Investigation of Neoclerodanes as Novel Opioid Ligands

Summary

Principal Investigator: THOMAS EDWARD PRISINZANO
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2004-07-01 - 2015-08-31
more information: NIH RePORT

Top Publications

  1. pmc Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A
    Wayne W Harding
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA
    J Nat Prod 69:107-12. 2006
  2. pmc Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone
    Nathan A Holtz
    Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA
    Drug Alcohol Depend 120:233-7. 2012
  3. pmc Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A
    Christopher W Cunningham
    Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045 7582, USA
    Pharmacol Rev 63:316-47. 2011
  4. pmc Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A
    Anthony Lozama
    Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
    J Nat Prod 74:718-26. 2011
  5. pmc Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum
    Matthew W Johnson
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224 6823, USA
    Drug Alcohol Depend 115:150-5. 2011
  6. pmc The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, New York, NY 10065, USA
    Psychopharmacology (Berl) 210:253-62. 2010
  7. pmc Identification of a novel "almost neutral" micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor
    Elliott J Sally
    Clinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA
    Synapse 64:280-8. 2010
  8. pmc A single injection of a novel κ opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats
    Aashish S Morani
    School of Biological Science, Victoria University of Wellington, Wellington, New Zealand
    Behav Pharmacol 23:162-70. 2012
  9. pmc Behavioral effects and central nervous system levels of the broadly available κ-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York, NY 10065, USA
    J Pharmacol Exp Ther 341:802-8. 2012
  10. pmc Palladium-catalyzed transformations of salvinorin A, a neoclerodane diterpene from Salvia divinorum
    Andrew P Riley
    Departments of Chemistry and Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045 7572, United States, and Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States
    Org Lett 15:5936-9. 2013

