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 #
5R01DA018151-08
Application #
8306178
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
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$342,060
Indirect Cost
$79,893
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Crowley, Rachel Saylor; Riley, Andrew P; Sherwood, Alexander M et al. (2016) Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability. J Med Chem 59:11027-11038
Marchant, Nathan J; Whitaker, Leslie R; Bossert, Jennifer M et al. (2016) Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats. Neuropsychopharmacology 41:402-9
Johnson, Matthew W; MacLean, Katherine A; Caspers, Michael J et al. (2016) Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans. J Psychopharmacol 30:323-9
Simonson, B; Morani, A S; Ewald, A W M et al. (2015) Pharmacology and anti-addiction effects of the novel κ opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A. Br J Pharmacol 172:515-31
Jamshidi, Raehannah J; Jacobs, Blaine A; Sullivan, Laura C et al. (2015) Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons. J Pharmacol Exp Ther 355:174-82
Vasiljevik, Tamara; Groer, Chad E; Lehner, Kurt et al. (2014) Studies toward the Development of Antiproliferative Neoclerodanes from Salvinorin A. J Nat Prod 77:1817-24
Freeman, Kevin B; Naylor, Jennifer E; Prisinzano, Thomas E et al. (2014) Assessment of the kappa opioid agonist, salvinorin A, as a punisher of drug self-administration in monkeys. Psychopharmacology (Berl) 231:2751-8
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
Riley, Andrew P; Groer, Chad E; Young, David et al. (2014) Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues. J Med Chem 57:10464-75
Kivell, Bronwyn M; Ewald, Amy W M; Prisinzano, Thomas E (2014) Salvinorin A analogs and other κ-opioid receptor compounds as treatments for cocaine abuse. Adv Pharmacol 69:481-511

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