designed to investigate the possible role of CA1-hippocampal OX1R on spatial learning and memory of rats following capsaicin-induced orofacial pain. METHODS: Orofacial pain was induced by subcutaneous intra lip injection of capsaicin (100 μg)...
May 2017: Basic and Clinical Neuroscience
https://www.readbyqxmd.com/read/28777177/chronic-insomnia-disorder
#5
Alon Y Avidan, David N Neubauer
PURPOSE OF REVIEW: Neurologists, along with all health care providers, commonly encounter patients with insomnia, which is a condition that impacts patients' underlying neurologic conditions in a bidirectional manner. While chronic insomnia is one of the most common sleep disturbances, only a small proportion of individuals with this condition discuss their sleep problems with their providers. When insomnia is described, it is more often in relationship to another medical problem, as opposed to an independent condition...
August 2017: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/28777172/narcolepsy-and-other-central-hypersomnias
#6
Yves Dauvilliers, Lucie Barateau
PURPOSE OF REVIEW: This article focuses on the clinical presentation, pathophysiology, diagnosis, differential diagnosis, and management of narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, Kleine-Levin syndrome, and other central disorders of hypersomnolence, as defined in the International Classification of Sleep Disorders, Third Edition (ICSD-3). RECENT FINDINGS: In ICSD-3, the names of some central disorders of hypersomnolence have been changed: narcolepsy with cataplexy and narcolepsy without cataplexy have been renamed narcolepsy type 1 and narcolepsy type 2, respectively...
August 2017: Continuum: Lifelong Learning in Neurology
https://www.readbyqxmd.com/read/28767209/preventive-effects-of-suvorexant-on-delirium-a-randomized-placebo-controlled-trial
#7
Kotaro Hatta, Yasuhiro Kishi, Ken Wada, Takashi Takeuchi, Shigeo Ito, Akiko Kurata, Kazunori Murakami, Manabu Sugita, Chie Usui, Hiroyuki Nakamura
OBJECTIVE: No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the prevention of delirium. METHODS: We conducted a multicenter, rater-blinded, randomized, placebo-controlled clinical trial in intensive care units and regular acute wards between April 2015 and March 2016. Eligible patients were 65 to 89 years old, newly admitted due to emergency, and able to take medicine orally and had an expected stay or life expectancy of 48 hours or more...
August 1, 2017: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/28762874/reactivation-of-hyperglycemia-induced-hypocretin-hcrt-gene-silencing-by-n-acetyl-d-mannosamine-in-the-orexin-neurons-derived-from-human-ips-cells
#8
Koji Hayakawa, Yasuharu Sakamoto, Osamu Kanie, Atsuko Ohtake, Shusaku Daikoku, Yukishige Ito, Kunio Shiota
Orexin neurons regulate critical brain activities for controlling sleep, eating, emotions, and metabolism, and impaired orexin neuron function results in several neurological disorders. Therefore, restoring normal orexin function and understanding the mechanisms of loss or impairment of orexin neurons represent important goals. As a step toward that end, we generated human orexin neurons from induced pluripotent stem cells (hiPSCs) by treatment with N-acetyl-d-mannosamine (ManNAc) and its derivatives. The generation of orexin neurons was associated with DNA hypomethylation, histone H3/H4 hyperacetylation, and hypo-O-GlcNAcylation on the HCRT gene locus, and, thereby, the treatment of inhibitors of SIRT1 and OGT were effective at inducing orexin neurons from hiPSCs...
August 1, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28762571/sex-specific-differences-in-cardiovascular-and-metabolic-hormones-with-integrated-signalling-in-the-paraventricular-nucleus-of-the-hypothalamus
#9
Spencer P Loewen, Alex R Paterson, Su Yi Loh, Mark F Rogers, Charles C T Hindmarch, David Murphy, Alastair V Ferguson
Many traditional cardiovascular hormones have been implicated in metabolic function. Conversely, many hormones traditionally involved in metabolic regulation have an effect on cardiovascular function. Many of these signalling molecules exert such effects through specific actions in the paraventricular nucleus (PVN), an integrative autonomic control centre located in the hypothalamus. Here, we focus on four cardiovascular/metabolic peptide hormones that signal within the PVN, angiotensin II, orexin, adiponectin, and nesfatin-1...
