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 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.
Millan
Mark J
MJ
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, 78290 Croissy/Seine, Paris, France. mark.millan@fr.netgrs.com
Maiofiss
Lisa
L
Cussac
Didier
D
Audinot
Valérie
V
Boutin
Jean-A
JA
Newman-Tancredi
Adrian
A
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003001:Cloning, Molecular; D016000:Cluster Analysis; D018491:Dopamine Agonists / Q000494:pharmacology; D006801:Humans; D051381:Rats; D043643:Receptor, Muscarinic M1; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000235:genetics; D011985:Receptors, Serotonin / Q000187:drug effects
D000978:Antiparkinson Agents; D018680:Cholinergic Antagonists; C493593:DRD3 protein, human; D018491:Dopamine Agonists; C493595:Drd3 protein, rat; D043643:Receptor, Muscarinic M1; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011943:Receptors, Adrenergic, beta; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D017981:Receptors, Neurotransmitter; D011985:Receptors, Serotonin