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dc.contributor.advisorPrisinzano, Thomas E
dc.contributor.authorCrowley, Rachel S.
dc.date.accessioned2019-05-10T15:35:16Z
dc.date.available2019-05-10T15:35:16Z
dc.date.issued2017-08-31
dc.date.submitted2017
dc.identifier.otherhttp://dissertations.umi.com/ku:15477
dc.identifier.urihttp://hdl.handle.net/1808/27823
dc.description.abstractIn the search for effective methods to mitigate the increasing rates of abuse and addiction of illicit substances, a variety of neurological pathways have been explored. Towards this goal of reducing drug abuse and ultimately overdose-related deaths, two avenues of research have emerged: 1) a preventative approach, the development of pain-relieving medications without the abuse and addiction liabilities associated with current therapies, and 2) a responsive approach, the development of medications for people suffering from drug abuse and addiction. The natural product salvinorin A can be manipulated towards both of these research avenues through the development of opioid receptor (MOR) agonists for treating pain with reduced abuse liabilities as well as through the development of  opioid receptor (KOR) agonists with improved pharmacokinetic properties towards the development of therapies that attenuate relapse and withdrawal. Previous structure-activity relationship (SAR) studies of salvinorin A identified that replacing the C2-acetate with a C2-benzoate results in a compound that is 4-fold selective for MORs over KORs. In an effort to increase this selectivity, to allow for probing the physiological effects induced upon activation of MORs with this non-morphine scaffold, a potent and selective MOR agonist kurkinorin (MOR EC50 = 1.2 ± 0.6 nM, and KOR > 10,000nM) was identified. Upon in vivo evaluation, kurkinorin was determined to elicit centrally-mediated antinociception with similar potency to morphine and a reduced tolerance, sedation, and reward profile in comparison to morphine. Through a SAR campaign, a variety of kurkinorin analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are more potent than kurkinorin at MORs, compounds that are biased towards β-arrestin-2 recruitment, and compounds that are biased towards G-protein activation have been identified. Salvinorin A suffers from poor pharmacokinetic properties, including low water solubility and rapid metabolism. In an effort to address this issue of water solubility, we sought to identify a point on the molecule through which its water solubility could be modified without sacrificing KOR activity. Previous studies indicated that salvinorin A’s lactone functionality was not necessary for KOR activity; therefore, the lactone was modified to further explore its necessity and tolerance to modification. Analogues that varied in chain length, stereochemistry, and polarity at the lactone position were synthesized and evaluated for their ability to activate KORs. Overall, small linear moieties were well-tolerated, while bulkier groups were not. Salvinorin A analogues that are potent KOR agonists with polar, ionizable moieties in the C17-position have been identified, and the lactone position has been validated as a position on the molecule through which the pharmacokinetic properties can be manipulated without significant loss of KOR activity. Salvinorin A has a very short half-life in humans ( 10,000nM) was identified. Upon in vivo evaluation, kurkinorin was determined to elicit centrally-mediated antinociception with similar potency to morphine and a reduced tolerance, sedation, and reward profile in comparison to morphine. Through a SAR campaign, a variety of kurkinorin analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are more potent than kurkinorin at MORs, compounds that are biased towards β-arrestin-2 recruitment, and compounds that are biased towards G-protein activation have been identified. Salvinorin A suffers from poor pharmacokinetic properties, including low water solubility and rapid metabolism. In an effort to address this issue of water solubility, we sought to identify a point on the molecule through which its water solubility could be modified without sacrificing KOR activity. Previous studies indicated that salvinorin A’s lactone functionality was not necessary for KOR activity; therefore, the lactone was modified to further explore its necessity and tolerance to modification. Analogues that varied in chain length, stereochemistry, and polarity at the lactone position were synthesized and evaluated for their ability to activate KORs. Overall, small linear moieties were well-tolerated, while bulkier groups were not. Salvinorin A analogues that are potent KOR agonists with polar, ionizable moieties in the C17-position have been identified, and the lactone position has been validated as a position on the molecule through which the pharmacokinetic properties can be manipulated without significant loss of KOR activity. Salvinorin A has a very short half-life in humans (<15 minutes upon inhalation). SAR work in the past has focused on developing analogues with reduced metabolic liabilities, specifically through replacement of the acetate moiety, while maintaining KOR activity. However, the metabolism of many of these compounds had not been directly compared, to one another or to salvinorin A. Therefore, we developed a method to analyze the metabolic profiles of salvinorin A and its analogues in liver microsomes. Through screening salvinorin A and its analogues, several modifications that increase metabolic stability in comparison with salvinorin A have been identified.
dc.format.extent284 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectPharmacology
dc.subjectOrganic chemistry
dc.subjectDrug addiction
dc.subjectMetabolism
dc.subjectpain
dc.subjectPharmacology
dc.subjectsalvinorin A
dc.subjectSemisynthesis
dc.titleExploration of Salvinorin A for the Development of Pain and Addiction Therapies
dc.typeDissertation
dc.contributor.cmtememberRafferty, Michael F
dc.contributor.cmtememberBlagg, Brain SJ
dc.contributor.cmtememberWolfe, Michael S
dc.contributor.cmtememberKrise, Jeffrey P
dc.thesis.degreeDisciplineMedicinal Chemistry
dc.thesis.degreeLevelPh.D.
dc.identifier.orcid0000-0001-6366-5577
dc.rights.accessrightsembargoedAccess


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