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Relationships Between the Catechol Substrate Binding Site and Amphetamine, Cocaine, and Mazindol Binding Sites in a Kinetic Model of the Striatal Transporter of Dopamine In Vitro
Author(s) -
Wayment Hollie,
Meiergerd Susan M.,
Schenk James O.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.70051941.x
Subject(s) - mazindol , amphetamine , dopamine transporter , dopamine , chemistry , dopamine plasma membrane transport proteins , binding site , dopaminergic , tyramine , catecholamine , pharmacology , dopamine uptake inhibitors , biochemistry , neuroscience , biology
Experiments were conducted to determine how (−)‐cocaine and S (+)‐amphetamine binding sites relate to each other and to the catechol substrate site on the striatal dopamine transporter (sDAT). In controls, m ‐tyramine and S (+)‐amphetamine caused release of dopamine from intracellular stores at concentrations ≥12‐fold those observed to inhibit inwardly directed sDAT activity for dopamine. In preparations from animals pretreated with reserpine, m ‐tyramine and S (+)‐amphetamine caused release of preloaded dopamine at concentrations similar to those that inhibit inwardly directed sDAT activity. S (+)‐Amphetamine and m ‐tyramine inhibited sDAT activity for dopamine by competing for a common binding site with dopamine and each other, suggesting that phenethylamines are substrate analogues at the plasmalemmal sDAT. (−)‐Cocaine inhibited sDAT at a site separate from that for substrate analogues. This site is mutually interactive with the substrate site ( K int = 583 n M ). Mazindol competitively inhibited sDAT at the substrate analogue binding site. The results with (−)‐cocaine suggest that the (−)‐cocaine binding site on sDAT is distinct from that of hydroxyphenethylamine substrates, reinforcing the notion that an antagonist for (−)‐cocaine binding may be developed to block (−)‐cocaine binding with minimal effects on dopamine transporter activity. However, a strategy of how to antagonize drugs of abuse acting as substrate analogues is still elusive.