The purpose of the work proposed here is to synthesize compounds which will antagonize the reinforcing and psychosis-inducing properties of cocaine stimulants by binding irreversibly to the stimulant recognition site on the dopamine transporter. This approach is based on previous findings with Metaphit, an acylating phencylidine derivative, which in vitro irreversibly inhibits both the terminals as well as the transport of dopamine nerve terminal.In vivo, Metaphit completely blocks the hyperactivity normally seen following the administration of cocaine and other stimulants. Potential irreversible antagonists of cocaine and other stimulants will be synthesized by adding reactive electrophilic groups to compounds known to be effective inhibitors both of stimulant binding to the dopamine transporter, as well as of the transport process itself. The compounds selected for modification are mazindol, the """"""""GBR' series of aryl 1,4-dialk(en)ylpiperazines, methylphenidate, and dopamine itself. The reactive groups to be introduced into their structures are the isothiocyanate, bromoacetamide, maleimide, and fluorosulfonyl moieties. The newly synthesized compounds will be screened, along with Fourphit (a isomer of Metaphit provided to us by an outside collaborator) for their ability to interact irreversibly with the dopamine transporter. This will be determined by measuring (1) their inhibitory activity at the stimulant recognition site in the [3H]methylphenidate radioreceptor assay and (2) their ability to irreversibly block [3H]dopamine uptake into synaptosomes. Selectivity for the dopamine transporter over the norepinephrine and serotonin transporter will be determined. Compounds found to irreversibly inhibit stimulant binding and dopamine uptake with some degree of selectivity will then be tested in vivo for their behavioral effects. Activity of the compounds will be examined in three separate behavioral paradigms designed to evaluate their potential to antagonize the reinforcing and acute and chronic psychosis-inducing properties of stimulant agents in humans. Compounds which show behavioral activity will then be tested Ex vivo for their ability to block [3H]methylphenidate binding and [3H]dopamine uptake. This will entail examining [3H]methylphenidate binding and dopamine uptake in vitro from brain tissue taken from rats treated with these compounds in vivo. Metabolites of dopamine will also be measured following treatment with the stimulant antagonists in order to correlate the stimulant antagonist properties of the synthesized compounds with their effect on dopamine turnover. This research will enable us to develop potential antagonists of stimulant drugs of abuse. It also lays the groundwork for the eventual isolation and purification of the dopamine transport complex.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA006305-03
Application #
3212960
Study Section
Special Emphasis Panel (SRCD (04))
Project Start
1989-09-30
Project End
1993-08-31
Budget Start
1991-12-01
Budget End
1993-08-31
Support Year
3
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Georgia Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Misra, Milind; Shi, Qing; Ye, Xiaocong et al. (2010) Quantitative structure-activity relationship studies of threo-methylphenidate analogs. Bioorg Med Chem 18:7221-38
Kim, Deog-Il; Deutsch, Howard M; Ye, Xiaocong et al. (2007) Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate. J Med Chem 50:2718-31
Kim, Deog-Il; Schweri, Margaret M; Deutsch, Howard M (2003) Synthesis and pharmacology of site specific cocaine abuse treatment agents: 8-substituted isotropane (3-azabicyclo[3.2.1]octane) dopamine uptake inhibitors. J Med Chem 46:1456-64
Schweri, M M; Deutsch, H M; Massey, A T et al. (2002) Biochemical and behavioral characterization of novel methylphenidate analogs. J Pharmacol Exp Ther 301:527-35
Deutsch, H M; Ye, X; Shi, Q et al. (2001) Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction. Eur J Med Chem 36:303-11
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Deutsch, H M; Collard, D M; Zhang, L et al. (1999) Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors. J Med Chem 42:882-95
Javanmard, S; Deutsch, H M; Collard, D M et al. (1999) Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-substituted-6-amino-5-phenylbicyclo[2.2.2]octanes. J Med Chem 42:4836-43
Schweri, M M; de Costa, B R; Rice, K C (1998) Fourphit, an acylating phencyclidine derivative, attenuates cocaine-induced hyperactivity in rats. Pharmacol Biochem Behav 60:615-23
Deutsch, H M; Shi, Q; Gruszecka-Kowalik, E et al. (1996) Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs. J Med Chem 39:1201-9

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