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
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde, 78290 Croissy/Seine, Paris, France.Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2002; 303(2):791-804. DOI: 10.1124/jpet.102.039867
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.
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- "According to a common view, a compound can be defined " preferential " for a given receptor when it binds in vitro with an affinity at least 10- fold higher than that of the second-best target. For example, the ergot-derivative DA agonists of the first generation had similar in vitro affinity for both D2 and D3 receptors (e.g., lisuride, pKi D2 = 9.18 and pKi D3 = 9.55) while the DA agonists of the second generation are characterised by a higher affinity for D3 (e.g., pramipexole, pKi D2= 5.77 and pKi D3 = 7.98; ropinirole pKi D2= 6.03 and pKi D3= 7.43) (Millan et al., 2002). According to this model, by dosing in the low effective dose range, D3-preferential compounds would bind primarily to the D3 receptors, delivering specific pharmacodynamic effects. "
ABSTRACT: Dopamine D3 receptors have been pharmacologically engaged in humans since the development of the first antipsychotics and ergot-derivative dopamine (DA) agonists, even without knowing it. These agents were generally non-selective, developed primarily to target D2 receptors. In the last 10 years the understanding of the clinical implication of D3 receptors has been progressing also due to the identification of D3 gene polymorphisms, the use of more selective PET ligands such as [(11)C]-(+)-PHNO and the learning regarding the clinical use of the D3-preferential D2/D3 agonists ropinirole and pramipexole. A new specific neuroplasticity role of D3 receptor regarding dendrite arborisation outgrowth in dopaminergic neurons was also proposed to support, at least in part, the slowing of disease observed in subjects with Parkinson׳s Disease treated with DA agonists. Similar mechanisms could be at the basis of the antidepressant-like effects observed with DA agonists when co-administered with standard of care. Severe adverse event occurring with the use of anti-parkinsonian DA agonists in predisposed subjects, i.e., impulse control disorders, are now suggested to be putatively related to overactive D3 receptors. Not surprisingly, blockade of D3 receptors was proposed as treatment for addictive disorders, a goal that could be potentially achieved by repositioning buspirone, an anxiolytic drug with D3-preferential antagonistic features, or with novel selective D3 antagonists or partial agonists currently in development for schizophrenia. At the moment ABT-925 is the only selective D3 antagonist tested in schizophrenic patients in Phase II, showing an intriguing cognitive enhancing effects supported by preclinical data. Finally, exploratory pharmacogenetic analysis suggested that ABT-925 could be effective in a subpopulation of patients with a polymorphism on the D3 receptor, opening to a possible personalised medicine approach. Copyright © 2015. Published by Elsevier B.V.
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- "a: Using [ 3 H]domperidone (Seeman et al., 2005). c: Using [ 125 I]iodosulpride (Millan et al., 2002). d: Using [ 125 I]iodosulpride (Freedman et al., 1994). "
ABSTRACT: In treating Parkinson's disease with dopaminergic agonists, such as pramipexole, ropinirole, pergolide, rotigotine, apomorphine or bromocriptine, it has been observed that a significant number of patients develop Impulse-Control Disorders such as compulsive shopping, pathological gambling, or hypersexuality. Because the dopamine agonists have high affinities for the dopamine D2 and D3 receptors, the drug dissociation constants of these drugs at the functional high-affinity states of these receptors, namely D2High and D3 high, were compared. The data show that, compared to the other dopamine agonist drugs, pramipexole has a relatively high selectivity for the dopamine D3 receptor, as compared to D2, suggesting that the D3 receptor may be a primary target for pramipexole. There is a trend showing that the proportion of Impulse-Control Disorders is related to the selectivity for D3 receptors over D2 receptors, with pramipexole having the highest association with, or frequency of, Impulse-Control disorders. While the number of studies are limited, the proportion of patients with Impulse-Control Disorder in Parkinson patients treated with an add-on agonist were 32% for pramipexole, 25% for ropinirole, 16% for pergolide, 22% for rotigotine, 10% for apomorphine, and 6.8% for bromocriptine. Clinically, temporary replacement of pramipexole by bromocriptine may provide relief or reversal of the impulsive behaviour associated with selective D3 stimulation by either pramipexole or ropinirole, while maintaining D2 stimulation needed for the anti-Parkinson action. This article is protected by copyright. All rights reserved.
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- "The brain inflammation has been shown to be accompanied by increased concentration of serum phenylalanine, i.e., by its impaired conversion into the neurotransmitters , in particular, dopamine . This dopamine pool shrinkage reduces, in turn, the probability of spontaneous binding of dopamine to its receptors, thus opening the gate for different effects of exogenetic APO molecules depending on their agonist affinities for various types of dopamine receptors . Significantly diminished beta predominance in the cortical EEG after injection of APO in A␤ 1-42 -treated rats (Fig. 6D, gray line) is in line with this suggestion and with supposedly potentiating effect of APO on A␤associated toxicity . "
ABSTRACT: We studied the effects of fullerene C60 nanoparticles, namely hydrated fullerene C60 (C60HyFn), on interrelations between EEG frequency spectra from the frontal cortex and the dorsal hippocampus (CA1) on an amyloid-β (Aβ) rat model of Alzheimer's disease (AD). Infusion of Aβ1-42 protein (1.5 μl) into the CA1 region two weeks before EEG testing diminished hippocampal theta (3.8-8.4 Hz) predominance and eliminated cortical beta (12.9-26.2 Hz) predominance observed in baseline EEG of rats infused with saline (control) or with C60HyFn alone. In contrast, these Aβ1-42 effects were abolished in rats pretreated with C60HyFn, 30 min apart. Dopaminergic mediation in AD has been shown to be involved in neuronal plasticity and Aβ transformation in different ways. To clarify its role in the cortex-hippocampus interplay in the Aβ model of AD, we used peripheral injection of a dopamine agonist, apomorphine (APO), at a low dose (0.1 mg/kg). In rats infused with C60HyFn or Aβ1-42 alone, APO attenuated the cortical beta predominance, with immediate and delayed phases evident in the Aβ1-42-rats. Pretreatment with C60HyFn diminished the APO effect in the Aβ1-42-treated rats. Thus, we show that intrahippocampal injection of Aβ1-42 dramatically disrupts cortical versus hippocampal EEG interrelations and that pretreatment with the fullerene eliminates this abnormality. We suggest that some effects of C60HyFn may be mediated through presynaptic dopamine receptors and that water-soluble C60 fullerenes have a neuroprotective potential.
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