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-dihydrochlor ide) is a potent dopamine autoreceptor agonist. We have carried out an analysis of the binding affinities of dopamine D2L, D2S, 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 D2L, D2S 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.