Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propylamino-benzthiazole-dihydrochloride) is a potent dopamine autoreceptor agonist. We have carried out an analysis of the binding affinities of dopamine D_2L, D_2S, D₃, and D₄ receptors for pramipexole using both [³H]pramipexole and [³H]spiperone as radioligands at cloned and heterologously expressed receptors. Studies were carried out using rat and human D_2L, D_2S and D₃ receptors with equivalent results. When the binding of pramipexole to the high affinity, guanine nucleotide-sensitive state of each receptor was analyzed, pramipexole is most selective for D₃ compared to D₂ and D₄ receptors. These results indicate a 5-fold selectivity of pramipexole for D₃ receptors, while quinpirole and bromocriptine are non-selective or more D₂/D₄ receptor selective. Two measurements of receptor activation for dopamine D₂, D₃, and D₄ receptors also show that pramipexole is most potent for activation of D₃ receptors. The dopamine D₃ receptor selectivity of pramipexole may explain the previously described properties of this drug, including its potent autoreceptor preference.