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Vol. 303, Issue 2, 791-804, November 2002

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

Mark J. Millan, Lisa Maiofiss, Didier Cussac, Valérie Audinot, Jean-A. Boutin and Adrian Newman-Tancredi

Departments of Psychopharmacology (M.J.M., D.C., A.N.-T.), Statistics (L.M.), and Molecular and Cellular Pharmacology (V.A., J.-A.B.), Institut de Recherches Servier, Paris, France

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 Parkinson's disease: human (h)D1, hD2S, hD2L, hD3, hD4, and hD5 receptors; human 5-hydroxytryptamine (5-HT)1A, h5-HT1B, h5-HT1D, h5-HT2A, h5-HT2B, and h5-HT2C receptors; halpha 1A-, halpha 1B-, halpha 1D-, halpha 2A-, halpha 2B-, halpha 2C-, rat alpha 2D-, hbeta 1-, and hbeta 2-adrenoceptors (ARs); and native histamine1 receptors. A correlation matrix (294 pKi 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 halpha 1-AR subtypes. Five percent of variance was attributable to axis 3, which distinguished drugs with marked affinity for hbeta 1- and hbeta 2-ARs versus hD5 and 5-HT2A 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 hD4 receptors, whereas piribedil and talipexole recognized dopaminergic receptors and halpha 2-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.

0022-3565/02/3032-0791$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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