Talk:Gaboxadol

tag
Removed cleanup tag because given the subject, this article is probably as good as it's ever going to get. 82.32.73.70 (talk) 20:17, 21 January 2009 (UTC)

Alcohol, not lactone
I'm pretty sure, after reading some journal articles, that the oxo group should in fact be an ol. This appears to be a synonym of the compound THIP, but I don't want to edit anything until (if ever) I get confirmation. Andares (talk) 23:55, 14 May 2009 (UTC)

Edit request
My name is Kelly Boothe and work for W2O Group, a public relations agency. In my role, I represent healthcare clients, including Ovid Therapeutics. I am aware of Wikipedia's policies and guidelines, including those on WP:COI, WP:RS, WP:V and WP:NPOV, and I will abide by them. My edit suggestions will be restricted to Talk pages, and I will not engage in directly editing any articles related to the companies which I present, aside from correcting blatant misinformation or obvious vandalism. On any pages where I may suggest changes, I will be sure to disclose relevant relationships in the interest of transparency. If you have any questions about my editing activities, please leave me a message on my User Talk page.

Current: Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimolthat was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen.[1] In the early 1980s gaboxadol was the subject of a series of pilot studies that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spasticity.[1] It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "adverse effect" for the treatment of insomnia, resulting in a series of clinical trials sponsored by Lundbeck and Merck.[1][2] In March, 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. It acts on the GABAsystem, but in a different way from benzodiazepines, Z-Drugs, and barbiturates. Lundbeck states that gaboxadol also increases deep sleep(stage 4). It is, however, not reinforcing like benzodiazepines are.[3] In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, whose plan is to develop it for FXS and Angelman Syndrome.[4] It is known internally in Ovid as OV101
 * Revisions to Gaboxadol page ==

Revised:
 * Adds new information about GABA system and GABAA receptors and tonic inhibition
 * Adds new information about ongoing clinical trials, and OV101’s Orphan Drug Designation from the U.S. Food and Drug Administration

Gaboxadol, also known as 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP), is a conformationally constrained derivative of the alkaloid muscimol that was first synthesized in 1977 by the Danish chemist Povl Krogsgaard-Larsen. In the early 1980s gaboxadol was the subject of a series of pilot studies that tested its efficacy as an analgesic and anxiolytic, as well as a treatment for tardive dyskinesia, Huntington's disease, Alzheimer's disease, and spasticity. It was not until 1996 that researchers attempted to harness gaboxadol's frequently reported sedative "adverse effect" for the treatment of insomnia, resulting in a series of clinical trials sponsored by Lundbeck and Merck. ] In March 2007, Merck and Lundbeck cancelled work on the drug, citing safety concerns and the failure of an efficacy trial. Data from recently-completed Phase 3 studies suggest that the overall clinical profile for gaboxadol in insomnia did not support further development. It is now understood that gaboxadol acts on the GABA system in a different way from other GABAA receptor-preferring drugs. Gaboxadol is a selective agonist of extrasynaptic (outside the synaptic gap) GABAA receptors, other GABA acting drugs, such as benzodiazepines, Z-Drugs, and barbiturates, act on the synaptic GABA receptors. It is thought this is why these drugs have a risk for tolerance and addiction while gaboxadol does not. In addition, gaboxadol’s actions on the extrasynaptic GABA A receptors are thought to be responsible for its action in the regulation of tonic inhibition. Tonic inhibition is essential for normal neuronal network activity, allowing a healthy brain to decipher signals correctly without being overloaded. Loss of tonic inhibition leads the brain to become inundated with signals and disrupts the ability to separate background noise from critical information. In 2015, Lundbeck sold its rights to the molecule to Ovid Therapeutics, who is developing the medicine as a potential treatment for Fragile X Syndrome and Angelman Syndrome under the name OV101. In September 2016, Ovid Therapeutics received Orphan Drug Designation from the U.S. Food and Drug Administration for OV101 for the treatment of Angelman syndrome. Gaboxadol is currently being tested in Phase 1 and 2 trials for adolescents and adults with Angelman syndrome or Fragile X syndrome. Symptoms of Angelman syndrome and Fragile X syndrome are believed in part to be a result of the reduced tonic inhibition, causing dysfunction of neuronal networks and the behavioral and cognitive features of these syndromes.

Gaboxadol is a δ-selective GABAA receptor agonist that binds and activates a specific subset of GABA receptors located extrasynaptically, and which mediate tonic inhibition. In a healthy brain, there is sufficient GABA present to stimulate synaptic and extrasynaptic GABAA receptors. However, in several neurological disorders including Angelman syndrome and Fragile X syndrome, ambient extracellular levels of GABA are reduced, triggering a loss of tonic inhibition. This loss of inhibition is responsible in part for many of the symptoms of these syndromes. It is believed that restoring tonic inhibition in individuals with Angelman syndrome and Fragile X syndrome may result in alleviating developmental, intellectual and behavioral challenges associated with the disorders.
 * Mechanism of Action

Ovid Therapeutics is currently investigating gaboxadol in a double-blind, placebo-controlled, randomized Phase 2 clinical trial, known as ‘STARS,’ looking at safety parameters and exploratory efficacy endpoints in adults with Angelman syndrome. The exploratory endpoints include evaluating measures of gross and fine motor skills, maladaptive behavior, sleep, clinical global impression and health-related quality of life measures. The trial is enrolling approximately 75 adults in the United States aged 18-49 years. [18] (https://clinicaltrials.gov/ct2/show/NCT02996305?term=angelman+syndrome&rank=6)
 * Clinical Trials

