Browsing by Subject "sigma-1 receptor"
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Item Prevention and treatment of diseases: a small molecule discovery and development approach(2016-08-01) Dalwani, Dhwanil A.; John A. SchetzThis work examined the structure-activity relationship, and molecular mechanisms of different structural classes of small molecules at their target receptors. Three different systems were explored and each chapter is devoted to a single system. All three systems utilized similar experimental approaches, and practical application of the same core pharmacological principles. The first system involved the evaluation of the structure-activity space of small molecules acting on the α-like octopamine receptors from the barnacle Balanus improvisus (BiOctR) and the fruit fly Drosophila melanogaster (DmOctR). A number of molecules belonging to the imidazole and imidazole structural class were determined to have high potency for the BiOctR and the DmOctR. This information will be useful in designing new OctR ligands that are highly selective for the OctRs over their mammalian off-targets. Similarly, for the second system, the structure-activity space of different structural classes of sigma-1 receptor (S1R) ligands were evaluated. Four novel EPGN compounds with more than 100-fold selectivity for the S1R over the sigma-2 receptor were identified which were able to stimulate S1R-mediated BDNF secretion. Potential therapeutic applications of these compounds include the treatment of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. The third system involved the identification of receptor off-targets of efavirenz that may be responsible for efavirenz’s neuropsychiatric adverse events (NPAEs). In this study, multiple receptor targets of efavirenz belonging to the serotonin receptor family and the muscarinic receptor family of G protein-coupled receptors (GPCR) were identified, and its mechanism of action at these targets was established. The most prominent finding of this study was that efavirenz functioned as an inverse agonist, antagonist and an allosteric modulator, depending on off-the target receptor. Knowing which off-target receptors efavirenz interacts with may help to understand the molecular mechanisms responsible for efavirenz’s NPAEs. Overall, the insights gained regarding the mechanisms of action of small molecules will aid in the discovery and development of novel compounds, or an improved understanding of known compounds with established or potential therapeutic value.Item SIGMA-1 RECEPTOR STIMULATION PROTECTS PURIFIED RETINAL GANGLION CELLS FROM ISCHEMIC INSULT THROUGH THE PHOSPHORYLATION OF EXTRACELLULAR SIGNAL REGULATED KINASE 1/2(2014-03) Mueller, Brett H.; Park, Yong; Ma, Hai-Ying; Yorio, ThomasPurpose (a): Sigma-1 receptor activation and mitogen-activated protein kinases (MAPKs) have been shown to have neuroprotective roles in protecting retinal ganglion cells (RGCs) from cell death. The purpose of this study was to determine if sigma-1 receptor stimulation with pentazocine could promote neuroprotection under conditions of ischemia through the phosphorylation of extracellular signal regulated kinase (pERK)1/2. Methods (b): Primary RGCs were isolated from P3-P7 Sprague-Dawley rats and purified by sequential immunopanning using a Thy 1.1 antibody. RGCs were cultured for 7 days before subjecting the cells to an ischemic insult (0.5% oxygen in glucose-free medium) for 6 hours. During the ischemic insult, RGCs were treated with pentazocine (sigma-1 receptor agonist) with or without BD1047 (sigma-1 receptor antagonist). In other experiments primary RGCs were treated with pentazocine, in the presence or absence of PD98059 (ERK1/2 inhibitor). Cell survival/death was assessed by staining with the calcein-AM/ethidium homodimer reagent. Levels of pERK1/2, total ERK1/2, and beta tubulin expression were determined with immunoblotting and immunofluorescence. Results (c): RGCs subjected to an ischemic insult demonstrated more than a 40% increase in cell death, compared to untreated controls. RGCs maintained under ischemia also showed a 50% decrease in expression of pERK1/2 (p<0.05). Cell death was attenuated when RGCs were treated with pentazocine under ischemic conditions and levels of pERK1/2 were increased more than 60% (p<0.05), compared to untreated RGCs subjected to ischemia. Treatment with BD1047 abrogated the pentazocine neuroprotection effects, and also attenuated the increase in levels of pERK1/2 (p<0.05). Finally, treatment with PD98059 also reversed the pentazocine mediated neuroprotective effects on RGCs, and abolished the expression of pERK1/2 (p<0.05). Conclusions (d): These results establish a direct relationship between sigma-1 receptor stimulation and neuroprotective effects under ischemia through the involvement of the MAPK/ERK1/2 pathway in purified RGCs. These findings support a role for sigma receptor agonists as potential neuroprotective agents.