PRAMIPEXOLE - A DOPAMINE D-3-PREFERRING COMPOUND THAT LACKS INTERACTIONS WITH SIGMA-BINDING SITES

Compounds which were previously thought to be D-2- or D-3-selective ha ve recently been demonstrated to interact with sigma binding sites. Th e present studies examined: 1) displacement of [H-3]pramipexole bindin g to transfected cells and striatum or nucleus accumbens homogenates b y haloperidol and 1,3-di(2-toyl)guanidine (DTG) and 2) pramipexole, a D-3 receptor agonist, displacement of [H-3] 1,3-di(2-toyl)guanidine ([ H-3]DTG) from dopamine-insensitive sigma binding sites in striatum and nucleus accumbens homogenates. [H-3]Pramipexole (2 nM) labeled 20.7+/ -3.1 fmol/mg protein in cell membranes which was displaced 91.4% by 1 mu M haloperidol and 36.8% by 1 mu M DTG suggesting selectivity for D- 3 receptors versus sigma receptors. Unlabeled DTG displaced [3H]pramip exole binding to cell membranes with low affinity (7.4+/-0.5 mu M). In both striatum and nucleus accumbens, [H-3]DTG identified dopamine-ins ensitive 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 displ aced by pramipexole with low affinity (IC50>1 mu M). These data sugges t that pramipexole, a D-3-preferring agonist without interactions at s igma receptors as an agonist, might be efficacious in the treatment of neuropsychiatric disorders.