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D3 modulators for the treatment of psychostimulant abuse

Drug addiction is a major societal and medical issue. The scope of this issue in the U.S. was quantified in the National Survey on Drug Use and Health which reported that in 2014 over 27 million people over the age of 12 had consumed an illicit drug in the past 30 days.  The same survey indicated that there were >7.1 million people in the U.S. suffering from addiction to illicit drugs (e.g. cocaine, heroin, oxycodone, etc.) and that the annual societal cost of dealing with this issue exceeds $600 billion.[i]  Cocaine is one of the most commonly abused illicit drugs.  This addictive psychostimulant was isolated from the coca plant (Erythroxylon coca) over 100 years ago,[ii] and while there are some validated medical uses (e.g. local anesthetic for surgeries of the eyes, ears, nose, and throat), its primary use is as a recreational, illicit drug.  As of 2014, over 1.5 million people in the U.S. reported being current user of cocaine.

As part of our on-going efforts to identify potential novel therapies for the treatment of cocaine addiction, we have been exploring the impact of modulating dopamine signaling using dopamine D3 receptor ligands.  The D3 receptor has been the subject of intense interest as a potential therapeutic target for the treatment of cocaine addiction based on multiple lines of evidence. It is known, for example, that both chronic and acute exposure to cocaine leads to increased D3 expression in the nucleus accumbens. This region is responsible for cognitive processing including behaviors associated with cocaine addiction.[iii]  In addition, D3 is highly expressed in key regions of the brain linked to cocaine addiction.[iv]  To date, we have prepared over 200 novel compounds and identified lead molecules with pharmacokinetic properties suitable for in vivo efficacy animal studies.

 

[i] Hedden, S. L.; Kennet, J.; Lipari, R.; Medley, G.; Tice, P.; Copello, E. A. P.; Kroutil, L. A.  “Behavioral Health Trends in the United States: Results from the 2014 National Survey on Drug Use and Health” Center for Behavioral Health Statistics and Quality, 2015, HHS Publication No. SMA 15-4927, NSDUH Series H-50, Retrieved from http://www.samhsa.gov/data/

[ii] Calatayud, J.; González, A. “History of the development and evolution of local anesthesia since the coca leaf”, Anesthesiology. 2003, 98, 6, 1503-1508.

[iii] (a) Staley, J. K.; Mash, D. C. “Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities.” Journal of Neuroscience, 1996, 16, 6100−6106. (b) Segal, D. M.; Moraes, C. T.; Mash, D. C. Up-regulation of D3 dopamine receptor mRNA in the nucleus accumbens of human cocaine fatalities.” Brain Research Molecular Brain Research 1997, 45, 335−339. (c) Mash, D. C.; Staley, J. K. D3 dopamine and kappa opioid receptor alterations in human brain of cocaine-overdose victims. Annals of the New York Academies of Science, 1999, 877, 507−522.

[iv] (a) Keck, T. M.; John, W. S.; Czoty, P. W.; Nader, M. A.; Hauck Newman, A. H. “Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis.” Journal of Medicinal Chemistry, 2015, 58, 5361−5380. (b) Newmana, A. H.; Blaylock, B. L.; Nader, M. A.; Bergman, J.; Sibley, D. R.; Skolnick, P. “Medication discovery for addiction: Translating the dopamine D3 receptor hypothesis.” Biochemical Pharmacology, 2012, 84, 882–890. (c) Payer, D.; Balasubramaniam, G.; Boileau, I. “What is the role of the D3 receptor in addiction? A mini review of PET studies with [11C]-(+)-PHNO.” Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2014, 52, 4–8. (d) Blaylock, B. L.; Nader, M. A. “Dopamine D3 Receptor Function and Cocaine Exposure”, Neuropsychopharmacology, 2012, 37, 297–298.

Temple University
Moulder Center for Drug Discovery Research

Temple University School of Pharmacy
3307 N Broad Street
Philadelphia, PA 19140