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dc.contributor.advisorSumien, Nathalie
dc.creatorClaudio, Maria del Carmen
dc.date.accessioned2021-12-16T21:15:10Z
dc.date.available2021-12-16T21:15:10Z
dc.date.issued2021-05
dc.identifier.urihttps://hdl.handle.net/20.500.12503/30765
dc.description.abstractCarisoprodol (CSP) is a centrally-acting prescription muscle relaxant that can directly activate, allosterically modulate and inhibit GABAA receptors. The GABAA receptor is a pentameric chloride ion channel in the cys-loop receptor family. The mechanism of GABAA's inhibitory role in the central nervous system lies in the resulting hyperpolarized state of the cell following chloride ion influx upon ligand binding. GABAA receptors are the target of many different clinically prescribed compounds because of the role they play in regulating the central nervous system. We used pharmacological and computational approaches to investigate the underlying mechanism mediating carisoprodols effects at GABAA receptors, with the ultimate goal of generating a new subunit selective compound related to the structure of carisoprodol and gaining a more thorough understanding of the molecular interaction governing carisoprodol's pharmacoglogical effects. Our evaluation of novel compounds related to the structure of carisoprodol did not yield promising leads, though the potential still remains for development of a novel carisoprodol-related compound with a unique selectivity profile. Probe for a binding site mediating carisoprodols postive modulatory effects and evaluation of additional novel compounds was eventually hindered by time. Our investigaiton into carisoprodol's direct gating effects involved a previously reported single amino acid residue, L415, located at the top of the fourth transmembrane domain (TM4) in the ɑ1 subunit of the GABAA receptor that is critical to carisoprodol's direct gating. Whether the residue is involved in a carisoprodol binding site remained unsolved. In studies probing for a binding site for carisprodol's direct activation of GABAA receptors, promising computaitonal docking data was not able to be validated with elecrophysiology and site-directed mutatgenesis studies, indicating that the residues revealed in docking studies do not form a binding pocket for carisprodol's direct activation effect. Our site directed mutagenesis, electrophysiology and molecular dynamic simulation studies to investigate carisoprodol's inhibitory effects at GABAA receptors revealed a binding site at the Cl- channel pore, in a mechanism similar to picrotoxin, providing a mechanism of action for carisoprodol's inhibitory effects at GABAA receptors.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.subjectGABA
dc.subjectGABAA receptor
dc.subjectcarisoprodol
dc.subject.meshgamma-Aminobutyric Acid
dc.subject.meshReceptors, GABA-A
dc.subject.meshCarisoprodol
dc.titleCarisoprodol's Pharmacological Properties at GABAA Receptors, In-vitro and In-silico Studies
dc.typeThesis
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberHuang, Ren-Qi
dc.contributor.committeeMemberGonzales, Eric B.
dc.contributor.committeeMemberDillon, Glenn H.
dc.contributor.committeeMemberMathew, Porunelloor A.
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