Detail Information

Publications40

  1. pmc Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A
    Wayne W Harding
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA
    J Nat Prod 69:107-12. 2006
    ..divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with delta opioid antagonist activity...
  2. pmc Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone
    Nathan A Holtz
    Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA
    Drug Alcohol Depend 120:233-7. 2012
    ..Treatment drugs were modafinil (MOD), an analeptic, and allopregnanolone (ALLO), a neuroactive steroid and progesterone metabolite...
  3. pmc Neuropharmacology of the naturally occurring kappa-opioid hallucinogen salvinorin A
    Christopher W Cunningham
    Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 66045 7582, USA
    Pharmacol Rev 63:316-47. 2011
    ....
  4. pmc Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A
    Anthony Lozama
    Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
    J Nat Prod 74:718-26. 2011
    ..The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products...
  5. pmc Human psychopharmacology and dose-effects of salvinorin A, a kappa opioid agonist hallucinogen present in the plant Salvia divinorum
    Matthew W Johnson
    Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21224 6823, USA
    Drug Alcohol Depend 115:150-5. 2011
    ..Under these prepared and supportive conditions, salvinorin A occasioned a unique profile of subjective effects having similarities to classic hallucinogens, including mystical-type effects...
  6. pmc The discriminative effects of the kappa-opioid hallucinogen salvinorin A in nonhuman primates: dissociation from classic hallucinogen effects
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, New York, NY 10065, USA
    Psychopharmacology (Berl) 210:253-62. 2010
    ....
  7. pmc Identification of a novel "almost neutral" micro-opioid receptor antagonist in CHO cells expressing the cloned human mu-opioid receptor
    Elliott J Sally
    Clinical Psychopharmacology Section, IRP, NIDA, NIH, DHHS, Baltimore, Maryland 21224, USA
    Synapse 64:280-8. 2010
    ..LTC-274 is a promising lead compound for developing a true MOR neutral antagonist...
  8. pmc A single injection of a novel κ opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats
    Aashish S Morani
    School of Biological Science, Victoria University of Wellington, Wellington, New Zealand
    Behav Pharmacol 23:162-70. 2012
    ..However, prodepressive effects were also produced and these effects may limit the therapeutic potential...
  9. pmc Behavioral effects and central nervous system levels of the broadly available κ-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York, NY 10065, USA
    J Pharmacol Exp Ther 341:802-8. 2012
    ..These are the first studies in vivo showing the sensitivity of salvinorin A effects to modulation by the P-glycoprotein transporter, a major functional component of the blood-brain barrier...
  10. pmc Palladium-catalyzed transformations of salvinorin A, a neoclerodane diterpene from Salvia divinorum
    Andrew P Riley
    Departments of Chemistry and Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045 7572, United States, and Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States
    Org Lett 15:5936-9. 2013
    ....
  11. pmc The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats
    Aashish S Morani
    School of Biological Science, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
    Eur J Pharmacol 720:69-76. 2013
    ..Future studies with Sal A analogues having affinities at other opioid receptors are warranted as they have the potential to identify compounds having effective anti-addiction properties. ..
  12. pmc Design, synthesis, and biological evaluation of aminoalkylindole derivatives as cannabinoid receptor ligands with potential for treatment of alcohol abuse
    Tamara Vasiljevik
    Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas 66045, USA
    J Med Chem 56:4537-50. 2013
    ....
  13. pmc Neoclerodanes as atypical opioid receptor ligands
    Thomas E Prisinzano
    Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Drive, 4070 Malott Hall, Lawrence, Kansas 66045 7572, United States
    J Med Chem 56:3435-43. 2013
    ..The information gained from these efforts is expected to facilitate the design of novel agents to treat pain, drug abuse, and other central nervous system disorders...
  14. pmc Discovery of a novel selective kappa-opioid receptor agonist using crystal structure-based virtual screening
    Ana Negri
    Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States
    J Chem Inf Model 53:521-6. 2013
    ..A selective novel KOP receptor agonist emerged as a notable result and is proposed as a new chemotype for the study of the KOP receptor in the etiology of drug addiction, depression, and/or pain...
  15. pmc Dose-related effects of salvinorin A in humans: dissociative, hallucinogenic, and memory effects
    Katherine A MacLean
    Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224 6823, USA
    Psychopharmacology (Berl) 226:381-92. 2013
    ..Salvinorin A is a kappa opioid agonist and the principal psychoactive constituent of the plant Salvia divinorum, which has increased in popularity as a recreational drug over the past decade. Few human studies have examined salvinorin A...
  16. pmc Semisynthetic neoclerodanes as kappa opioid receptor probes
    Kimberly M Lovell
    Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA
    Bioorg Med Chem 20:3100-10. 2012
    ..Collectively, these findings suggest that different aromatic groups appended directly to the decalin core may be well tolerated by KOP receptors, and may generate further ligands with affinity and activity at KOP receptors...
  17. pmc Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats
    Aashish S Morani
    School of Biological Sciences, Victoria University of Wellington, P O Box 600, Wellington, New Zealand
    Pharmacol Biochem Behav 94:244-9. 2009
    ..0mg/kg, I.P.) had no effect on operant responding to obtain sucrose reinforcement or on cocaine-induced hyperactivity. These findings show that Sal A, like other traditional KOPr agonists attenuates cocaine-induced drug-seeking behavior...
  18. pmc Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors
    Denise S Simpson
    Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045 7582, USA
    Org Biomol Chem 7:3748-56. 2009
    ..This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity...
  19. ncbi Synthetic studies of neoclerodane diterpenes from Salvia divinorum: preparation and opioid receptor activity of salvinicin analogues
    Denise S Simpson
