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Use of identical assay conditions for cocaine analog binding and dopamine uptake to identify potential cocaine antagonists.

Abstract：

:The addictive and euphorogenic properties of cocaine are thought to result from inhibition of the dopamine transporter (DAT). Recent evidence suggests that dopamine and cocaine bind to distinct sites on the transporter protein. Therefore it should be possible to design drugs which specifically inhibit cocaine recognition by the DAT while permitting the transporter to maintain its function of accumulating dopamine. One way to monitor such activity is to compare the inhibition constants of test agents for inhibition of radiolabelled dopamine uptake (Kiuptake) and inhibition of the binding of a cocaine ligand such as [3H]2 beta-carbomethoxy-3 beta-3 beta-(fluorophenyl)tropane (CFT; Kibind) and select for compounds with Kiuptake/Kibind ratios greater than unity. Because others have shown that compounds can exhibit Kiuptake/Kibind ratios greater than unity when the assays are performed under non-identical conditions, we have established these assays under identical conditions of time, temperature and buffer using a Chinese hamster ovary (CHO) cell line which stably expresses the human DAT. Kinetic and saturation analyses were performed on both assay and over 200 structurally diverse compounds were screened. Using identical assay parameters, several series of compounds having Kiuptake/Kibind ratios significantly greater than unity were identified. Such compounds include local anesthetics (procaine, dibucaine, tolperisone, dyclonine, diperodone), antipsychotic agents (10-(diethylaminopropionyl)phenothiazine), antidepressants (desipramine, imipramine, protriptyline), a diuretic (5-N-methyl-N-isobutyl-amilioride), an anticholinergic agent (prindinol), a PKC inhibitor (H-8), a calcium channel antagonist (loperamide) and an antimalarial compound (chloroquine). To our knowledge, even though these compounds exhibit low binding affinities (3-24 microM), they represent some of the most cocaine site-selective compounds identified to date using identical assay parameters.

journal_name

Drug Alcohol Depend

journal_title

Drug and alcohol dependence

authors

Slusher BS,Tiffany CW,Olkowski JL,Jackson PF

doi

10.1016/s0376-8716(97)00102-6

subject

Has Abstract

pub_date

1997-10-25 00:00:00

pages

43-50

issue

eissn

0376-8716

issn

1879-0046

pii

S0376-8716(97)00102-6

journal_volume

pub_type

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Use of identical assay conditions for cocaine analog binding and dopamine uptake to identify potential cocaine antagonists.