PRAMIPEXOLE - A DOPAMINE-RECEPTOR AGONIST FOR TREATMENT OF PARKINSONS-DISEASE

Pramipexole is a potent agonist at both presynaptic autoreceptors and noninnervated dopamine (DA) CNS receptors. These characteristics are d emonstrated by potent inhibition of DA synthesis and release and by re duction in the dopaminergic firing rate. Pramipexole has also proven h ighly effective in animal models in which the dopaminergic afferents t o the striatum have been destroyed. In rats with unilateral lesions of the medial forebrain bundle, pramipexole has a potent stimulatory eff ect. In monkeys pretreated with N-methyl-4-phenyl-1,2,3,6-tetrahydropy ridine parkinsonian symptoms are fully antagonized by intramuscular pr amipexole in doses below 0.1 mg/kg, thus predicting a high antiparkins onian potential. In addition, an antidyskinetic action of pramipexole was shown in haloperidol-sensitized rhesus monkeys; the dose that full y relieved the symptoms in 50% of the animals was 0.1 mg/kg. Receptor- binding experiments and functional assays have characterized pramipexo le as a full DA-receptor agonist with specificity for the D-2-receptor subfamily. This affinity profile is uniformly selective for the S(-) enantiomer, which is pramipexole. Within the D-2-receptor subfamily, p ramipexole binds with highest affinity to D-3 receptors (K-i = 0.5 nmo l/L), indicating a seven- and tenfold greater selectivity for D-3 rece ptors compared with D-2 and D-4 receptors. By contrast, other DA-recep tor agonists, such as quinpirole and bromocriptine, are nonselective o r are more selective for D-2/D-4 receptors. The receptor affinity rati o of pramipexole (D3 > D(2)L = D2S > D-4) has been confirmed by satura tion binding experiments and by its potency in functional activation o f the receptor subtypes.