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA
    J Med Chem 50:3596-603. 2007
    ..This indicates that additional structural modifications of 1a may lead to analogues with higher potency and utility as drug abuse medications...
  20. ncbi A comparison of noninternalizing (herkinorin) and internalizing (DAMGO) mu-opioid agonists on cellular markers related to opioid tolerance and dependence
    Heng Xu
    Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, Maryland 21224, USA
    Synapse 61:166-75. 2007
    ..Viewed collectively with published data, the current data indicate that both internalizing and noninternalizing mu-agonists produce cellular signs of tolerance and dependence...
  21. ncbi Differential helical orientations among related G protein-coupled receptors provide a novel mechanism for selectivity. Studies with salvinorin A and the kappa-opioid receptor
    Timothy A Vortherms
    Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
    J Biol Chem 282:3146-56. 2007
    ..These findings imply that differences in the helical orientation of helix 2 are critical for the selectivity of salvinorin A binding to KOR and provide a structurally novel basis for ligand selectivity...
  22. pmc An opioid agonist that does not induce mu-opioid receptor--arrestin interactions or receptor internalization
    C E Groer
    Department of Pharmacology, The Ohio State University College of Medicine, 333 W 10th Avenue, 5184A Graves Hall, Columbus, OH 43210, USA
    Mol Pharmacol 71:549-57. 2007
    ....
  23. ncbi Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, The Rockefeller University, Box 171, 1230 York Avenue, New York NY 10021, USA
    J Pharmacol Exp Ther 320:300-6. 2007
    ..The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay...
  24. ncbi Salvinorin A: allosteric interactions at the mu-opioid receptor
    Richard B Rothman
    Clinical Psychopharmacology Section, Intramural Research Program, National Institute of Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA
    J Pharmacol Exp Ther 320:801-10. 2007
    ..Viewed collectively, these data support the hypothesis that Salvinorin A allosterically modulates the mu-opioid receptor...
  25. ncbi Synthesis of salvinorin A analogues as opioid receptor probes
    Kevin Tidgewell
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA
    J Nat Prod 69:914-8. 2006
    ..Here, we report the semisynthesis of neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further development of novel opioid receptor ligands...
  26. ncbi Synthetic studies of neoclerodane diterpenes from Salvia divinorum: selective modification of the furan ring
    Wayne W Harding
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
    Bioorg Med Chem Lett 16:3170-4. 2006
    ..In addition, a procedure has been found to remove the furan skeleton completely. Biological results indicate that replacement of the furan ring with an N-sulfonylpyrrole leads to reduced affinity and efficacy at kappa opioid receptors...
  27. pmc Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position
    Kenneth G Holden
    Holden Laboratories, Carmel, CA 93923, USA
    Bioorg Med Chem Lett 17:6111-5. 2007
    ..These observations suggest that the ketone of 2b is a key structural feature responsible for mu agonist activity...
  28. ncbi Galpha-subunits differentially alter the conformation and agonist affinity of kappa-opioid receptors
    Feng Yan
    Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
    Biochemistry 47:1567-78. 2008
    ..These data are significant because they demonstrate that Galpha-subunits differentially modulate the conformation and agonist affinity of a prototypical GPCR...
  29. pmc Chemical methods for the synthesis and modification of neoclerodane diterpenes
    Anthony Lozama
    Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52240, USA
    Bioorg Med Chem Lett 19:5490-5. 2009
    ..Recently, the neoclerodane diterpene, salvinorin A (12) has been investigated due to its unique pharmacological profile. This review will discuss the chemical methods used to chemically modify and synthesize 12...
  30. pmc Evaluation of the transport, in vitro metabolism and pharmacokinetics of Salvinorin A, a potent hallucinogen
    Zeynep S Teksin
    Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA
    Eur J Pharm Biopharm 72:471-7. 2009
    ..Salvinorin A is rapidly eliminated after i.p. dosing, in accordance with its fast onset and short duration of action. Further, it appears to be a substrate for various oxidative enzymes and multi-drug resistant protein, P-gp...
  31. pmc Natural products as tools for neuroscience: discovery and development of novel agents to treat drug abuse
    Thomas E Prisinzano
    Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045, USA
    J Nat Prod 72:581-7. 2009
    ..This review will detail recent progress in a program directed toward investigating psychoactive natural products with the goal of treating drug abuse by targeting kappa opioid receptors...
  32. pmc Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: fast onset and entry into cerebrospinal fluid
    Eduardo R Butelman
    Laboratory on the Biology of Addictive Diseases, Rockefeller University Box 171, 1230 York Ave, New York, NY 1006, USA
    J Pharmacol Exp Ther 328:588-97. 2009
    ..These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans...
  33. pmc Differential effects of opioid agonists on G protein expression in CHO cells expressing cloned human opioid receptors
    Heng Xu
    Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, DHHS, Baltimore, MD 21224, USA
    Brain Res Bull 77:49-54. 2008
    ....
  34. pmc The effects of herkinorin, the first mu-selective ligand from a salvinorin A-derived scaffold, in a neuroendocrine biomarker assay in nonhuman primates
    Eduardo R Butelman
    The Rockefeller University, Box 171, 1230 York Ave, New York, NY 10065, USA
    J Pharmacol Exp Ther 327:154-60. 2008
    ..c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier...
  35. pmc Herkinorin analogues with differential beta-arrestin-2 interactions
    Kevin Tidgewell
    Division of Medicinal and Natural Products Chemistry, The University of Iowa, Iowa City, Iowa 52242, USA
    J Med Chem 51:2421-31. 2008
    ....
  36. pmc Effects of acute and repeated administration of salvinorin A on dopamine function in the rat dorsal striatum
    Brenda J Gehrke
    Integrative Neuroscience Section, NIH NIDA Intramural Research Program, Baltimore, MD 21224, USA
    Psychopharmacology (Berl) 197:509-17. 2008
    ..Acute systemic administration of salvinorin A, a naturally occurring kappa-opioid receptor (KOPr) agonist, decreases locomotion and striatal dopamine (DA) overflow...

