Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. II. Agonist and Antagonist Properties at Subtypes of Dopamine D2-Like Receptor and α1/α2-Adrenoceptor

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Abstract
The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D2SHORT(S), hD2LONG(L), hD3, and hD4.4receptors and at hα2A-, hα2B-, hα2C-, and hα1A-adrenoceptors (ARs). As determined by guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding, no ligand displayed “full” efficacy relative to dopamine (100%) at all “D2-like” sites. However, at hD2S receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (Emax≥100%); TL99, talipexole, and apomorphine were highly efficacious (79–92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40–55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD2L receptors, with terguride and roxindole acting as antagonists. At hD3 receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD4 receptors, highest efficacies (∼70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD2S versus hD2L sites were highly correlated (r = 0.79), they correlated only modestly to hD3/hD4 sites (r = 0.44–0.59). In [35S]GTPγS studies of hα2A-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at hα2B- and hα2C-ARs. Using [3H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at hα1A-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist properties at multiple subtypes of D2-like receptor and α1/α2-AR, actions, which likely contribute to their contrasting functional profiles.