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University of Kentucky UKnowledge Theses and Dissertations--Pharmacy College of Pharmacy 2014 LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE Zheng Cao University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Cao, Zheng, "LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE" (2014). Theses and Dissertations--Pharmacy. 32. https://uknowledge.uky.edu/pharmacy_etds/32 This Doctoral Dissertation is brought to you for free and open access by the College of Pharmacy at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Pharmacy by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Zheng Cao, Student Dr. Linda P. Dwoskin, Major Professor Dr. Jim R. Pauly, Director of Graduate Studies LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE DISSERTATION A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Pharmacy at the University of Kentucky By Zheng Cao Lexington, Kentucky Director: Dr. Linda Dwoskin, Professor of Pharmaceutical Sciences Lexington, Kentucky 2014 Copyright © Zheng Cao 2014 ABSTRACT OF DISSERTATION LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE Methamphetamine interacts with vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine (DA) uptake and promotes DA release from presynaptic vesicles, increasing cytosolic DA available for methamphetamine- induced reverse transport by DA transporters. By inhibiting VMAT2, lobelane, a defunctionalized, saturated lobeline analog, decreases methamphetamine- evoked DA release and methamphetamine self-administration in rats. In this dissertation structure-activity relationships around the lobelane structure were investigated on racemic lobelane analogs with varying methylene linker lengths at central piperidine ring. Affinity for dihydrotetrabenazine (DTBZ) sites on VMAT2 and for inhibition of VMAT2 function was determined to be 0.88-63 and 0.024-4.6 µM, respectively, and positively correlated. The most potent and selective analog, (±)-cis-2-benzyl-6-(3-phenylpropyl)piperidine [(±)-GZ-730B], for VMAT2 uptake was identified as the lead. The ability of (±)-GZ-730B to inhibit methamphetamine-evoked [3H]DA release from striatal synaptic vesicles and endogenous DA release from striatal slices was determined. The lead analog- induced inhibition of methamphetamine-evoked vesicular [3H]DA release did not translate to inhibition of methamphetamine-evoked DA release in the more intact striatal slices. Moreover, poor water solubility of these lobelane analogs prohibited further in vivo work. Subsequent work focused on analogs with the C-3 and C-4 carbons in the piperidine ring eliminated to afford racemic acyclic lobelane analogs. Generally, acyclic analogs exhibited greater water solubility and less lipophilicity compared to lobelane. Acyclic analogs exhibited affinities (Ki 3 = 0.096-17 μM) for [ H]DTBZ sites that correlated positively with affinity (Ki = 3.3- 300 nM) for inhibition of [3H]DA uptake. Pure enantiomers of potent racemic analogs were synthesized, and found to potently, selectively, and competitively inhibit [3H]DA uptake at VMAT2 and to release vesicular [3H]DA in a biphasic manner. Lead enantiomer (R)-N-(1-phenylpropan-2-yl)-3-phenylpropan-1-amine [(R)-GZ-924] inhibited methamphetamine-evoked [3H]DA release from striatal synaptic vesicles, but not from the more intact striatal slices. Surprisingly, (R)- GZ-924 inhibited nicotine-evoked [3H]DA overflow from striatal slices, revealing nonspecific effects. Importantly, (R)-GZ-924 inhibited methamphetamine self- administration in rats. However, the analog also inhibited food-maintained responding, revealing a lack of specificity. The lead analog will not be pursued further as a pharmacotherapy due to the lack of specificity. Further evaluation of the pharmacophore is needed to discover analogs which specifically inhibit the neurochemical and behavioral effect of methamphetamine. KEYWORDS: Lobeline, Lobelane, Methamphetamine, Vesicular Monoamine Tranporter-2, (R)-GZ-924 Zheng Cao Student’s Signature 03/15/14 Date LOBELANE ANALOGS WITH VARIOUS METHYLENE LINKER LENGTHS AND ACYCLIC LOBELANE ANALOGS AS POTENTIAL PHARMACOTHERAPIES TO TREAT METHAMPHETAMINE ABUSE by Zheng Cao Dr. Linda P. Dwoskin Director of Dissertation Dr. Jim R. Pauly Director of Graduate Studies December 4, 2012 Acknowledgement I would like to thank my advisor Dr. Linda Dwoskin for the support and guidance that help my scientific career. In addition, I would like to thank my committee members: Dr. Michael Bardo, Dr. Kimberly Nixon, and Dr. Kyung-Bo Kim for their time and advice. I would like to thank Dr. Lawrence Gottlob for agreeing to be my outside examiner. I would like to thank former and current members in Dr. Dwoskin’s lab: Dr.Justin Nickell, Dr. Kiran Babu Siripurapu, Agripina Deaciuc, Dr. Andrew Smith, Dr. Mahesh Darna, Dr. David Horton, Dr. Vidya Narayanaswami, and Dr. Sucharita Sen Somkuwar. Their frequent discussion with me improved my English speaking and the understanding of their and my own project. I would like to thank Dr. Peter Crooks and Dr. Guangrong Zheng for synthesis of the compounds and their expertise on chemistry. I would like to thank members in Dr. Bardo’s lab: Dr. Josh Beckmann, Dr. Carrie Wilmouth and Emily Denehy for performing the behavior study and their expertise. I would like to thank Catina Rossoll and Charolette Garland for their assistance and coordination. This research was supported by NIH DA13519 and UL1TR000117. The University of Kentucky holds patents on lobeline and the analogs described in the current work. A potential royalty stream to LPD, GZ and PAC may occur consistent with University of Kentucky policy. I would like to thank my parents, Hongzhi Cao and Weimin Hu, for years of support and love. You are the best parents. I would like to thank my wife, iii Xiaoyan Zhang, for your love and patience and I could never finish this dissertation without you. iv Table of Contents Acknowledgement .......................................................................................................... iii List of Tables ................................................................................................................ viii List of Figures ................................................................................................................. ix CHAPTER 1 Introduction ............................................................................................ 1 1.1 Methamphetamine ............................................................................................ 1 1.1.1 Physicochemical Characteristics ............................................................... 1 1.1.2 History and Background ............................................................................ 1 1.1.3 Pharmacokinetics ...................................................................................... 5 1.1.4 Clinical Pharmacology ............................................................................... 6 1.2 DA and Reward ................................................................................................ 8 1.2.1 DA Biosynthesis, Metabolism and Storage ................................................ 8 1.2.2 DA Receptors ...........................................................................................10 1.2.3 Dopaminergic Pathways ...........................................................................11 1.2.4 DA Transporter (DAT) ..............................................................................12

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