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And Metabotropic Glutamate Receptor 5 (MGLU5) Irreversible Probes for Identifying Anti-Psychostimulant Therapeutics Ranganadh Velagaleti

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And Metabotropic Glutamate Receptor 5 (MGLU5) Irreversible Probes for Identifying Anti-Psychostimulant Therapeutics Ranganadh Velagaleti Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Spring 2014 Dopamine Transporter (DAT) and Metabotropic Glutamate Receptor 5 (MGLU5) Irreversible Probes for Identifying Anti-Psychostimulant Therapeutics Ranganadh Velagaleti Follow this and additional works at: https://dsc.duq.edu/etd Recommended Citation Velagaleti, R. (2014). Dopamine Transporter (DAT) and Metabotropic Glutamate Receptor 5 (MGLU5) Irreversible Probes for Identifying Anti-Psychostimulant Therapeutics (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/ etd/1306 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. For more information, please contact [email protected]. DOPAMINE TRANSPORTER (DAT) AND METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) IRREVERSIBLE PROBES FOR IDENTIFYING ANTI-PSYCHOSTIMULANT THERAPEUTICS A Dissertation Submitted to the Graduate School of Pharmaceutical Sciences Duquesne University In partial fulfillment of the requirements for the degree of Doctor of Philosophy By Ranganadh Velagaleti May 2014 Copyright by Ranganadh Velagaleti 2014 DOPAMINE TRANSPORTER (DAT) AND METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) IRREVERSIBLE PROBES FOR IDENTIFYING ANTI-PSYCHOSTIMULANT THERAPEUTICS By Ranganadh Velagaleti Approved February 17, 2014 ________________________________ ________________________________ David J. Lapinsky, Ph.D. Aleem Gangjee, Ph.D. Committee Chair, Associate Professor of Committee Member, Professor of Medicinal Chemistry, Graduate School of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA University, Pittsburgh, PA _ _______________________________ ________________________________ Patrick T. Flaherty, Ph.D. Marc W. Harrold, Ph.D. Committee Member, Associate Professor Committee Member, Professor of of Medicinal Chemistry, Graduate School Medicinal Chemistry, Graduate School of of Pharmaceutical Sciences, Duquesne Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA University, Pittsburgh, PA ________________________________ ________________________________ Christopher K. Surratt, Ph.D. David A. Johnson, Ph.D. Committee Member, Professor of Division Head of Pharmaceutical Pharmacology, Graduate School of Sciences, Duquesne University, Pharmaceutical Sciences, Duquesne Pittsburgh, PA University, Pittsburgh, PA iii ABSTRACT DOPAMINE TRANSPORTER (DAT) AND METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLU5) IRREVERSIBLE PROBES FOR IDENTIFYING ANTI-PSYCHOSTIMULANT THERAPEUTICS By Ranganadh Velagaleti May 2014 Dissertation supervised by Dr. David J. Lapinsky Numerous behavioral studies indicate that dopamine transporter (DAT) inhibitors and metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) possess promising anti-addiction therapeutic properties. However, the lack of human DAT (hDAT) and mGlu5 X-ray crystal structures makes it difficult to understand how these promising anti-addiction compounds interact with their major drug targets at the molecular level. This knowledge gap represents an important problem towards rationally designing new therapeutics for numerous addiction disorders. The objective of this research was to develop irreversible chemical probes based on select DAT inhibitors and mGlu5 NAMs in order to map the corresponding binding sites and poses of these compounds within their major drug targets. The central hypothesis was that these compounds could be derivatized, without significant loss in pharmacological activity, with a functional group capable of forming a covalent bond to their target protein and, if iv necessary, a tag functional group. These probes would then allow proteomic experiments to be coupled with computational modeling in order to directly map the ligand-binding sites of these promising anti-addiction compounds within their target proteins. The central hypothesis was tested by pursuing two specific aims: 1) identification of non- tropane DAT inhibitor photoprobes suitable for DAT structure-function studies, and 2) identification of irreversible mGlu5 NAM ligands as chemical probes suitable for mGlu5 structure-function studies. Under the first aim, methylphenidate (MP) and GBR-12909 as non-tropane DAT inhibitors were structurally modified to contain a photoreactive group (e.g., aryl azide, benzophenone) and a tag (e.g., 125I, terminal alkyne, aliphatic azide). These compounds were then subjected to DAT pharmacological evaluation in order to identify suitable candidates for DAT structure-function studies. Under the second