Research Grants30

  1. Development of Novel Medication Strategies for Opiate Abuse
    Yasmin L Hurd; Fiscal Year: 2013
    ..Overall, the development of a targeted treatment for opioid relapse would be of tremendous medical value to our veteran population. ..
  2. Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)
    Christopher J Evans; Fiscal Year: 2013
    ..Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center. ..
  3. Pilot Longitudinal Data Collection to Inform Public Health_Fragile X Syndrome
    W Ted Brown; Fiscal Year: 2013
    ....
  4. CDART - Center for Drug Abuse Research Translation
    Michael T Bardo; Fiscal Year: 2013
    ..The long-range goal is to improve the design and implementation of targeted anti-drug preventive interventions. ..
  5. Translational Research of Cocaine, Striatum, and Impulsivities
    Marc N Potenza; Fiscal Year: 2013
    ..Together, data from these highly integrated, translational studies should advance our understanding of CD and help target the development of more effective prevention and treatment strategies. ..
  6. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  7. Learning to avoid pain: Computational mechanisms and application to methamphetami
    TOR DESSART WAGER; Fiscal Year: 2013
    ..abstract_text> ..
  8. Discovery of Bifunctional NOP/Opioid Receptor Ligands for Drug Abuse Therapy
    Nurulain T Zaveri; Fiscal Year: 2013
    ..abstract_text> ..
  9. Translational Methamphetamine AIDS Research Center (TMARC)
    Igor Grant; Fiscal Year: 2013
    ..TMARC's ultimate vision is to become a national resource for translational multidisciplinary research and training in the neuropathogenesis of HIV and substance use. ..
  10. Stimulant Pharmacotherapy: Noradrenergic Targets
    THOMAS RICHARD KOSTEN; Fiscal Year: 2013
    ..5. To attract and train new drug abuse pharmacotherapy investigators through our Center's Core facilities and projects. 6. To disseminate our findings through education and international collaborations. ..
  11. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  12. Kappa-Opioid Receptor Mediated Regulation of Dopamine Transport
    Sammanda Ramamoorthy; Fiscal Year: 2013
    ..Furthermore, they will provide new insights as to the role of DAT phosphorylation in regulating synaptic DA clearance and behavior. ..
  13. Development of Novel Opioid Peptides for Cocaine Abuse
    Jane V Aldrich; Fiscal Year: 2013
    ..This research is expected to produce candidates that can be rationally and productively advanced into late preclinical development as potential treatments for cocaine addiction and relapse. ..
  14. DRUGS OF ABUSE - ROLE OF PROTEIN PHOSPHORYLATION
    Paul Greengard; Fiscal Year: 2013
    ..Results from the three Projects will complement each other. In addition, there will be a significant level of collaboration between the three Projects, as well as close interaction of the three Projects with the Scientific Core. ..
  15. Novel Ligands that Selectively Desensitize alpha4beta nAChRs for Smoking Cessatio
    Kenneth J Kellar; Fiscal Year: 2013
    ..A major goal of our proposed research is that it will lead to the development a new class of CNS therapeutics, selective a4p2 nAChR desensitizers, to aid smoking cessation. ..
  16. Structure and Function of Neurotransmitter Transporters
    Harel Weinstein; Fiscal Year: 2013
    ....
  17. Adenosine Receptor Involvement in Methamphetamine Reward and Relapse
    Ryan K Bachtell; Fiscal Year: 2013
    ..g. D1 antagonist-A1 agonist) that could specifically target heteromeric receptors localized to specific subpopulations of neurons within specific neural circuits that undergo methamphetamine- induced alterations. ..
  18. Development of Potential Treatment Medications for Drug Abuse
    Bruce E Blough; Fiscal Year: 2013
    ..The target compounds will be small molecules that are expected to penetrate the CNS and have reasonable stability so that they will be useful medications and can be used as in vitro and in vivo probes. ..
  19. Oral Mucosal Immunity in Vulnerable HIV Infected Populations
    Aaron Weinberg; Fiscal Year: 2013
    ..All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A). ..
  20. CENTER ON INTERSYSTEM REGULATION BY DRUGS OF ABUSE
    Ellen M Unterwald; Fiscal Year: 2013
    ..Cutting edge research being conducted by members of CSAR is supported and enhanced by utilizing the expertise, methodologies, and techniques provided by the Cores. ..
  21. NOVEL MEDICATION APPROACHES FOR SUBSTANCE ABUSE
    HERBERT DAVID KLEBER; Fiscal Year: 2013
    ..abstract_text> ..
  22. Development of Orexin-1 Receptor Antagonists for Drug Addiction
    Paul J Kenny; Fiscal Year: 2013
    ..This integrated multidisciplinary research plan will capitalize on the unique drug discovery capabilities at Scripps Florida, and promises to yield novel therapeutic entities for the prevention of relapse in human tobacco smokers. ..