Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. I. A Multivariate Analysis of the Binding Profiles of 14 Drugs at 21 Native and Cloned Human Receptor Subtypes

Because little comparative information is available concerning receptor profiles of antiparkinson drugs, affinities of 14 agents were determined at diverse receptors implicated in the etiology and/or treatment of Parkinson9s disease: human (h)D₁, hD_2S, hD_2L, hD₃, hD₄, and hD₅ receptors; human 5-hydroxytryptamine (5-HT)_1A, h5-HT_1B, h5-HT_1D, h5-HT_2A, h5-HT_2B, and h5-HT_2Creceptors; hα_1A-, hα_1B-, hα_1D-, hα_2A-, hα_2B-, hα_2C-, rat α_2D-, hβ₁-, and hβ₂-adrenoceptors (ARs); and native histamine₁ receptors. A correlation matrix (294 pK_i values) demonstrated substantial "covariance". Correspondingly, principal components analysis revealed that axis 1, which accounted for 76% variance, was associated with the majority of receptor types: drugs displaying overall high versus modest affinities migrated at opposite extremities. Axis 2 (7% of variance) differentiated drugs with high affinity for hD₄ and H₁ receptors versus hα₁-AR subtypes. Five percent of variance was attributable to axis 3, which distinguished drugs with marked affinity for hβ₁- and hβ₂-ARs versus hD₅and 5-HT_2A receptors. Hierarchical (cluster) analysis of global homology generated a dendrogram differentiating two major groups possessing low versus high affinity, respectively, for multiple serotonergic and hD₅ receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD₂, hD₃, and hD₄receptors, whereas piribedil and talipexole recognized dopaminergic receptors and hα₂-ARs. Within the second group, lisuride and terguride manifested high affinities for all sites, with roxindole/bromocriptine, cabergoline/pergolide, and 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin (TL99)/apomorphine comprising three additional subclusters of closely related ligands. In conclusion, an innovative multivariate analysis revealed marked heterogeneity in binding profiles of antiparkinson agents. Actions at sites other than hD₂ receptors likely participate in their (contrasting) functional profiles.