DOPAMINE-RECEPTOR SUBTYPE-SELECTIVE AGONISTS IN THE TREATMENT OF PARKINSONS-DISEASE

Dopamine agonists have a number of potential advantages over levodopa in the symptomatic treatment of Parkinson's disease. To evaluate whether the relative affinity of an agonist for the D-1, D-2, and D-3 subtypes of dopamine receptors influences its antiparkinsonian or dyskinesiogenic effect, results with levodopa were compared with those of three dopamine agonists having differing binding profiles. The antiparkinsonian response to apomorphine tended to be slightly but not significantly lower than with levodopa, whereas the response to both N-propyl-norapomorphine (NPA) and N-0923 averaged approximately 33% lower than that for levodopa. The severity of choreiform dyskinesias induced by the latter two agonists also tended to be somewhat less than those associated with levodopa. The ratio of dyskinesias to antiparkinsonian efficacy for levodopa and all the agonists evaluated were thus very similar. Evaluation of the clinical results for these dopaminomimetics with respect to their dopamine receptor affinity profile suggests that comparable binding affinities for the D-1 and D-2 receptors may be associated with greater antiparkinsonian activity, which tends to diminish as relative D-2 selectivity is enhanced. A relatively high affinity for D-2 or D-3 receptors appears to be associated with a diminished antiparkinsonian response, which in both cases is associated with a somewhat reduced tendency to induce dyskinesias. A relative affinity for the D-1 receptor appears to have little effect on either antiparkinsonian activity or the potential for dyskinesias. It is conceivable that D-1/D-2/D-3-nonselective agonists that approximate the receptor affinity profile of dopamine might prove most advantageous in patients with parkinsonism.