The major goal of this application is to discover and develop medications for the treatment of substance abuse. Furthermore, we expect that the compounds developed will also serve as biochemical probes useful in gaining a better understanding of the biochemical and molecular mechanisms of cocaine, and amphetamine addiction and withdrawal. The initial objective of this proposal is to design, synthesize, and evaluate dopamine (DA), serotonin (5-HT), and norepinephrine (NE) releasers. To date, most efforts towards an "agonist" therapy of stimulant addiction have concentrated on the discovery of selective DA uptake blockers. However increasing evidence shows that dual DA/5-HT selective or non-selective compounds may be required to "correct" the totality of stimulant-induced deficits during withdrawal. Experimental results published since the original grant application also suggests that releasers as a class may be effective synaptic agonist treatments. The optimal balance of activity between these three neurotransmitter systems is not known;however it is assumed that DAergic activity must be present with some combination of other activity. Thus, the primary objective of this application is to further develop the dual DA/5HT and non-selective "universal" releaser leads generated during the initial project period. These compounds may also be useful for treating other psychiatric disorders such as depression, anxiety, and stress. The target compounds will be small molecules that are expected to penetrate the CNS and have reasonable stability so that they will be useful medications and can be used as in vitro and in vivo probes.

Public Health Relevance

Stimulant abuse and addiction continues to be a major societal problem the United States. Mounting evidence suggests that one of the best methods for combating stimulant addiction is the agonist approach in which drugs replace the biochemical deficits caused by chronic stimulant. Such an approach may be the only way to address the wide ranges of symptoms observed during withdrawal as well as the urge to relapse into drug taking behavior. Dual dopamine/serotonin releasers represent one approach to such agonist therapies and will be developed in this research program.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012970-12
Application #
8253789
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Shih, Ming L
Project Start
1999-09-30
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
12
Fiscal Year
2012
Total Cost
$448,505
Indirect Cost
$208,430
Name
Research Triangle Institute
Department
Type
DUNS #
004868105
City
Research Triangle
State
NC
Country
United States
Zip Code
27709
Blough, Bruce E; Landavazo, Antonio; Partilla, John S et al. (2014) Alpha-ethyltryptamines as dual dopamine-serotonin releasers. Bioorg Med Chem Lett 24:4754-8
Banks, Matthew L; Bauer, Clayton T; Blough, Bruce E et al. (2014) Abuse-related effects of dual dopamine/serotonin releasers with varying potency to release norepinephrine in male rats and rhesus monkeys. Exp Clin Psychopharmacol 22:274-84
Marusich, Julie A; Antonazzo, Kateland R; Wiley, Jenny L et al. (2014) Pharmacology of novel synthetic stimulants structurally related to the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV). Neuropharmacology 87:206-13
Blough, Bruce E; Landavazo, Antonio; Decker, Ann M et al. (2014) Interaction of psychoactive tryptamines with biogenic amine transporters and serotonin receptor subtypes. Psychopharmacology (Berl) 231:4135-44
Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R et al. (2013) Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology 38:2698-707
Banks, Matthew L; Blough, Bruce E; Fennell, Timothy R et al. (2013) Role of phenmetrazine as an active metabolite of phendimetrazine: evidence from studies of drug discrimination and pharmacokinetics in rhesus monkeys. Drug Alcohol Depend 130:158-66
Banks, Matthew L; Blough, Bruce E; Negus, S Stevens (2013) Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys. Neuropsychopharmacology 38:395-404
Marusich, Julie A; Lefever, Timothy W; Novak, Scott P et al. (2013) Prediction and Prevention of Prescription Drug Abuse: Role of Preclinical Assessment of Substance Abuse Liability. Methods Rep RTI Press :1-14
Banks, Matthew L; Blough, Bruce E; Negus, S Stevens (2013) Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys. Drug Alcohol Depend 131:204-13
Kohut, Stephen J; Fivel, Peter A; Blough, Bruce E et al. (2013) Effects of methcathinone and 3-Cl-methcathinone (PAL-434) in cocaine discrimination or self-administration in rhesus monkeys. Int J Neuropsychopharmacol 16:1985-98

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