This application is for the continuation of support of a collaborative program with Dr. Michael Kuhar of the Addiction Research Center (ARC) to study the biochemical mechanism of cocaine addiction. The potency of cocaine and cocaine-like drugs in self-administration studies correlates with their potencies in inhibiting radioligand binding to the dopamine uptake site. Since there is no correlation for binding to a large number of other pre- and post-synaptic binding sites the cocaine receptor related to substance abuse appears to be the one associated with dopamine uptake inhibition. We propose to: (1) conduct a structure-activity study oh cocaine analogs; (2) develop new cocaine analogs which will bind specifically and irreversibly to the receptor; (3) develop new cocaine derivatives that will be suitable for purification of the receptor by affinity chromatography; and (4) develop new cocaine analogs for use in Single Photon Emission Tomography (SPECT). Information gained from these studies will lead to a better understanding of the basic biochemical mechanism(s) of cocaine addiction. Our program has been expanded to include collaboration with Dr. Robert Balster of the Medical College of Virginia who will conduct drug discrimination studies in rats land drug self-administration studies in rhesus monkeys on selected compounds. We hope that these collaborative programs which combine design of analogs by molecular modeling, chemical synthesis, receptor binding, and functional studies will identify analogs that will share some but not all of the actions of cocaine and thus may lead to therapeutically useful drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005477-07
Application #
2117716
Study Section
Special Emphasis Panel (SRCD (45))
Project Start
1988-07-01
Project End
1996-06-30
Budget Start
1994-08-01
Budget End
1995-06-30
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Research Triangle Institute
Department
Type
DUNS #
131606022
City
Research Triangle Park
State
NC
Country
United States
Zip Code
27709
Carroll, F Ivy; Kosten, Thomas R; Buda, Jeffrey J et al. (2018) A Double-Blind, Placebo-Controlled Trial Demonstrating the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of RTI-336. Front Pharmacol 9:712
Rosenberg, Marisa B; Carroll, F Ivy; Negus, S Stevens (2013) Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J Pain 14:246-59
RĂ¼edi-Bettschen, Daniela; Wood, Sherri L; Gunnell, Melinda G et al. (2013) Vaccination protects rats from methamphetamine-induced impairment of behavioral responding for food. Vaccine 31:4596-602
Andersen, Monica L; Sawyer, Eileen K; Carroll, F Ivy et al. (2012) Influence of chronic dopamine transporter inhibition by RTI-336 on motor behavior, sleep, and hormone levels in rhesus monkeys. Exp Clin Psychopharmacol 20:77-83
Gichinga, Moses G; Olson, Jeremy P; Butala, Elizabeth et al. (2011) Synthesis and Evaluation of Metabotropic Glutamate Receptor Subtype 5 Antagonists Based on Fenobam(). ACS Med Chem Lett 2:882-884
Gichinga, Moses G; Olson, Jeremy P; Butala, Elizabeth et al. (2011) Preparation of a Series of 5-Methyl-3-(substituted)-[1,2,4]triazines. Tetrahedron Lett 52:3345-3346
Carroll, F Ivy; Blough, Bruce E; Pidaparthi, Ramakrishna R et al. (2011) Synthesis of mercapto-(+)-methamphetamine haptens and their use for obtaining improved epitope density on (+)-methamphetamine conjugate vaccines. J Med Chem 54:5221-8
Czoty, Paul W; Martelle, Jennifer L; Carroll, F Ivy et al. (2010) Lower reinforcing strength of the phenyltropane cocaine analogs RTI-336 and RTI-177 compared to cocaine in nonhuman primates. Pharmacol Biochem Behav 96:274-8
Negus, S S; Mello, N K; Kimmel, H L et al. (2009) Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys. Pharmacol Biochem Behav 91:333-8
Laurenzana, Elizabeth M; Hendrickson, Howard P; Carpenter, Dylan et al. (2009) Functional and biological determinants affecting the duration of action and efficacy of anti-(+)-methamphetamine monoclonal antibodies in rats. Vaccine 27:7011-20

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