Abstract
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-HT2Creceptors; hα1A-, hα1B-, hα1D-, hα2A-, hα2B-, hα2C-, rat α2D-, hβ1-, and hβ2-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 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-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 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.
Footnotes
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↵1 Rat α2D-ARs are the rodent homolog of human hα2A-ARs, to which they show marked differences as concerns affinities of certain drug classes (Hieble et al., 1995).
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↵2 A more detailed discussion of the actions of drugs at hD2S, hD2L, hD3, and hD4 receptors, multiple classes of α1- and α2-AR and multiple subtypes of 5-HT receptor is to be found in the accompanying articles, which document drug efficacies at these sites.
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DOI: 10.1124/jpet.102.039867
- Abbreviations:
- DA
- dopamine
- l-DOPA
- l-dihydroxyphenylacetic acid
- h
- human
- AR
- adrenoceptor
- 5-HT
- 5-hydroxytryptamine
- TL99
- 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin
- H
- histamine
- M1
- muscarinic
- PCA
- principle component analysis
- PC
- principle component
- Received June 12, 2002.
- Accepted July 22, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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