Discovery of Bifunctional NOP/Opioid Receptor Ligands for Drug Abuse Therapy

Summary

Principal Investigator: Nurulain T Zaveri
Abstract: There is a clinical need for substance abuse medications that are effective against comorbid drug abuse. Addiction to multiple abused substances presents a complex clinical problem, treatment for which may require multiple pharmacological approaches via multiple mechanisms of action. Further, there are several phases of drug addiction in patients (acquisition, withdrawal, craving, relapse) that may not adequately treated by a single mechanism of action of a single drug. Therefore, pharmacotherapies that target dual or multiple mechanisms of complementary pharmacology may provide novel approaches for the effective treatment of drug addiction. A case in point is buprenorphine, a nonselective mu opioid receptor partial agonist/kappa antagonist/nociceptin receptor partial agonist, which is clinically effective against cocaine and heroin addiction, and recently shown to be effective against alcohol abuse as well. Buprenorphine's activity at the nociceptin receptor is thought to play a role in its efficacy in treating cocaine and alcohol addiction. The nociceptin receptor NOP is known to be involved in reward pathways, and nociceptin/Orphanin FQ (N/OFQ), the endogenous agonist for the NOP receptor, has been shown to block self-administration and acquisition of conditioned place preference (CPP) to several drugs of abuse;in particular, morphine, cocaine, amphetamines, and alcohol. A small-molecule NOP agonist has also been shown to block acquisition of morphine and ethanol place preference and reinstatement of drug-seeking. We hypothesize that compounds that target both the NOP receptor and the opioid receptors, and have a desirable mixed profile of NOP agonist/opioid activity, will provide new pharmacotherapeutic approaches for polydrug addiction treatment. Our preliminary data show that a compound with NOP full agonist and mu opioid receptor weak partial agonist activity attentuates acquisition of morphine CPP. We have developed several novel NOP agonists and have extensive structure-activity relationships for NOP affinity and selectivity versus opioid receptors. Using this as a foundation, we propose to design NOP/opioid 'multiple'ligands that have a desired mixed profile of activity as potential agents for drug abuse therapy. Our specific aims are to (i) design novel NOP/opioid mixed ligands with an optimized profile of NOP full agonist activity and selected opioid receptor efficacy, suitable pharmacokinetic properties and blood-brain barrier penetration (ii) to characterize the mixed ligands in vitro for their NOP and opioid affinity and functional profile, evaluate their metabolic stability and determine an overall receptor profile;and (iii) to examine ligands with selected profiles in vivo for their effect on the acquisition of morphine and cocaine CPP, and on drug- and stress-induced reinstatement of morphine and cocaine CPP. We expect that we will identify several novel NOP-opioid mixed ligands with desirable efficacy profiles and suitable drug-like characteristics for further development as pharmacotherapies for the treatment of polydrug addiction. PUBLIC HEALTH RELEVANCE: Addiction to multiple abused substances is quite commonplace among addicts and represents a serious treatment problem and an unmet clinical need. Development of pharmacotherapies that have multiple targeted mechanisms of action in a single agent can provide a single new treatment option for the various aspects of the addiction process and/or for patients addicted to multiple drugs. The discovery of bifunctional NOP/opioid receptor ligands, as proposed in this application, offers the advantage of combining dual-targeted activities of known complementary pharmacology and broad anti-addictive effects, into single agents that can be developed as pharmacotherapies for polydrug addiction.
Funding Period: 2009-09-30 - 2014-08-30
more information: NIH RePORT

Top Publications

  1. pmc SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice
    Taline V Khroyan
    Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA
    J Pharmacol Exp Ther 320:934-43. 2007
  2. pmc Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain
    Devki D Sukhtankar
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    J Pharmacol Exp Ther 346:11-22. 2013
  3. pmc Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP receptor-selective scaffolds. Part I
    Nurulain T Zaveri
    Astraea Therapeutics, LLC 320 Logue Avenue, Mountain View, CA 94043, USA
    Bioorg Med Chem Lett 23:3308-13. 2013
  4. pmc Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity
    Jacqueline Vazquez-Derose
    SRI International, Menlo Park, CA 94025, USA
    Eur J Pharmacol 699:200-6. 2013
  5. pmc Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111
    M Marti
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    Br J Pharmacol 168:863-79. 2013
  6. pmc Homology modeling and molecular dynamics simulations of the active state of the nociceptin receptor reveal new insights into agonist binding and activation
    Pankaj R Daga
    Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, California 94043, USA
    Proteins 80:1948-61. 2012
  7. pmc Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists
    Taline V Khroyan
    Policy Division, SRI International, Menlo Park, California 94025, USA
    J Pharmacol Exp Ther 331:946-53. 2009
  8. pmc Activity of new NOP receptor ligands in a rat peripheral mononeuropathy model: potentiation of morphine anti-allodynic activity by NOP receptor antagonists
    Taline V Khroyan
    Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA
    Eur J Pharmacol 610:49-54. 2009
  9. pmc Activities of mixed NOP and mu-opioid receptor ligands
    B Spagnolo
    Section of Pharmacology, Department of Experimental and Clinical Medicine, National Institute of Neuroscience, University of Ferrara, Ferrara, Italy
    Br J Pharmacol 153:609-19. 2008
  10. pmc Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II
    V Blair Journigan
    Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, CA 94043, United States
    Bioorg Med Chem 22:2508-16. 2014

