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 demonstrated by potent inhibition of DA synthesis and release and by reduction in the dopaminergic firing rate. Pramipexole has also proven highly effective in animal models in which the dopaminergic afferents to the striatum have been destroyed. In rats with unilateral lesions of the medial forebrain bundle, pramipexole has a potent stimulatory effect. In monkeys pretreated with N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine parkinsonian symptoms are fully antagonized by intramuscular pramipexole in doses below 0.1 mg/kg, thus predicting a high antiparkinsonian potential. In addition, an antidyskinetic action of pramipexole was shown in haloperidol-sensitized rhesus monkeys; the dose that fully relieved the symptoms in 50% of the animals was 0.1 mg/kg. Receptor-binding experiments and functional assays have characterized pramipexole 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, pramipexole binds with highest affinity to D-3 receptors (K-i = 0.5 nmol/L), indicating a seven- and tenfold greater selectivity for D-3 receptors compared with D-2 and D-4 receptors. By contrast, other DA-receptor agonists, such as quinpirole and bromocriptine, are nonselective or are more selective for D-2/D-4 receptors. The receptor affinity ratio of pramipexole (D3 > D(2)L = D2S > D-4) has been confirmed by saturation binding experiments and by its potency in functional activation of the receptor subtypes.