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.

Article Details

Citation

Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A

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.

J Pharmacol Exp Ther. 2002 Nov;303(2):791-804.

PubMed ID
12388666 [ View in PubMed
]
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)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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
CabergolineAlpha-1A adrenergic receptorProteinHumans
Unknown
Binder
Details
CabergolineAlpha-1B adrenergic receptorProteinHumans
Unknown
Binder
Details
CabergolineAlpha-1D adrenergic receptorProteinHumans
Unknown
Binder
Details
CabergolineBeta-1 adrenergic receptorProteinHumans
Unknown
Binder
Details
CabergolineBeta-2 adrenergic receptorProteinHumans
Unknown
Binder
Details
CabergolineD(1) dopamine receptor (Protein Group)Protein groupHumans
Unknown
Agonist
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Apomorphine5-hydroxytryptamine receptor 1BKi (nM)2951.21N/AN/ADetails
Apomorphine5-hydroxytryptamine receptor 1DKi (nM)1230.27N/AN/ADetails
Apomorphine5-hydroxytryptamine receptor 2AKi (nM)120.23N/AN/ADetails
Apomorphine5-hydroxytryptamine receptor 2CKi (nM)102.33N/AN/ADetails
ApomorphineAlpha-2A adrenergic receptorKi (nM)141.25N/AN/ADetails
ApomorphineAlpha-2B adrenergic receptorKi (nM)66.07N/AN/ADetails
ApomorphineAlpha-2C adrenergic receptorKi (nM)36.31N/AN/ADetails
ApomorphineDopamine D1 receptorKi (nM)371.54N/AN/ADetails
ApomorphineDopamine D5 receptorKi (nM)14.79N/AN/ADetails
Bromocriptine5-hydroxytryptamine receptor 1AKi (nM)12.88N/AN/ADetails
Bromocriptine5-hydroxytryptamine receptor 1BKi (nM)354.81N/AN/ADetails
Bromocriptine5-hydroxytryptamine receptor 1DKi (nM)10.72N/AN/ADetails
Bromocriptine5-hydroxytryptamine receptor 2AKi (nM)107.15N/AN/ADetails
Bromocriptine5-hydroxytryptamine receptor 2CKi (nM)741.31N/AN/ADetails
BromocriptineAlpha-1B adrenergic receptorKi (nM)1.38N/AN/ADetails
BromocriptineAlpha-1D adrenergic receptorKi (nM)1.12N/AN/ADetails
BromocriptineAlpha-2A adrenergic receptorKi (nM)10.96N/AN/ADetails
BromocriptineAlpha-2B adrenergic receptorKi (nM)34.67N/AN/ADetails
BromocriptineAlpha-2C adrenergic receptorKi (nM)28.18N/AN/ADetails
BromocriptineDopamine D1 receptorKi (nM)691.83N/AN/ADetails
BromocriptineDopamine D5 receptorKi (nM)537.03N/AN/ADetails