Functional potencies of new antiparkinsonian drugs at recombinant human dopamine D1, D2 and D3 receptors

We measured the affinities of bromocriptine, pramipexole, pergolide and ropinirole at human recombinant dopamine D-1, D-2 and D-3 receptors in binding and functional tests. All four compounds bound with high affinity at the dopamine D-3 receptor; bromocriptine and pergolide also had high affinity for the dopamine D-2 receptor, while only pergolide had significant, although moderate, affinity for the dopamine D-1 receptor. Only pergolide had high potency and intrinsic activity at the dopamine D-1 receptor for stimulating cyclic AMP accumulation. In addition, the potencies and efficacies of pergolide and bromocriptine, as well as that of dopamine, at the dopamine D-1 receptor were increased in the presence of forskolin, an adenylate cyclase activator. All four compounds were highly potent agonists at dopamine D-2 and D-3 receptors, as measured in a mitogenesis assay. Bromocriptine was ten times more potent and pramipexole and ropinirole ten times less potent at the dopamine D-2 than at the dopamine D-3 receptor, whereas pergolide was equipotent at the two receptors. These results suggest that the activity of recently developed antiparkinsonian drugs at either the dopamine D-1 or the dopamine D-3 and not only the dopamine D-2 receptors should be taken into account in analyses of their mechanisms of action in therapeutics. (C) 1999 Elsevier Science B.V. All rights reserved.