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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

Abstract: 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 (Kint = 583 nM). 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.