Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric morbidity, as well as enhancing transmission of HIV-1, hepatitis B and C, and drug resistant tuberculosis, and thus causing massive public health costs. Presently, there are no FDA approved treatments for psychostimulant abuse. A growing body of evidence has shown that ? opioid (KOP) receptors are involved in the modulation of some of the abuse related effects of psychostimulants. Notably, repeated or chronic psychostimulant administration results in a prolonged upregulation of the KOP receptor/ dynorphin system. The KOP receptor/ dynorphin system is a major part of the brain's counter-regulatory esponse to enhanced dopaminergic acitivity, which is a major initial event underlying psychostimulant-induced reinforcement and abuse potential. Kappa opioid receptors have also been implicated in the actions of Salvia divinorum, a hallucinogenic mint plant that is currently unscheduled and readily available to the public over the Internet. Due to the recent increase in the popularity of Salvia divinorum among both European and American teens, the DEA has recently placed it on the list of drugs to watch. It is predictable that its misuse will increase rapidly. The central hypothesis of this proposal is that structural modification of salvinorin A will lead to identification of novel kappa opioid receptor ligands with the potential to treat drug dependence and its relapse. The long-term goal of this research is to develop neoclerodane-derived KOP ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD).
The specific aims of this proposal are (1) optimize the activity of neoclerodanes at KOP receptors;(2) identify novel naturally occurring neoclerodanes with KOP activity;and (3) determine the biological activity of compounds in vivo. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP- targeted drugs for the treatment of drug abuse and major neuropsychiatric disorders.

Public Health Relevance

Stimulant dependence is a chronic relapsing disease that results from the prolonged effects of drugs on the brain. At present, there are no FDA-approved therapeutic agents available for the treatment of stimulant abuse or for the prevention of its relapse. This project seeks develop neoclerodane-derived ? opioid (KOP) receptor ligands with pharmacotherapeutic potential in psychostimulant addiction and relapse, as well as neuropsychiatric disorders (including anxiety, depression and stress-related disorders such as PTSD). The design, synthesis, isolation, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with KOP receptors. This information is expected to facilitate the identification of clinically useful KOP-targeted drugs for the treatment of drug abuse and other neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018151-09
Application #
8523815
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Hillery, Paul
Project Start
2004-07-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$328,042
Indirect Cost
$76,362
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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Kivell, Bronwyn; Uzelac, Zeljko; Sundaramurthy, Santhanalakshmi et al. (2014) Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1/2-dependent mechanism. Neuropharmacology 86:228-40
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Vasiljevik, Tamara; Franks, Lirit N; Ford, Benjamin M et al. (2013) Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse. J Med Chem 56:4537-50
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MacLean, Katherine A; Johnson, Matthew W; Reissig, Chad J et al. (2013) Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects. Psychopharmacology (Berl) 226:381-92
Morani, Aashish S; Ewald, Amy; Prevatt-Smith, Katherine M et al. (2013) The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats. Eur J Pharmacol 720:69-76
Negri, Ana; Rives, Marie-Laure; Caspers, Michael J et al. (2013) Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening. J Chem Inf Model 53:521-6
Lovell, Kimberly M; Vasiljevik, Tamara; Araya, Juan J et al. (2012) Semisynthetic neoclerodanes as kappa opioid receptor probes. Bioorg Med Chem 20:3100-10

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