Gaboxadol is also being explored in an Ovid Therapeutics-sponsored, single dose, single-arm, open-label, Phase 1 clinical trial for adolescents (age 13-17) who have been diagnosed with either Angelman syndrome or Fragile X syndrome. The trial is evaluating the pharmacokinetics, safety and tolerability of gaboxadol. [19] (https://clinicaltrials.gov/ct2/show/NCT03109756?term=Ovid+Therapeutics&rank=2)

In previously conducted clinical trials in primary insomnia enrolling over 4,000 adults, gaboxadol was observed to have favorable safety and oral bioavailability profiles. In one of the trials conducted by Lundbeck, there were reports of hallucinations in drug abusers at 30mg and 45mg doses of gaboxadol, which are higher than the 10mg and 15mg doses that were effective for sedation. In addition, some patients treated with gaboxadol in the Lundbeck Phase 3 trials experienced headaches, nausea and dizziness.
 * Adverse Effects
 * New section

1 Morris, Hamilton (August 2013). "Gaboxadol". Harper's Magazine. Retrieved 2014-11-20. 2 US Patent 4278676 - Heterocyclic compounds 3 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 3 Roth, T; Lines, C; Vandormael, K; Ceesay, P; Anderson, D; Snavely, D (2010). “Effect of Gaboxadol on Patient-reported Measures of Sleep and Waking Function in Patients with Primary Insomnia: Results from Two Randomized, Controlled, 3-month Studies”. Journal of Clinical Sleep Medicine. 6 (1): 30-39. . 4 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 5 Roden, W; Peugh, L; Jansen, L (2010). “Altered GABAA Receptor Subunit Expression and Pharmacology in Human Angelman Syndrome Cortex”. Neuroscience Letters. 483 (3): 167–172. doi:10.1016/j.neulet.2010.08.001. 6 Carroll, John (11 April 2017). “Jeremy Levin spotlights a trendy new way to build a pipeline with his $86M IPO for Ovid”. Endpoints News. Retrieved 2017-08-22. 7 Melao, Alice (12 July 2017). “Ovid’s Therapy for Angelman Syndrome OV101 Is Focus of Clinical Trials”. Angelman Syndrome News. Retrieved 2017-08-22. 8 Egawa, K; Kitagawa, K; Inoue, K; Takayama, M; Takayama, C; Saitoh, S; Kishino, T; Kitagawa, M; Fukuda, A (2012). “Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome”. Science Translational Medicine. 4 (163): 1-11. doi:10.1126/scitranslmed.3004655. 9 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 10 Roth, T; Lines, C; Vandormael, K; Ceesay, P; Anderson, D; Snavely, D (2010). “Effect of Gaboxadol on Patient-reported Measures of Sleep and Waking Function in Patients with Primary Insomnia: Results from Two Randomized, Controlled, 3-month Studies”. Journal of Clinical Sleep Medicine. 6 (1): 30-39. 11 Egawa, K. & Fukuda, A. (2013). “ Pathophysiological power of improper tonic GABAA conductances in mature and immature models”. Frontiers in Neural Circuits. 7:1-15. doi:10.3389/fncir.2013.00170. 12 Egawa, K; Kitagawa, K; Inoue, K; Takayama, M; Takayama, C; Saitoh, S; Kishino, T; Kitagawa, M; Fukuda, A (2012). “Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome”. Science Translational Medicine. 4 (163): 1-11. doi:10.1126/scitranslmed.3004655. 13 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 14 Egawa, K; Kitagawa, K; Inoue, K; Takayama, M; Takayama, C; Saitoh, S; Kishino, T; Kitagawa, M; Fukuda, A (2012). “Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome”. Science Translational Medicine. 4 (163): 1-11. doi:10.1126/scitranslmed.3004655. 15 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 16 Egawa, K; Kitagawa, K; Inoue, K; Takayama, M; Takayama, C; Saitoh, S; Kishino, T; Kitagawa, M; Fukuda, A (2012). “Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome”. Science Translational Medicine. 4 (163): 1-11. doi:10.1126/scitranslmed.3004655. 17 Whissel, P; Lecker, I; Wang, D; Yu, J; Orser, B (2015). “Altered expression of dGABAA receptors in health and disease”. Neuropharmacology. 88: 24-35. doi:10.1016/j.neuropharm.2014.08.003. 18 Melao, Alice (12 July 2017). “Ovid’s Therapy for Angelman Syndrome OV101 Is Focus of Clinical Trials”. Angelman Syndrome News. Retrieved 2017-08-22. 19 Ovid Therapeutics, Inc., Form S-1 Registration Statement Under the Securities Act of 1933. Filed April 10 2017. https://www.sec.gov/Archives/edgar/data/1636651/000119312517118846/d286200ds1.htm, accessed 2017-08-22. 20 Ovid Therapeutics, Inc., Form S-1 Registration Statement Under the Securities Act of 1933. Filed April 10 2017. https://www.sec.gov/Archives/edgar/data/1636651/000119312517118846/d286200ds1.htm, accessed 2017-08-22.
 * References

KellyF5 (talk) 22:47, 17 November 2017 (UTC)


 * Hi KellyF5 - thanks for complying with the PAID policy. That is awesome. There is pretty nothing we can use here.  I will explain at your talk page. Jytdog (talk) 05:53, 18 November 2017 (UTC)