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Dalwadi, Dhwanil, A, PREVENTION and TREATMENT of DISEASES: a SMALL MOLECULE DISCOVERY and DEVELOPMENT. Doctor of Philosophy (Bio

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Dalwadi, Dhwanil, A, PREVENTION and TREATMENT of DISEASES: a SMALL MOLECULE DISCOVERY and DEVELOPMENT. Doctor of Philosophy (Bio Dalwadi, Dhwanil, A, PREVENTION AND TREATMENT OF DISEASES: A SMALL MOLECULE DISCOVERY AND DEVELOPMENT. Doctor of Philosophy (Biomedical Sciences), August, 2016, 227 pp., 6 tables, 32 illustrations, 256 references. This 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. PREVENTION AND TREATMENT OF DISEASES: A SMALL MOLECULE DISCOVERY AND DEVELOPMENT APPROACH Dhwanil A Dalwadi, BSc hon APPROVED: ______________________________________________________ Major Professor ______________________________________________________ Committee Member ______________________________________________________ Committee Member ______________________________________________________ Committee Member ______________________________________________________ University Member ______________________________________________________ Chair, Department of Pharmacology and Neuroscience ______________________________________________________ Dean, Graduate School of Biomedical Sciences ______________________________________________________ PREVENTION AND TREATMENT OF DISEASES: A SMALL MOLECULE DISCOVERY AND DEVELOPMENT APPROACH DISSERTATION Presented to the Graduate Council of the Graduate School of Biomedical Sciences University of North Texas Health Science Center at Fort Wroth In Partial Fulfillment of the Requirements For the Degree of DOCTOR OF PHILOSOPHY By Dhwanil A. Dalwadi, BSc hon Fort Wroth, Texas August 2016 Copyright by Dhwanil A. Dalwadi 2016 ii ACKNOWLEDGEMENTS I wish to thank my mentor Dr. John A Schetz for his guidance and the opportunity to work on exciting projects. I would also like to thank my committee members for their support and valuable input that helped to make this project a success. iii TABLE OF CONTENTS LIST OF TABLES……………………………………………………………………………...viii LIST OF ILLUSTRATIONS…………………………………..…………………………………ix I. INTRODUCTION…………………………………………………………………………….1 Classical versus reverse pharmacology……………………………………………………….2 Application of pharmacological principles for evaluating small molecules at receptor targets………………………………………………………………………………………….4 In vitro experimental approaches to studying receptor-ligand interactions…………………...7 Estimating agonist affinity from functional assays using the operational model of agonism………………………………………………………………………………………..9 Estimating antagonists affinity from functional assays using Schild analysis………………11 Application of theory………………………………………………………………………...13 References……………………………………………………………………………………28 II. EXPLORATION OF THE STRUCTURE-ACTIVITY SPACE OF CLONED Α-LIKE OCTOPAMINE RECEPTORS FROM A MARINE BARNACLE AND A TERRESTRIAL FLY………………………………………………………………………..33 Abstract………………………………………………………………………………………33 Introduction…………………………………………………………………………………..34 Materials and methods……………………………………………………………………….40 Chemicals………………………………………………………………………………...40 Establishment of a stable cell line expressing the Barnacle Balanus Improvisus and D. melanogaster octopamine receptors (BiOctR and DmOctR, respectively)……………...40 Profiling of BiOctR by radioligand binding……………………………………………..41 iv Assessment of sodium sensitivity of BiOctR……………………………………………43 Protein Assay…………………………………………………………………………….43 Intracellular Calcium assay: measurement of Gq-coupled response……………………..43 Operational model of agonism and Schild-shift analysis………………………………..44 Cyprid motility assay…………………………………………………………………….45 Results………………………………………………………………………………………..46 Discussion……………………………………………………………………………………56 Conclusion…………………………………………………………………………………...61 References……………………………………………………………………………………79 III. NOVEL SELECTIVE SIGMA-1 RECEPTOR LIGANDS FACILITATE BDNF RELEASE FROM A NEURONAL CELL………………………………………………………………86 Abstract………………………………………………………………………………………86 Introduction…………………………………………………………………………………..87 Materials and methods……………………………………………………………………….92 Chemical and reagents…………………………………………………………………...92 Cell culture……………………………………………………………………………….92 Measurement of BDNF secretion via in situ ELISA…………………………………….93 Measuring receptor density with radioligand binding…………………………………...94 Measuring the ligand affinities at S1R and S2R receptors by radioligand binding……...95 Measurement of the effect of sigma ligands on IP3-induced change in intracellular calcium…………………………………………………………………………………...95 Effect of sigma ligands on NGF induced neurite sprouting……………………………..96 Results………………………………………………………………………………………..97 Discussion…………………………………………………………………………………..104 v Conclusion………………………………………………………………………………….111 References…………………………………………………………………………………..126 IV. MOLECULAR MECHANISMS OF SEROTONERGIC ACTION OF THE HIV-1 ANTIRETROVIRAL EFAVIRENZ……………………………………………………….135 Abstract……………………………………………………………………………………..135 Introduction…………………………………………………………………………………138 Materials and methods……………………………………………………………………...141 Chemicals……………………………………………………………………………….141 Profiling serotonin receptors by radioligand binding…………………………………..141 Measuring the affinity of efavirenz for selected serotonin receptor subtypes using competition radioligand binding………………………………………………………..143 Intracellular Calcium and IP-One Assay: measurement of Gq-coupled response……...144 Effect of prolonged exposure to efavirenz on receptor density and Gq-coupled activation of the 5-HT2A receptor………………………………………………………………….145 Cyclic adenosine monophosphate (cAMP) Assay: measurement of Gs-coupled responses Inhibition of monoamine oxidase A (MAO-A) activity………………………………..146 Inhibition of monoamine oxidase A (MAO-A) activity………………………………..147 Protein Assay…………………………………………………………………………...147 Measurement of 5-HT3A and GABAA receptor currents using electrophysiology……..147 Results………………………………………………………………………………………149 Discussion…………………………………………………………………………………..158 Conclusion………………………………………………………………………………….166 References…………………………………………………………………………………..195 Acknowledgements…………………………………………………………………………207 Author contribution…………………………………………………………………………208 vi Funding sources…………………………………………………………………………….208 Conflict of interest………………………………………………………………………….208 V. CONCLUSION……………………………………………………………………………..209 Exploration of the structure-activity space of cloned α-like octopamine receptors from a marine barnacle and a terrestrial fly………………………………………………………...209 Novel selective Sigma-1 receptor ligands facilitate BDNF release from a neuronal cell line……………………………………………………………………………………...212 Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz……...215 Summary statement…………………………………………………………………………217 References…………………………………………………………………………………..218 vii LIST OF TABLES Table 2-1 BiOctR has affinity for α-adrenergic receptor antagonists, D2 dopamine receptor antagonists and a histamine H1 receptor antagonist……………………………………………...76 Table 2-2 Table 2. Imidazoles are potent agonists at the BiOctR and have higher affinity than biogenic amines………………………………………………………………………………….77 Table 3-1 PRE-084 is the most selective prototypical agonist and BD1063 is the most selective prototypical antagonist………………………………………………………………………….123 Table 3-2 Effect of specific substructural modifications on selectivity for S1R over S2R…….124 Table 3-3 Efficacy of S1R ligands that function as agonists of BDNF secretion……………....125 Table 4-1 Conditions for measuring efavirenz’s ability to displace radioligands specifically bound to the serotonin receptor subtypes……………………………………………………….142
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