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 #
3R01DA018151-07S1
Application #
8472068
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
2011-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2012
Total Cost
$17,255
Indirect Cost
$1,278
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Ewald, Amy W M; Bosch, Peter J; Culverhouse, Aimee et al. (2017) The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and ?-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects. Psychopharmacology (Berl) 234:2499-2514
Paton, K F; Kumar, N; Crowley, R S et al. (2017) The analgesic and anti-inflammatory effects of Salvinorin A analogue ?-tetrahydropyran Salvinorin B in mice. Eur J Pain 21:1039-1050
Valenza, Marta; Butelman, Eduardo R; Kreek, Mary Jeanne (2017) ""Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats"". Psychopharmacology (Berl) 234:2219-2231
Sherwood, Alexander M; Crowley, Rachel Saylor; Paton, Kelly F et al. (2017) Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability. J Med Chem 60:3866-3878
Zhou, Yan; Crowley, Rachel Saylor; Ben, Konrad et al. (2017) Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone. Brain Res 1662:75-86
Karad, Somnath Narayan; Pal, Mohan; Crowley, Rachel S et al. (2017) Synthesis and Opioid Activity of Tyr1 -?[(Z)CF=CH]-Gly2 and Tyr1 -?[(S)/(R)-CF3 CH-NH]-Gly2 Leu-enkephalin Fluorinated Peptidomimetics. ChemMedChem 12:571-576
Sherwood, Alexander M; Williamson, Samuel E; Crowley, Rachel S et al. (2017) Modular Approach to pseudo-Neoclerodanes as Designer ?-Opioid Ligands. Org Lett 19:5414-5417
Yilmaz, Anil; Crowley, Rachel Saylor; Sherwood, Alexander M et al. (2017) Semisynthesis and Kappa-Opioid Receptor Activity of Derivatives of Columbin, a Furanolactone Diterpene. J Nat Prod 80:2094-2100
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 ? Opioid Analgesic with Reduced Abuse Liability. J Med Chem 59:11027-11038
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

Showing the most recent 10 out of 63 publications