Detail Information

Publications10

  1. pmc SR 16435 [1-(1-(bicyclo[3.3.1]nonan-9-yl)piperidin-4-yl)indolin-2-one], a novel mixed nociceptin/orphanin FQ/mu-opioid receptor partial agonist: analgesic and rewarding properties in mice
    Taline V Khroyan
    Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA
    J Pharmacol Exp Ther 320:934-43. 2007
    ..In summary, the mixed NOP/mu-opioid partial agonist SR 16435 exhibited both NOP and mu-opioid receptor-mediated behaviors...
  2. pmc Effects of spinally administered bifunctional nociceptin/orphanin FQ peptide receptor/μ-opioid receptor ligands in mouse models of neuropathic and inflammatory pain
    Devki D Sukhtankar
    Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    J Pharmacol Exp Ther 346:11-22. 2013
    ..Such ligands therefore display a promising profile as spinal analgesics...
  3. pmc Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP receptor-selective scaffolds. Part I
    Nurulain T Zaveri
    Astraea Therapeutics, LLC 320 Logue Avenue, Mountain View, CA 94043, USA
    Bioorg Med Chem Lett 23:3308-13. 2013
    ..This initial SAR suggests pharmacophoric elements that may be modified to modulate/increase opioid affinity, while maintaining high affinity for the NOP receptor, to result in potent bifunctional small-molecule NOP/MOP ligands...
  4. pmc Retrodialysis of N/OFQ into the nucleus accumbens shell blocks cocaine-induced increases in extracellular dopamine and locomotor activity
    Jacqueline Vazquez-Derose
    SRI International, Menlo Park, CA 94025, USA
    Eur J Pharmacol 699:200-6. 2013
    ..These studies confirm the widespread involvement of NOP receptors in drug addiction and further validate the utility of an NOP receptor agonist as a medication for treatment of drug addiction...
  5. pmc Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111
    M Marti
    Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy
    Br J Pharmacol 168:863-79. 2013
    ....
  6. pmc Homology modeling and molecular dynamics simulations of the active state of the nociceptin receptor reveal new insights into agonist binding and activation
    Pankaj R Daga
    Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, California 94043, USA
    Proteins 80:1948-61. 2012
    ..Both agonists show extensive polar interactions with residues at the extracellular end of the TM domain and EL2 loop, suggesting agonist-induced reorganization of polar networks, during receptor activation...
  7. pmc Nociceptin/orphanin FQ receptor activation attenuates antinociception induced by mixed nociceptin/orphanin FQ/mu-opioid receptor agonists
    Taline V Khroyan
    Policy Division, SRI International, Menlo Park, California 94025, USA
    J Pharmacol Exp Ther 331:946-53. 2009
    ....
  8. pmc Activity of new NOP receptor ligands in a rat peripheral mononeuropathy model: potentiation of morphine anti-allodynic activity by NOP receptor antagonists
    Taline V Khroyan
    Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA
    Eur J Pharmacol 610:49-54. 2009
    ..Increased levels of the NOP receptor are implicated in the reduced efficacy of morphine in neuropathic pain. Our results suggest the utility of NOP receptor antagonists for potentiating opioid efficacy in chronic pain...
  9. pmc Activities of mixed NOP and mu-opioid receptor ligands
    B Spagnolo
    Section of Pharmacology, Department of Experimental and Clinical Medicine, National Institute of Neuroscience, University of Ferrara, Ferrara, Italy
    Br J Pharmacol 153:609-19. 2008
    ..Compounds that activate both NOP and mu-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds...
  10. pmc Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II
    V Blair Journigan
    Astraea Therapeutics, LLC, 320 Logue Avenue, Mountain View, CA 94043, United States
    Bioorg Med Chem 22:2508-16. 2014
    ..The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors. ..