Cocaine is a psychomotor stimulant with rewarding or """"""""reinforcing"""""""" property. The pharmacological effect responsible for the rewarding and hence the abuse liability is an section on the dopamenergic synapses. Cocaine prolongs the activity of dopamine in the synapse by blocking the dopamine receptor mechanism. The potency of cocaine and cocaine-like drugs in self- administration studies correlates with their potencies in inhibiting 3H-mazindol binding to the dopamine uptake site in the rat striatum. 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. In this study the design, synthesis and receptor binding evaluation of cocaine analogs are proposed as a method of investigating the biochemical mechanism of cocaine abuse liability. Molecular modeling studies were used to investigate the conformational energetics of possible pharmacophore binding modes for cocaine and to design the cocaine analogs proposed for study. Since the unique structural and stereochemical requirements seen in biological systems are due to a complementary three- dimensional interaction between a drug and its receptor site, the experimental determination of these requirements can be used to construct a picture of the receptor. This information will provide new and unique tools for biochemical studies and could translate into new agents for the treatment of cocaine addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA005477-01
Application #
3211839
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1988-07-01
Project End
1991-03-31
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
1
Fiscal Year
1988
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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