This is a competing revised renewal application to continue the syntheses and evaluation of mixed kappa/mu opioids that may be useful for the treatment of cocaine abuse and dependence. We have found that both acute and chronic treatment with the mixed k/? opioids - cyclorphan and butorphan (MCL-101) reduced cocaine self-administration dose-dependently and produced fewer side effects than k-selective agonists. In an effort to further extend the duration of action and to manipulate relative affinity and efficacy k and ? receptors, we propose innovative approaches to the synthesis of mixed k/? opioids. (1) Synthesis of morphinans with aminothiazole substitution of the phenol moiety in opioids. (2) Based on our success with the bioisosteric modifications of the N-alkyl and 3-hydroxyl functions of cyclorphan and MCL-101 that resulted in compounds with high affinity and selectivity at k/? receptors, our further investigation will be directed to the introduction of functional groups in the ring-C (cyclohexyl ring), and the synthesis of 3-amino- and 6-aminomorphinans. (3) The affinity and selectivity of new compounds will be determined by using radioligand binding assays that are selective for mu, delta, and kappa opioid receptors. (4) The efficacy of compounds to couple to G proteins will be determined by measuring [35S]GTPgS binding to membranes from Chinese hamster ovary (CHO) cells that are stably transfected with one of the human opioid receptors. (5) The mouse warm-water tail flick and writhing assays will be used to determine the potency and selectivity of new compounds in vivo. (6) Determine the dose-effect time course functions of selected compounds on basal and cocaine- potentiated brain stimulation using intracranial-stimulation (ICSS). These assays will result in the development of pharmacological profiles of compounds that will assist in identifying compounds that will be the best candidates to test in preclinical monkey studies that could be carried out at McLean Hospital under a separate grant. The proposed research will be conducted at two independent sites. The synthesis component and the intracranial-stimulation studies (ICSS) will be conducted at McLean Hospital under the direction of John L. Neumeyer, Ph.D. and Elena Chartoff, Ph.D., and the pharmacological evaluation component will be conducted at the University of Rochester under the direction of Jean M. Bidlack, Ph.D.

Public Health Relevance

Cocaine abuse continues to be a major public health problem and no consistently effective pharmacotherapy has been developed, thus, treatment is complicated by the diversity of cocaine abuse patterns as well as by concurrent abuse of opioids, alcohol and other substances. Although a wide range of medications including dopamine agonists/antagonists, reuptake inhibitors, antidepressants, anti-convulsants and opioid agonists/antagonists have been studied in clinical trials, the findings were often inconclusive. This proposal focuses on the development of pharmacotherapeutics that are neither dopamine receptor blockers nor dopamine agonists;rather, we have focused on kappa and mu opioid agonists and antagonists since these compounds offer a novel approach to the problem of opioid and cocaine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (56))
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Shih, Ming L
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Mclean Hospital
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Bidlack, Jean M (2014) Mixed ?/? partial opioid agonists as potential treatments for cocaine dependence. Adv Pharmacol 69:387-418
Provencher, Brian A; Sromek, Anna W; Li, Wei et al. (2013) Synthesis and pharmacological evaluation of aminothiazolomorphinans at the mu and kappa opioid receptors. J Med Chem 56:8872-8
Neumeyer, John L; Zhang, Bin; Zhang, Tangzhi et al. (2012) Synthesis, binding affinity, and functional in vitro activity of 3-benzylaminomorphinan and 3-benzylaminomorphine ligands at opioid receptors. J Med Chem 55:3878-90
Zhang, Bin; Zhang, Tangzhi; Sromek, Anna W et al. (2011) Synthesis and binding affinity of novel mono- and bivalent morphinan ligands for ?, ?, and ? opioid receptors. Bioorg Med Chem 19:2808-16
Zhang, Tangzhi; Yan, Zhaohua; Sromek, Anna et al. (2011) Aminothiazolomorphinans with mixed ? and ? opioid activity. J Med Chem 54:1903-13
Hupp, Christopher D; Neumeyer, John L (2010) Rapid access to morphinones: removal of 4, 5-ether bridge with Pd-catalyzed triflate reduction. Tetrahedron Lett 51:2359-2361
Fulton, Brian S; Knapp, Brian L; Bidlack, Jean M et al. (2010) Effect of linker substitution on the binding of butorphan univalent and bivalent ligands to opioid receptors. Bioorg Med Chem Lett 20:1507-9
Decker, Michael; Si, Yu-Gui; Knapp, Brian I et al. (2010) Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors. J Med Chem 53:402-18
Decker, Michael; Fulton, Brian S; Zhang, Bin et al. (2009) Univalent and bivalent ligands of butorphan: characteristics of the linking chain determine the affinity and potency of such opioid ligands. J Med Chem 52:7389-96
Chen, Xue-Qin; Zhang, Jing; Neumeyer, John L et al. (2009) Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects. PLoS ONE 4:e5811

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