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dc.contributor.advisorGabrielsen, Mari
dc.contributor.advisorWushur, Imin
dc.contributor.authorHadi, Ali Muataz
dc.date.accessioned2022-05-18T09:43:08Z
dc.date.available2022-05-18T09:43:08Z
dc.date.issued2020-05-14en
dc.description.abstractγ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the CNS. GABA exerts its function on both ionotropic ligand-gated GABAA receptors and metabotropic GABAB G-protein coupled receptors (GPCRs). Disruption in the GABAergic system has been associated with numerous neurological and psychiatric disorders in humans. These include developmental dysfunctions, epilepsy, sleep disorders, drug and alcohol dependence, schizophrenia, motor coordination disorders, anxiety, autism, inability to regulate emotions, Huntington's disease, and Parkinson's disease. Hence, developing drugs to act on such a remarkable system can attract much attention and be beneficial. In recent years, there has been colossal attention toward development of allosteric modulators of GPCRs. These compounds provide high selectivity, novel modes of action and may lead to unique therapeutic agents for the treatment of many neurological and psychiatric human disorders. Baclofen, a GABAB receptor agonist, is still the only GABAB receptor approved drug, and is used for the treatment of muscle spasticity associated with spinal cord injury and multiple sclerosis; however, numerous side effects hamper its clinical use. Allosteric modulators, on the other hand, are expected to have a much better side-effect profile than traditional orthosteric drugs. In the current study, in silico and in vitro methods were adopted to screen for potential negative allosteric modulators within the MolPort database. A sequential combination of ligand- and structure-based virtual screening was first performed to reduce the significant number of chemical compounds followed by the in vitro experimental testing. The virtual screening procedure facilitated the selection of 16 hit compounds that were purchased and tested experimentally using an in vitro functional assay. Only one compound, A-8, was tested in a dose-response cAMP assay, and results indicate that it is a negative allosteric modulator. In addition, analysis of the initial test results suggests that A-9 might be a negative allosteric modulator and that A-20 might be a positive allosteric modulator. Further accurate experimental tests are required for these compounds.en_US
dc.identifier.urihttps://hdl.handle.net/10037/25162
dc.language.isoengen_US
dc.publisherUiT Norges arktiske universitetno
dc.publisherUiT The Arctic University of Norwayen
dc.rights.holderCopyright 2020 The Author(s)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0en_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)en_US
dc.subject.courseIDFAR-3911
dc.subjectVDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711en_US
dc.subjectVDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711en_US
dc.titleThe search of new negative allosteric GABAB receptor modulators using in silico and in vitro approachesen_US
dc.typeMastergradsoppgaveno
dc.typeMaster thesisen


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Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0)