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VJ Aloyo, JS Ruffin, PS Pazdalski, AL Kirifides and JA Harvey
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia, USA.
The binding of the potent cocaine analog, WIN 35,428 ((-)-2-beta- carbomethoxy-3-beta-(4-fluorophenyl)tropane 1,5-napthalenedisulfonate), was investigated in adult Dutch Belted rabbits by using membrane fractions prepared from fresh caudate nucleus. The consistent finding of this study was that [3H]WIN 35,428 binds to a single class of sites. For example: 1) kinetic analysis revealed that the rate of association and dissociation of [3H]WIN 35,428 was linear; 2) analyses of saturation experiments or homotopic displacement with cold WIN 35,428 by three separate methods statistically favored a one-site model; and 3) heterotropic displacement with drugs that bind to the dopamine (DA) transporter consistently yielded only a single class of binding sites as reflected by a complete displacement of [3H]WIN 35,428 and Hill slopes of approximately 1 (range, 0.89-1.06). The rank order of potencies (Ki) obtained in the competition experiments was: mazindol > nomifensine > (-)-cocaine > bupropion > (-)-norcocaine >> desipramine > DA > (+)-cocaine >> norepinephrine > citalopram > 5-hydroxytryptamine. The affinities of these drugs at the [3H]WIN 35,428 binding site was significantly correlated (r = 0.96, P < .001) with their potencies for inhibiting the uptake of DA, but not the uptake of norepinephrine or 5- hydroxytryptamine. Because [3H]WIN 35,428 binding was fully displaced by cocaine and the displacement was stereoselective, with (-)-cocaine being 200-fold more potent than (+)-cocaine, we conclude that [3H]WIN 35,428 was binding to a single cocaine site. Taken together, these findings indicate that [3H]WIN 35,428 binds to a single cocaine site on the DA transporter of the rabbit with a Kd of 3.2 +/- 0.4 nM and a maximum binding of 0.39 +/- 0.04 pmol/mg of caudate tissue.
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