Carbazole Based Multifunctional Dopamine Agonists and Related Molecules As Potential Symptomatic and Disease Modifying Therapeutic Agents for Parkinson’S Disease
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Wayne State University Wayne State University Dissertations January 2018 Carbazole Based Multifunctional Dopamine Agonists And Related Molecules As Potential Symptomatic And Disease Modifying Therapeutic Agents For Parkinson’s Disease Asma S.mohamed Elmabruk Wayne State University, [email protected] Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Chemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, and the Nanoscience and Nanotechnology Commons Recommended Citation Elmabruk, Asma S.mohamed, "Carbazole Based Multifunctional Dopamine Agonists And Related Molecules As Potential Symptomatic And Disease Modifying Therapeutic Agents For Parkinson’s Disease" (2018). Wayne State University Dissertations. 2022. https://digitalcommons.wayne.edu/oa_dissertations/2022 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. CARBAZOLE BASED MULTIFUNCTIONAL DOPAMINE AGONISTS AND RELATED MOLECULES AS POTENTIAL SYMPTOMATIC AND DISEASE MODIFYING THERAPEUTIC AGENTS FOR PARKINSON’S DISEASE by ASMA ELMABRUK DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2018 MAJOR: PHARMACEUTICAL SCIENCES Approved By: Advisor Date iii © COPYRIGHT BY ASMA ELMABRUK 2018 All Rights Reserve ii DEDICATION This work is dedicated to the spirit of my father, to my mom, my husband, my siblings, my children, and my friends who have always been there for me. ii iii ACKNOWLEDGMENTS It is such a great honor and pleasure for me to have the privilege to work with all the lab crews in order to accomplish this mission. I am very delighted to get the opportunity to convey my gratitude to all the members who assisted with this research. I would like to show my deep appreciation to my advisor Dr. Aloke Dutta. I will not be able to make it this far if it was not for Dr.Dutta’s advice, wisdom, and guidance. My journey with him was full of fun and excitement. In addition, I got the opportunity to imbibe from this wonderful professor golden strategies and techniques of how to run a research study in the future. Dr. Dutta is an inspiration and a role model of a great scholar. I also want to express my profound gratefulness to my committee members Dr. David Pitts, Zhihui Qin, and Ladisalau Kovari for their supervision and crucial support, which made them a vital part in my desertification. Furthermore I want to thank our department chair George Corcoran and helper Dr.Randall Commissaris. Dr. Pitts and Dr. Corcoran were there for me when my father passed. When I was grieving over my father, they gave me moral support that made me stronger to overcome any sort of hardship that I faced during my journey. I greatly acknowledge the benefits that I gained from their assistance of our present and past lab members Dr. Dan Luo, Tran Vo, Dr. Banibrata Das, Liping Xu, Dr. Bidyut Dinda, Pranay Ravipati , Dr. Deepthi Yedlapudi, Dr. Somava Santra Dr. Horrick Sharma, Dr. Seenuvasan Vedachalam, Dr. Chandrashekhar Voshavar , and Fahd Dholkwala. I sincerely want to show my praise and appreciation towards, NINDS Grant (NS 047198, AKD) for providing financial support for this research, and the department of iii iv pharmaceutical sciences at the Wayne State University for giving me the opportunity to pursue my graduate study here. iv v TABLE OF CONTENTS Dedication…………………………………………………………………………………….…. ii Acknowledgements……………………………………………………………….…………… iii List of table. ………………………………………………………………….………………….x List of figures. ………………………………………………………………………………….. xi List of schemes. ……………………………………………………………………….……... xiv Chapter 1- introduction………………………………………………………………………….1 1.1. Parkinson’s disease……………………………………………………………………..1 1.2. Prevalence of PD…………………………………………………….………………… 5 1.3. Factors implicated in the pathogenesis of the disease……………………………….6 1.3.1. Mitochondrial dysfunction and oxidative stress……………………………….………7 1.3.1.1. Enzymatic and auto-oxidative da metabolism PD…………………………….9 1.3.1.2. Compromised antioxidant defense pathways ……………………………………. 13 1.3.2. Protein aggregation…………………………………………………………………....14 1.3.3. Genetic factors………………………………………………………………………....16 1.3.4. Environmental factors………………………………………………………………....17 1.4. Therapeutic strategies in PD……………………………………………………..…...18 1.4.1. symptomatic therapy………………………………………………………………….19 1.4.1.1. Levodopa therapy……………………………………………………………...19 1.4.1.2. Dopamine agonist……………………………………………........................ 