August 1, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28757457/dual-transmitter-systems-regulating-arousal-attention-learning-and-memory
#10
REVIEW
Sherie Ma, Balázs Hangya, Christopher S Leonard, William Wisden, Andrew L Gundlach
An array of neuromodulators, including monoamines and neuropeptides, regulate most behavioural and physiological traits. In the past decade, dramatic progress has been made in mapping neuromodulatory circuits, in analysing circuit dynamics, and interrogating circuit function using pharmacogenetic, optogenetic and imaging methods This review will focus on several distinct neural networks (acetylcholine/GABA/glutamate; histamine/GABA; orexin/glutamate; and relaxin-3/GABA) that originate from neural hubs that regulate wakefulness and related attentional and cognitive processes, and highlight approaches that have identified dual transmitter roles in these behavioural functions...
July 27, 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28755843/serum-level-of-orexin-a-leptin-adiponectin-and-insulin-in-north-indian-obese-women
#11
Sameeksha Mishra, Vani Gupta, Supriya Mishra, Rekha Sachan, Akash Asthana
BACKGROUND AND AIMS: Obesity is regulated by different metabolic factors like leptin, adiponectin insulin and neuropeptide orexin-A. The aim of this study is to assess the role of these hormones and their interrelationship with obesity in north Indian women. METHOD: A total of 168 obese women with Body Mass Index (BMI)>30kg/m(2) and 150 lean women (BMI<25kg/m(2)) as control were recruited in this study. Women with obesity were further subdivided into two groups according to their BMI, 71 overweight women with the BMI 25-29...
July 21, 2017: Diabetes & Metabolic Syndrome
https://www.readbyqxmd.com/read/28747887/nutrient-sensing-another-chemosensitivity-of-the-olfactory-system
#12
REVIEW
A-Karyn Julliard, Dolly Al Koborssy, Debra A Fadool, Brigitte Palouzier-Paulignan
Olfaction is a major sensory modality involved in real time perception of the chemical composition of the external environment. Olfaction favors anticipation and rapid adaptation of behavioral responses necessary for animal survival. Furthermore, recent studies have demonstrated that there is a direct action of metabolic peptides on the olfactory network. Orexigenic peptides such as ghrelin and orexin increase olfactory sensitivity, which in turn, is decreased by anorexigenic hormones such as insulin and leptin...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28741623/effects-of-suvorexant-a-dual-orexin-hypocretin-receptor-antagonist-on-impulsive-behavior-associated-with-cocaine
#13
Taylor A Gentile, Steven J Simmons, Mia N Watson, Krista L Connelly, Eugen Brailoiu, Yanan Zhang, John W Muschamp
Hypothalamic hypocretin (orexin) peptides mediate arousal, attention, and reward processing. Fibers containing orexins project to brain structures that govern motivated behavior, including the ventral tegmental area (VTA). A number of psychiatric conditions, including attention deficit hyperactivity disorder (ADHD) and substance use disorders, are characterized by deficits in impulse control, however the relationship between orexin and impulsive behavior is incompletely characterized. The effects of systemic or centrally administered orexin receptor (OXR) antagonists on measures of impulsive-like behavior in rats were evaluated using the five-choice serial reaction time task (5-CSRTT) and delay discounting procedures...
July 25, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28739044/essential-structure-of-orexin-1-receptor-antagonist-ynt-707-part-i-role-of-the-4-5-epoxy-ring-for-binding-with-orexin-1-receptor
#14
Naoshi Yamamoto, Sayaka Ohrui, Takahiro Okada, Masahiro Yata, Tsuyoshi Saitoh, Noriki Kutsumura, Yasuyuki Nagumo, Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Yukiko Ishikawa, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Masashi Yanagisawa, Hiroshi Nagase
The essential structure of the orexin 1 receptor (OX1R) antagonist YNT-707 (2) was clarified, particularly the roles to OX1R antagonist activities of the 3-OMe, the 4,5-epoxy ring, the 14-hydroxy group, and the orientation of the 6-amide side chain. The 3-OMe and 17-sulfonamide group were shown to be essential for the OX1R antagonistic activity. The 4,5-epoxy ring plays an important role for the active orientation of the 6-amide group. The 14-hydroxy group could lower the activity of the 6β-amide isomer by the interaction of the 14-hydroxy group with the 6-amide group, which could orient the 6-amide group toward the upper side of the C-ring...
