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
| Autor: | Adrian Newman-Tancredi, Valérie Audinot, Lisa Maiofiss, Millan Mark, Didier Cussac, Jean-A. Boutin |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Pharmacology Biology Binding Competitive Terguride Cholinergic Antagonists Antiparkinson Agents chemistry.chemical_compound Roxindole Receptors Adrenergic alpha-2 Receptors Adrenergic alpha-1 Internal medicine Receptors Adrenergic beta medicine Animals Cluster Analysis Humans Receptors Histamine H1 Cloning Molecular Receptor Binding Sites Receptors Dopamine D2 Receptors Dopamine D1 Receptor Muscarinic M1 Receptors Dopamine D3 Receptors Muscarinic Talipexole Rats Receptors Neurotransmitter Apomorphine Antiparkinson drug Endocrinology chemistry Dopamine receptor Receptors Serotonin Dopamine Agonists Molecular Medicine medicine.drug Lisuride |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 303:791-804 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.102.039867 |
| Popis: | 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)D(1), hD(2S), hD(2L), hD(3), hD(4), and hD(5) receptors; human 5-hydroxytryptamine (5-HT)(1A), h5-HT(1B), h5-HT(1D), h5-HT(2A), h5-HT(2B), and h5-HT(2C) 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 histamine(1) 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 hD(4) and H(1) 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 hD(5) and 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 hD(5) receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD(2), hD(3), and hD(4) 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 hD(2) receptors likely participate in their (contrasting) functional profiles. |
| Databáze: | OpenAIRE |
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