Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists
Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They b...
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| Formato: | Online |
| Idioma: | inglés |
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Frontiers Media SA
2021
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| Acceso en liña: | 18662 |
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| _version_ | 1869527978902290432 |
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| author | Michel Alexander Steiner Christopher J Winrow |
| author_browse | Christopher J Winrow Michel Alexander Steiner |
| author_facet | Michel Alexander Steiner Christopher J Winrow |
| author_sort | Michel Alexander Steiner |
| collection | Directory of Open Access Books |
| description | Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia. |
| format | Online |
| id | doab-20.500.12854ir-50340 |
| institution | Directory of Open Access Books |
| language | eng |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Frontiers Media SA |
| publisherStr | Frontiers Media SA |
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| spelling | doab-20.500.12854ir-503402024-04-01T14:15:19Z Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists Michel Alexander Steiner Christopher J Winrow RC346-429 R5-920 RC321-571 RC435-571 RM1-950 Q1-390 Neuroscience Addiction hypocretin Anxiety orexin orexin receptor antagonist Neuropeptide insomnia thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKJ Neurology and clinical neurophysiology Orexin/hypocretin neuropeptides, produced by a few thousand neurons in the lateral hypothalamus, are of critical importance for the control of vigilance and arousal of vertebrates, from fish to amphibians, birds and mammals. Two orexin peptides, called orexin-A and orexin-B, exist in mammals. They bind with different affinities to two distinct, widely distributed, excitatory G-protein- coupled receptors, orexin receptor type 1 and type 2 (OXR-1/2). The discovery of an OXR mutation causing canine narcolepsy, the narcolepsy-like phenotype of orexin peptide knockout mice, and the orexin neuron loss associated with human narcoleptic patients laid the foundation for the discovery of small molecule OXR antagonists as novel treatments for sleep disorders. Proof of concept studies from Glaxo Smith Kline, Actelion Pharmaceuticals Ltd. and Merck have now consistently demonstrated the efficacy of dual OXR antagonists (DORAs) in promoting sleep in rodents, dogs, non-human primates and humans. Some of these antagonists have completed late stage clinical testing in primary insomnia. Orexin drug discovery programs have also been initiated by other large pharmaceutical companies including Hoffmann La Roche, Novartis, Eli Lilly and Johnson & Johnson. Orexins are increasingly recognized for orchestrating the activity of the organism’s arousal system with appetite, reward and stress processing pathways. Therefore, in addition to models of insomnia, pharmacological effects of DORAs have begun to be investigated in rodent models of addiction, depression and anxiety. The first clinical trials in diabetic neuropathy, migraine and depression have been initiated with Merck’s MK-6096 (www.clinicaltrials.gov). Whereas the pharmacology of DORAs is established for their effects on wakefulness, pharmacological effects of selective OXR-1 or OXR-2 antagonists (SORAs) have remained less clear. From an evolutionary point of view, the OXR-2 was expressed first in most vertebrate lineages, whereas the OXR-1 is believed to result from a gene duplication event, when mammals emerged. Yet, both receptors do not have redundant function. Their brain expression pattern, their intracellular signaling, as well as their affinity for orexin-A and orexin-B differs. During the past decade most preclinical research on selective OXR-1 antagonism was performed with SB-334867. Only in recent years, other selective OXR-1 and OXR-2 antagonists with optimized selectivity profiles and pharmacokinetic properties have been discovered, and phenotypes of OXR-1 and OXR-2 knockout mice were described. The present Research Topic (referred to in the Editorial as “special topics issue”) comprises submissions of original research manuscripts as well as reviews, directed towards the neuropharmacology of OXR antagonists. The submissions are preclinical papers dealing with dual and/or selective OXR antagonists that shed light on the differential contribution of endogenous orexin signaling through both OXRs for cellular, physiological and behavioral processes. Some manuscripts also report on convergence or divergence of DORA vs. SORA effects with phenotypes expressed by OXR-1 or OXR-2 knockout animals. Ultimately these findings may help further define the potential of DORAs and SORAs in particular therapeutic areas in insomnia and beyond insomnia. 2021-02-11T16:20:52Z 2021-02-11T16:20:52Z 2016-03-10 08:14:32 2014 book 18662 16648714 9782889193301 https://directory.doabooks.org/handle/20.500.12854/50340 eng Frontiers Research Topics image/jpeg Attribution 4.0 International http://www.frontiersin.org/books/Insomnia_and_beyond_-_Exploring_the_therapeutic_potential_of_orexin_receptor_antagonists/361#nogo http://journal.frontiersin.org/researchtopic/1357/insomnia-and-beyond---exploring-the-therapeutic-potential-of-orexin-receptor-antagonists Frontiers Media SA 10.3389/978-2-88919-330-1 10.3389/978-2-88919-330-1 bf5ce210-e72e-4860-ba9b-c305640ff3ae 9782889193301 219 open access |
| spellingShingle | RC346-429 R5-920 RC321-571 RC435-571 RM1-950 Q1-390 Neuroscience Addiction hypocretin Anxiety orexin orexin receptor antagonist Neuropeptide insomnia thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKJ Neurology and clinical neurophysiology Michel Alexander Steiner Christopher J Winrow Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title | Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title_full | Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title_fullStr | Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title_full_unstemmed | Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title_short | Insomnia and beyond - Exploring the therapeutic potential of orexin receptor antagonists |
| title_sort | insomnia and beyond exploring the therapeutic potential of orexin receptor antagonists |
| topic | RC346-429 R5-920 RC321-571 RC435-571 RM1-950 Q1-390 Neuroscience Addiction hypocretin Anxiety orexin orexin receptor antagonist Neuropeptide insomnia thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKJ Neurology and clinical neurophysiology |
| topic_facet | RC346-429 R5-920 RC321-571 RC435-571 RM1-950 Q1-390 Neuroscience Addiction hypocretin Anxiety orexin orexin receptor antagonist Neuropeptide insomnia thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKJ Neurology and clinical neurophysiology |
| url | 18662 |
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