aim, thiazole- and pyridine-based mGlu5 NAMs were structurally modified to contain either a photoreactive group (e.g., aryl azide, benzophenone) or an affinity labeling group (e.g., methanethiosulfonate, maleimide) and a tag (e.g., 125I, terminal alkyne, aliphatic azide). These compounds were then subjected to mGlu5 pharmacological evaluation in order to identify suitable chemical probe candidates for mGlu5 structure-function studies. At present, several irreversible chemical probes from these specific aims have advanced to the proteomics stage of the experimental research strategy. v Dedicated to My Family vi ACKNOWLEDGEMENTS I sincerely thank my research advisor, Dr. David J. Lapinsky, for his continual guidance and necessary help throughout these years in order to try and bring out the best in me. I will be forever grateful to him for his accessibility and consistent support with respect to addressing numerous issues associated with my research. I convey my deep gratitude for his continuous direction in completing the graduate program as well as his great emotional support. I express thanks to my dissertation committee members Dr. Aleem Gangjee, Dr. Patrick Flaherty, Dr. Marc Harrold, Dr. Christopher Surratt, and Dr. David Johnson for their valuable time in extending guidance towards completing the graduate program in medicinal chemistry at Duquesne University. I sincerely thank Dr. Christopher Surratt, and Dr. Karen Gregory for the biological evaluation of my compounds. I thank Miss Jackie Farrer, Miss Nancy Hosni, Miss Deborah Willson, and Miss Mary Caruso for their unconditional support in administrative affairs. I would also like to thank the Department of Medicinal Chemistry and the Graduate School of Pharmaceutical Sciences at Duquesne University for both admission and financial assistance, without which I could not have accomplished my goal of earning a Ph.D. in medicinal chemistry. Finally, I am grateful to all my friends and family members for their timely direction and emotional support during this experience. vii TABLE OF CONTENTS Page Abstract .............................................................................................................................. iv Dedication .......................................................................................................................... vi Acknowledgements ........................................................................................................... vii List of Figures .................................................................................................................. xix List of Schemes ............................................................................................................... xxii List of Abbreviations ..................................................................................................... xxxi 1. Biological Literature Review ...................................................................................... 1 1.1. The Problem of Cocaine Abuse .......................................................................... 1 1.2. Cocaine and the Dopaminergic System .............................................................. 3 1.2.1. The Dopaminergic System .................................................................. 3 1.2.2. Effects of Cocaine on the Dopaminergic System ................................ 4 1.3. The DAT ............................................................................................................. 6 1.3.1. Chemical Composition and Structure of the DAT .............................. 6 1.3.2. Proposed Mechanism of Dopamine Reuptake by the DAT ................ 7 1.4. DAT Ligands .................................................................................................... 11 1.4.1. DAT Substrates ................................................................................. 11 1.4.2. DAT Inhibitors .................................................................................. 12 1.4.2.1. “Cocaine-Like” DAT Inhibitors ......................................... 12 1.4.2.1.1. Tropanes ........................................................... 12 1.4.2.1.2. Methylphenidate (MP) ..................................... 13 1.4.2.2. “Atypical” DAT Inhibitors ................................................. 14 1.4.2.2.1. Benztropines ..................................................... 14 1.4.2.2.2. GBR-12909 ...................................................... 15 1.4.3. Unique Behavioral Responses of DAT Inhibitors ............................. 16 1.5. Cocaine and the Glutamatergic System ............................................................ 18 1.5.1. The Glutamatergic System ................................................................ 18
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