PRAMIPEXOLE BINDING AND ACTIVATION OF CLONED AND EXPRESSED DOPAMINE D-2, D-3 AND D-4 RECEPTORS

Pramipexole (SND 919; ahydro-6-propylamino-benzthiazole-dihydrochlorid e) is a potent dopamine autoreceptor agonist. We have carried out an a nalysis of the binding affinities of dopamine D-2L, D-2S, D-3, and D-4 receptors for pramipexole using both [H-3]pramipexole and [H-3]spiper one as radioligands at cloned and heterologously expressed receptors. Studies were carried out using rat and human D-2L, D-2S and D-3 recept ors with equivalent results. When the binding of pramipexole to the hi gh affinity, guanine nucleotide-sensitive state of each receptor was a nalyzed, pramipexole is most selective for D-3 compared to D-2 and D-4 receptors. These results indicate a 5-fold selectivity of pramipexole for D-3 receptors, while quinpirole and bromocriptine are non-selecti ve or more D-2/D-4 receptor selective. Two measurements of receptor ac tivation for dopamine D-2, D-3, and D-4 receptors also show that prami pexole is most potent for activation of D-3 receptors. The dopamine D- 3 receptor selectivity of pramipexole may explain the previously descr ibed properties of this drug, including its potent autoreceptor prefer ence.