July 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28735928/efficacy-and-safety-of-almorexant-in-adult-chronic-insomnia-a-randomized-placebo-controlled-trial-with-an-active-reference
#15
Jed Black, Giora Pillar, Jan Hedner, Olli Polo, Ouali Berkani, Sara Mangialaio, Abdel Hmissi, Gary Zammit, Goran Hajak
BACKGROUND AND OBJECTIVES: The orally active dual OX1R and OX2R antagonist, almorexant, targets the orexin system for the treatment of primary insomnia. This clinical trial assessed the effect of almorexant on sleep maintenance and other sleep endpoints, and its safety and tolerability in adults. PATIENTS AND METHODS: Prospective, randomized, double-blind, placebo-controlled, active referenced trial in male and female adults aged 18-64 years with chronic, primary insomnia...
August 2017: Sleep Medicine
https://www.readbyqxmd.com/read/28733226/allatoregulatory-like-systems-and-changes-in-cytosolic-ca-2-modulate-feeding-behavior-in-hydra
#16
María Eugenia Alzugaray, Jorge Rafael Ronderos
Allatotropin (AT) and allatostatin-C (AST-C) are neuropeptides originally characterized by their ability to modulate the secretion of juvenile hormones in insects. Beyond the allatoregulatory function, these neuropeptides are pleiotropic acting as myoregulators not only in insects, but also in other groups of invertebrates. We have previously proposed the existence of AT and AST-C like systems in Hydra sp., a member of the phylum Cnidaria, which is a basal group of Metazoa, sharing a common ancestor with Bilateria...
July 18, 2017: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28727208/differential-expression-of-appetite-regulating-genes-in-avian-models-of-anorexia-and-obesity
#17
Jiaqing Yi, Jingwei Yuan, Elizabeth R Gilbert, Paul B Siegel, Mark A Cline
Chickens from lines that have been selected for low (LWS) or high (HWS) juvenile body weight for more than 57 generations provide a unique model to research appetite regulation. The LWS display different severities of anorexia while all HWS become obese. Herein we measured mRNA abundance of various factors in appetite-associated nuclei in the hypothalamus. The lateral hypothalamus (LHA), paraventricular nucleus (PVN), ventromedial hypothalamus (VMH), dorsomedial nucleus (DMN), and arcuate nucleus (ARC) were collected from 5 day-old chicks that were fasted for 180 minutes or provided continuous access to food...
July 20, 2017: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/28717967/orexin-a-hypocretin-modulates-leptin-receptor-mediated-signaling-by-allosteric-modulations-mediated-by-the-ghrelin-ghs-r1a-receptor-in-hypothalamic-neurons
#18
Mireia Medrano, David Aguinaga, Irene Reyes-Resina, Enric I Canela, Josefa Mallol, Gemma Navarro, Rafael Franco
The hypothalamus is a key integrator of nutrient-seeking signals in the form of hormones and metabolites originated in both the central nervous system and the periphery. The main autocrine and paracrine target of orexinergic-related hormones such as leptin, orexin/hypocretin, and ghrelin are neuropeptide Y neurons located in the arcuate nucleus of the hypothalamus. The aim of this study was to investigate the expression and the molecular and functional relationships between leptin, orexin/hypocretin and ghrelin receptors...
July 17, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28709906/effects-of-feeding-time-on-daily-rhythms-of-neuropeptide-and-clock-gene-expression-in-the-rat-hypothalamus
#19
Dawei Wang, Anne-Loes Opperhuizen, Jane Reznick, Nigel Turner, Yan Su, Gregory J Cooney, Andries Kalsbeek
Shiftworkers are exposed to several adverse health conditions, one being eating at night. Food consumption at an unnatural time-of-day is thought to be one of the main factors responsible for the increased risk of developing metabolic diseases, such as obesity and diabetes mellitus. The underlying mechanism is considered to include disruption of the circadian organization of physiology, leading to disruption of metabolism. When food is consumed at night, the hypothalamus, a brain region central to homeostasis, receives contradicting input from the central clock and the systemic circulation...
July 11, 2017: Brain Research
https://www.readbyqxmd.com/read/28707143/clinical-sleep-wake-disorders-ii-focus-on-insomnia-and-circadian-rhythm-sleep-disorders
#20
Kai Spiegelhalder, Christoph Nissen, Dieter Riemann
Insomnia and circadian rhythm sleep disorders affect large proportions of the population and have pronounced effects on quality of life and daytime performance. While the neurobiology of insomnia is not yet fully understood, circadian rhythm sleep disorders are assumed to be caused by a mismatch between the individual circadian phase position and the desired sleep-wake schedule. Benzodiazepines and non-benzodiazepine positive allosteric GABAA receptor modulators improve sleep onset and maintenance in the short-term treatment of insomnia...
July 14, 2017: Handbook of Experimental Pharmacology
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