Abstract

The objective of the proposed research is to synthesize and evaluate the preclinical biological and behavioral effects of novel compounds targeted for development as new cocaine abuse therapeutic agents. Novel compounds will be prepared and tested in vitro and in vivo paradigms to investigate the heterogeneous character (low affinity and high affinity binding components) of the dopamine transporter associated with cocaine binding. This study should elucidate the behavioral effects and abuse liability associated with the high affinity site and the low affinity site corresponding to cocaine binding. A greater understanding of these effects should aid in the development of new cocaine abuse therapeutic agents. Novel compounds will be synthesized to be developed as potent selective dopamine transporter ligands which can be rapidly transported into the brain and are long-lived in in vivo. The compounds will be tested in in vitro and in vivo paradigms to explore the effects of drug transport on abuse liability. In addition, dopamine transporter selectivity (versus serotonin transporter) and secondary receptor binding (sigma-receptors) will be investigated. It is anticipated that a highly selective dopamine transporter ligand with a fast onset of activity will be identified for development as a therapeutic agent for acute cocaine overdose as well as chronic cocaine addiction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011528-05
Application #
6378734
Study Section
Special Emphasis Panel (ZDA1-KXN-G (20))
Program Officer
Biswas, Jamie
Project Start
1997-09-30
Project End
2003-07-31
Budget Start
2001-08-01
Budget End
2003-07-31
Support Year
5
Fiscal Year
2001
Total Cost
$257,932
Indirect Cost

  Institution

Name
Louisiana State University-University of New Orleans
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70148

  Publications

Hong, Weimin C; Kopajtic, Theresa A; Xu, Lifen et al. (2016) 2-Substituted 3?-Aryltropane Cocaine Analogs Produce Atypical Effects without Inducing Inward-Facing Dopamine Transporter Conformations. J Pharmacol Exp Ther 356:624-34
Thaxton, Amber; Izenwasser, Sari; Wade, Dean et al. (2013) 3-Aryl-3-arylmethoxyazetidines. A new class of high affinity ligands for monoamine transporters. Bioorg Med Chem Lett 23:4404-7
Cararas, Shaine A; Izenwasser, Sari; Wade, Dean et al. (2011) Further structure-activity relationship studies on 8-substituted-3-[2-(diarylmethoxyethylidenyl)]-8-azabicyclo[3.2.1]octane derivatives at monoamine transporters. Bioorg Med Chem 19:7551-8
Shu, Hong; Noble, April R; Zhang, Suhong et al. (2010) Enantioselective syntheses of both enantiomers of cis-pyrrolidine 225H. Tetrahedron 66:4428-4433
Gu, Xiaobo; Izenwasser, Sari; Wade, Dean et al. (2010) Synthesis and structure-activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands. Bioorg Med Chem 18:8356-64
Kaur, Harneet; Izenwasser, Sari; Verma, Abha et al. (2009) Synthesis and monoamine transporter affinity of 3alpha-arylmethoxy-3beta-arylnortropanes. Bioorg Med Chem Lett 19:6865-8
Miao, Lei; Dimaggio, Stassi C; Shu, Hong et al. (2009) Enantioselective syntheses of both enantiomers of noranabasamine. Org Lett 11:1579-82
Zhang, Suhong; Izenwasser, Sari; Wade, Dean et al. (2006) Synthesis of dopamine transporter selective 3-diarylmethoxymethyl-8-arylalkyl-8-azabicyclo[3.2.1]octane derivatives. Bioorg Med Chem 14:7943-52
Lomenzo, Stacey A; Rhoden, Jill B; Izenwasser, Sari et al. (2005) Synthesis and biological evaluation of meperidine analogues at monoamine transporters. J Med Chem 48:1336-43
Rhoden, Jill B; Bouvet, Maud; Izenwasser, Sari et al. (2005) Structure-activity studies of 3'-4'-dichloro-meperidine analogues at dopamine and serotonin transporters. Bioorg Med Chem 13:5623-34

Showing the most recent 10 out of 14 publications