The aims of the proposal are in accord with the mission of the Medications Development Division of NIDA to provide new treatments for substance abuse. The principal aim of the project is to provide potential treatment agents for opiate and polydrug dependence by targeting single chemical entities that mimic the profile produced by a buprenorphine/naltrexone combination. There is evidence from both clinical and preclinical research that this combination can help prevent relapse to drug taking behavior. The target compounds lack of mu opioid receptor efficacy will render the compounds safe and ethically acceptable for use in both opioid using and non-opioid using addicts. Efficacy as treatment agents will come from the compounds kappa opioid receptor antagonist activity, coupled with agonism at NOP (nociceptin) receptors. Lead compounds have been identified within the orvinol series, a series which has produced several compounds of clinical or veterinary utility, including buprenorphine. A number of lead compounds, previously evaluated in vitro, will be re-synthesized and further evaluated to confirm that they have the desired properties in vivo, including an extended duration of action. Mu and kappa opioid receptor efficacy, as well as NOP receptor affinity can be controlled through appropriate choice of C20 substituents in the orvinol series. Using molecular modeling we have established a structural relationship between these orvinols and related series of ligands that should allow the rationale design of further compounds possessing the desired pharmacological profile. These new series of ligands also access the region of space accessed by the C20 substituents in the orvinols. To evaluate newly synthesized compounds, assays have been chosen that will allow the desired profile to be identified in vitro, before then using behavioral assays with select compounds to determine their opioid activity in vivo and assess their ability to act as relapse prevention agents in a model of drug relapse.

Public Health Relevance

Drug abuse and addiction, including polydrug abuse, continues to be a major problem in the United States and throughout the world. One of the main problems in drug abuse treatment is the high rate of relapse to drug taking.
This research aims to provide improved treatment agents that can be used as relapse prevention agents. The target compounds will not have the side effects associated with current treatments for opioid abuse, such as abuse potential or respiratory depression and will therefore have an increased safety profile.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA007315-20
Application #
8308962
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Kline, Richard
Project Start
1991-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
20
Fiscal Year
2012
Total Cost
$310,382
Indirect Cost
$9,484
Name
University of Bath
Department
Type
DUNS #
424400661
City
Bath
State
Country
United Kingdom
Zip Code
BA2 7-AY
Almatroudi, Abdulrahman; Husbands, Stephen M; Bailey, Christopher P et al. (2015) Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice. J Psychopharmacol 29:812-21
Cueva, Juan Pablo; Roche, Christopher; Ostovar, Mehrnoosh et al. (2015) C7β-methyl analogues of the orvinols: the discovery of kappa opioid antagonists with nociceptin/orphanin FQ peptide (NOP) receptor partial agonism and low, or zero, efficacy at mu opioid receptors. J Med Chem 58:4242-9
Zielińska, Marta; Ben Haddou, Tanila; Cami-Kobeci, Gerta et al. (2015) Anti-inflammatory effect of dual nociceptin and opioid receptor agonist, BU08070, in experimental colitis in mice. Eur J Pharmacol 765:582-90
Hillhouse, Todd M; Porter, Joseph H (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol 23:1-21
Bailey, Chris P; Husbands, Stephen M (2014) Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies. Expert Opin Drug Discov 9:1333-44
Casal-Dominguez, Joseph J; Furkert, Daniel; Ostovar, Mehrnoosh et al. (2014) Characterization of BU09059: a novel potent selective κ-receptor antagonist. ACS Chem Neurosci 5:177-84
Kumar, Vinod; Ridzwan, Irna E; Grivas, Konstantinos et al. (2014) Selectively promiscuous opioid ligands: discovery of high affinity/low efficacy opioid ligands with substantial nociceptin opioid peptide receptor affinity. J Med Chem 57:4049-57
Sobczak, Marta; Cami-Kobeci, Gerta; Sałaga, Maciej et al. (2014) Novel mixed NOP/MOP agonist BU08070 alleviates pain and inhibits gastrointestinal motility in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms. Eur J Pharmacol 736:63-9
Casal-Dominguez, Joseph J; Clark, Mary; Traynor, John R et al. (2013) In vivo and in vitro characterization of naltrindole-derived ligands at the κ-opioid receptor. J Psychopharmacol 27:192-202
Kumandan, Sreekanth; Mahadevan, Navin R; Chiu, Kevin et al. (2013) Activation of the unfolded protein response bypasses trastuzumab-mediated inhibition of the PI-3K pathway. Cancer Lett 329:236-42

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