The aims of the proposal are in accord with the mission of the Addiction Treatment Discovery Program (ATDP): To discover potential pharmacological treatments for substance abuse in humans, with an emphasis on relapse prevention, through preclinical testing and evaluation of compounds. The principal goal of the project is to provide potential treatment agents for 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 behaviour, including both opioids and cocaine. The target compounds lack of, or very limited, 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 also come from the compounds kappa opioid receptor antagonist activity, coupled with agonism at NOP (nociceptin) receptors and antagonism at delta opioid receptors. Lead compounds have been identified during the current funding period from within the orvinol and naltrexone series. These series have already produced several compounds of clinical or veterinary utility, including buprenorphine and naltrexone. Key, recent medicinal chemistry discoveries by our group including, 1) the role of a methyl group at C7 in the orvinol series in reducing efficacy at kappa receptors and increasing NOP activity and 2) the role of the C14 side chain in the naltrexone series in allowing substantial NOP activity to be introduced to this series of opioid antagonists, has allowed compounds with the desired profile to be developed. These discoveries will be extended; in particular, ligands from the orvinol series have been identified for further evaluation with one currently undergoing extensive in vivo testing and evaluation of its ADME-tox profile. Follow-on/back-up compounds are also being developed. The significance of this work is that it will tell us whether single compounds can be developed that can block relapse to both opioid and cocaine use, what types of relapse are blocked (drug-, stress- or cue-primed) and will allow us to move our identified candidate therapeutics closer to the clinic.

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 issues in the treatment of drug abuse is the high rate of relapse to drug taking. This project aims to satisfy this unmet medical need for more efficient and effective methods to treat relapse. It will achieve this by following up on our current studies that have identified compounds with activity in animal models of drug taking behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA007315-21A1
Application #
8817952
Study Section
Special Emphasis Panel (DDNS)
Program Officer
Kline, Richard
Project Start
1991-08-01
Project End
2019-11-30
Budget Start
2015-02-01
Budget End
2015-11-30
Support Year
21
Fiscal Year
2015
Total Cost
$365,870
Indirect Cost
$11,996
Name
University of Bath
Department
Type
DUNS #
424400661
City
Bath
State
Country
United Kingdom
Zip Code
BA2 7-AY
Kumar, Vinod; Polgar, Willma E; Cami-Kobeci, Gerta et al. (2018) Synthesis, Biological Evaluation, and SAR Studies of 14?-phenylacetyl Substituted 17-cyclopropylmethyl-7, 8-dihydronoroxymorphinones Derivatives: Ligands With Mixed NOP and Opioid Receptor Profile. Front Psychiatry 9:430
Hill, Rob; Disney, Alex; Conibear, Alex et al. (2018) The novel ?-opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception. Br J Pharmacol 175:2653-2661
Zieli?ska, Marta; Jarmu?, Agata; Wasilewski, Andrzej et al. (2017) Methyl-orvinol-Dual activity opioid receptor ligand inhibits gastrointestinal transit and alleviates abdominal pain in the mouse models mimicking diarrhea-predominant irritable bowel syndrome. Pharmacol Rep 69:350-357
Lacin, Emre; Muller, Arnaud; Fernando, Marian et al. (2016) Construction of Cell-based Neurotransmitter Fluorescent Engineered Reporters (CNiFERs) for Optical Detection of Neurotransmitters In Vivo. J Vis Exp :
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
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
Cueva, Juan Pablo; Roche, Christopher; Ostovar, Mehrnoosh et al. (2015) C7?-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
Zieli?ska, 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
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
Sobczak, Marta; Cami-Kobeci, Gerta; Sa?aga, 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

Showing the most recent 10 out of 22 publications