HALOGENATED MAZINDOL ANALOGS AS POTENTIAL INHIBITORS OF THE COCAINE BINDING-SITE AT THE DOPAMINE TRANSPORTER

A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homolog s of mazindol were prepared and evaluated for their ability to displac e [H-3]WIN 35,428 binding and to inhibit uptake of [H-3]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2'-chloro (6) and 2'-bromo (16) analogs of mazindol displaced [H-3]WIN 35,428 bi nding and inhibited [H-3]DA uptake more effectively than (R)-cocaine. Structure-activity studies indicated that best inhibition of [H-3]WIN 35,428 binding occurred in the imidazo series with compounds containin g one or two Cl or Br atoms in the 3'- or 4'-position of the free phen yl group. Replacement of the imidazo ring by a pyrimido or diazepino r ing enhanced binding inhibition. The most potent inhibitors of [H-3]WI N 35,428 binding and [H-3]DA uptake were yl)-2,3,4,6-tetrahydropyrimid o[2,1-a]isoindol-6-ol (23; IC50 1.0 nM; 8x mazindol) and ,3,4,5-tetrah ydro-7H-diazepino[2,1-a]isoindol-7-ol (28; IC50 0.26 nM; 32x mazindol) , respectively. No significant differences was found between binding a nd uptake inhibition. Mazindol and the pyrimido and diazepino homologs 24 and 27 showed a selectivity for the DA uptake over the serotonin ( 5-HT) uptake site of 5-, 250-, and 465-fold, respectively, and display ed weak or no affinity for a variety of neurotransmitter receptor site s.