Cocaine dependence is a problem of national significance. A considerable effort has been expended in the study of its mechanisms of action. Notwithstanding, to date no cocaine pharmacotherapy has been approved by the FDA. The reinforcing properties and stimulant effects of cocaine are associated with its propensity to bind to the dopamine transporter (DAT). Tropane analogs are potent inhibitors of the DAT. Among the strategies utilized for the design of cocaine therapies is the development of compounds which bind to the same site. The 3-phenyltropanes have been prominent among these and structure activity relationship studies have largely focused on this series of cocaine analogs. The goal of this proposal is to design novel tropanes as potential pharmacotherapies for cocaine dependence.
The specific aims are to synthesize and evaluate biologically five classes of novel tropanes: 8-oxa-3-aryltropanes, 6- or 7-hydroxytropanes, 6- or 7-hydroxy-8-oxa-3-aryltropanes, 2,3-didehydro-8-aza- and 8-oxa-tropanes, and 6-or 7-hydroxylated 2,3-didehydro-8-aza- and 8-oxatropanes. Carefully selected compounds will be prepared and their inhibition of monoamine transport will be determined. Potent and selective compounds will be assayed for inhibition of dopamine uptake and those compounds which inhibit cocaine uptake with minimal effect on dopamine uptake will be subjected to behavioral studies. It is anticipated that these studies will lead to a disclosure of SAR on aspects of the tropanes hitherto uninvestigated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011542-04
Application #
6174719
Study Section
Special Emphasis Panel (ZDA1-KXN-G (20))
Program Officer
Biswas, Jamie
Project Start
1997-09-30
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
2000
Total Cost
$256,992
Indirect Cost
Name
Organix, Inc.
Department
Type
DUNS #
City
Woburn
State
MA
Country
United States
Zip Code
01801
Torun, Lokman; Madras, Bertha K; Meltzer, Peter C (2012) Synthesis and structure-activity relationship studies of 3-biaryl-8-oxabicyclo[3.2.1]octane-2-carboxylic acid methyl esters. Bioorg Med Chem 20:2762-72
Purushotham, Madhusudhan; Sheri, Anjaneyulu; Pham-Huu, Duy-Phong et al. (2011) The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes. Bioorg Med Chem Lett 21:48-51
Meltzer, Peter C; Kryatova, Olga; Pham-Huu, Duy-Phong et al. (2008) The synthesis of bivalent 2beta-carbomethoxy-3beta-(3,4-dichlorophenyl)-8-heterobicyclo[3.2.1]octanes as probes for proximal binding sites on the dopamine and serotonin transporters. Bioorg Med Chem 16:1832-41
Pham-Huu, Duy-Phong; Deschamps, Jeffrey R; Liu, Shanghao et al. (2007) Synthesis of 8-thiabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. Bioorg Med Chem 15:1067-82
Meltzer, Peter C; Butler, David; Deschamps, Jeffrey R et al. (2006) 1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogues: a promising class of monoamine uptake inhibitors. J Med Chem 49:1420-32
Meltzer, Peter C; McPhee, Mark; Madras, Bertha K (2003) Synthesis and biological activity of 2-carbomethoxy-3-catechol-8-azabicyclo[3.2.1]octanes. Bioorg Med Chem Lett 13:4133-7
Meltzer, Peter C; Wang, Pinglang; Blundell, Paul et al. (2003) Synthesis and evaluation of dopamine and serotonin transporter inhibition by oxacyclic and carbacyclic analogues of methylphenidate. J Med Chem 46:1538-45
Madras, Bertha K; Fahey, Michele A; Miller, Gregory M et al. (2003) Non-amine-based dopamine transporter (reuptake) inhibitors retain properties of amine-based progenitors. Eur J Pharmacol 479:41-51
Meltzer, Peter C; Liu, Shanghao; Blanchette, Heather et al. (2002) Design and synthesis of an irreversible dopamine-sparing cocaine antagonist. Bioorg Med Chem 10:3583-91
Meltzer, P C; Wang, B; Chen, Z et al. (2001) Synthesis of 6- and 7- hydroxy-8-azabicyclo[3.2.1]octanes and their binding affinity for the dopamine and serotonin transporters. J Med Chem 44:2619-35

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