20 1.4.1.3. Monoamine oxidase inhibitors (MAO-Is)…………………………………….21 1.4.1.4. Catechol-O-methyl transferase inhibitors (COMT-Is)……………………....22 1.4.1.5. NMDA glutamate type receptor……………………………………………….22 v vi 1.4.2. Neuroprotective therapy……………………………………………………………….24 1.4.2.1. Mechanisms of neuroprotection…………………………………………………….25 1.5. An overview of dopamine receptor system………………………………………....26 1.6. The clinical trial of neuroprotection in PD with dopamine receptor agonists…………………………………………………………………….……………………..26 Chapter 2. The unmet and emergence need to develop single medication with multifunctional to treat Parkinson’s disease. .……………..…………….…………………….29 2.1. Previous work of development of a multifunctional agent to treat neurodegenerative diseases……………………………………………………………………………………....…..30 2.1.1. Combination of anticholinesterases and muscarinic M2 receptor antagonism…....31 2.1.2. Combination of iron chelating and MAO inhibitors…………………………………...31 2.1.3. Combination of iron chelating and MAO inhibitors…………………………………...31 2.1.4 Combination of anticholinesterases and NMDA receptor antagonism…………….32 2.1.5. Combination of MAO-B and COMT inhibitors…….....……………………………….33 2.1.6. Combination of neuroleptic D2 receptor antagonist and an SSRI………………….33 2.1.7. Combination of squalene synthase inhibitor and anti-inflammatory………………..33 2.2. Development of multifunctional ligands to treat PD…………………………………....34 2.2.1. Development of multifunctional ligands to treat PD with a neuroprotective property……………………………………………………………………………………….......35 2.2.2. Development of multifunctional ligands with MAO I property as neuroprotective therapeutic agents for PD……………………………………………………………………….37 2.2.3. Development of multifunctional ligands to treat depression associated with PD…………………………………………...…………………………………………………….40 Chapter 3- hypothesis and specific aims. 3.1. Hypothesis…………………………………………………………………………......….46 3.2. General aims……………………………………………………………………………....47 vi vii 3.3. Specific aims. ……………………………………………………………………………..48 3.3.1. In Vitro binding Studies (Radioligand binding assay) ………………...…………….48 3.3.2. In Vitro Functinal Studies ([35S] GTPγS Binding in vitro functional assay)) ……....49 3.3.3. Neuroprotection study) …………………………………………………........……….49 3.3.4. In vitro Antioxidant study………………………………………………...…………….49 3.3.5. In vitro Monoamine oxidase inhibitors assay………………………………………...49 3.3.6. In vivo assay with rat model of PD……………..…………………………………….49 Chapter 4- result and discussion 4.1. Overview. …………………………………..…………………………………………..50 4.2. Design, Synthesis and Pharmacological Characterization of Carbazole Based Dopamine Agonists as Potential Symptomatic and Neuroprotective Therapeutic Agents for Parkinson’s Disease. …………………………………………………………………………....50 4.2.1. Chemistry involved in the synthesis of carbazole based D2/D3 agonists. ……………………………………………………………………………………………………..53 4.2.2. In vitro characterization of the Carbazole Based Dopamine Agonists molecules. ………………………………………………………………………………………………….….57 4.2.2.1. Potency and Agonism at DA D2 and D3 Receptors……………………….....57 4.2.2.2. Antioxidant assay of the lead compounds……………………………......….63 4.2.2.3. Neuroprotection Studies with PC12 cell line…………………………………65 4.2.3. In vivo Efficacy of lead molecules from carbazole series compounds…………….67 4.2.3.1. Reversal of Reserpine-induced Hypolocomotion in Rats by (-)-11b, (-)- 15a, (-)-15c and Ropinirole……………………………………………………………….….….67 4.3. Design, and synthesis of novel multifunctional dopamine D2 /D3 receptors agonists containing a propargyl moiety for potential MAO-B inhibitory activity……………………….69 4.3.1. Synthesis of multifunctional dopamine D2/D3 receptor MAO-B inhibitors…….…..69 4.3.2. In vitro D2/D3 receptor binding and functional assays with multifunctional MAOB- inhibitors…………………………………………………………………………………………..73 vii viii 4.3.3. MAO inhibition assay with multifunctional MAO-inhibitors…………………...…….76 4.4. Design, development and synthesize and pharmacological studies of monoamine reuptake blockers………………………………………………………………………………..78 4.4.1. Chemistry involved in the syntheses of multifunctional D2/D3 agonist to treat depression in PD………………………………………………………………………………....80 4.4.2. 1H NMR spectrum (normal proton NMR, 2-D COSY NMR, 1H homo decoupling...84 4.4.3. (HMDC), and nuclear overhauser experiments (NOE)) studies for the synthesized compounds……………………………………………………………………………………….84 4.4.3.1. The Study structure of epoxide 61…………………………..………………..84 4.4.3.2. The Study structure of compound 60a (D-620) ……………………………..86 4.4.3.3. In vitro evaluation of the binding affinity and functional potency for the triple reuptake inhibtor compounds………………………………….…………….………………….91 Chapter 5- materials and methods…………………………………………………….……..93 5.1. Chemistry. …………………………………………………………………….………..93 5.2. Evaluation of binding affinity and functional potencies at dopamine D2 and D3 receptors.