Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric co-morbidity, and also enhances transmission of HIV-1, hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Growing evidence shows that that ? opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides, the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants, and particularly relapse. The plant-derived hallucinogen, salvinorin A (a neoclerodane), from the mint Salvia divinorum, is a structurally unique KOP-agonist. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects, but these desirable actions are accompanied by undesirable effects, including the aforementioned hallucinations, sedation and dysphoria/aversion. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as lead pharmacotherapeutic agents for psychostimulant addiction, as shown by their in vitro and in vivo profiles in translational models, including a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane leads will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction, relapse, and co-morbid neuropsychiatric disorders.
The Specific Aims of this proposal are (1) optimize the activity of novel neoclerodanes, including innovative synthetic trans-decalin analogs, at KOP receptors; (2) determine and optimize the in vivo activity of novel neoclerodanes as KOPr ligands in mice, and for their ability to decrease cocaine-induced effects; and (3) determine and optimize the activity of novel neoclerodanes prioritized from Aims 1 and 2, in translational non- human primate models. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically useful KOP-r targeted medications for the treatment of drug addiction.

Public Health Relevance

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, and evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically usefu opioid- targeted drugs for the treatment of drug addiction and major neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018151-13
Application #
9429043
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Hillery, Paul
Project Start
2016-05-01
Project End
2021-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
13
Fiscal Year
2018
Total Cost
Indirect Cost
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