Pramipexole: A dopamine D₃-preferring compound that lacks interactions with sigma binding sites

Compounds which were previously thought to be D₂- or D₃-selective have recently been demonstrated to interact with sigma binding sites. The present studies examined: 1) displacement of [³H]pramipexole binding to transfected cells and striatum or nucleus accumbens homogenates by haloperidol and 1,3-di(2-toyl)guanidine (DTG) and 2) pramipexole, a D₃ receptor agonist, displacement of [³H]1,3-di(2-toyl)guanidine ([³H]DTG) from dopamine-insensitive sigma binding sites in striatum and nucleus accumbens homogenates. [³H]Pramipexole (2 nM) labeled 20.7 ± 3.1 fmol/mg protein in cell membranes which was displaced 91.4% by 1 μM haloperidol and 36.8% by 1 μM DTG suggesting selectivity for D₃ receptors versus sigma receptors. Unlabeled DTG displaced [³H]pramipexole binding to cell membranes with low affinity (7.4 ± 0.5 μM). In both striatum and nucleus accumbens, [³H]DTG identified dopamine-insensitive sites with moderate affinity (297 ± 15.8 fmol/mg; 29.0 ± 5.5 nM and 255 ± 5.8 fmol/mg; 26.3 ± 4.2 nM, respectively) which was displaced by pramipexole with low affinity (IC₅₀ > 1 μM). These data suggest that pramipexole, a D₃-preferring agonist without interactions at sigma receptors as an agonist, might be efficacious in the treatment of neuropsychiatric disorders.