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
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.
- SourceAvailable from: Philip Seeman
[Show abstract] [Hide abstract]
- "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.Synapse 01/2015; 69(4). DOI:10.1002/syn.21805 · 2.43 Impact Factor
[Show abstract] [Hide abstract]
- "Apomorphine is an archetype nonspecific dopamine agonist that activates both D1-like and D2-like receptors, with some preference for the latter subtypes (Millan et al., 2002). At lower doses (<0.5 mg/kg), apomorphine generally inhibits motor activity in rodents in a dose-dependent manner; this effect is due to a preferential action at presynaptic D2-like autoreceptors, which attenuates endogenous dopaminergic activity through a feedback mechanism (Strombom, 1976; Gainetdinov et al., 1996). "
ABSTRACT: G protein-coupled trace amine-associated receptor 1 (TAAR1) is expressed in several brain regions and modulates dopaminergic activity partially by affecting D2 dopamine receptor function. In vitro, the nonselective dopamine agonist apomorphine can activate mouse and rat TAAR1. The aim of the present study was to evaluate whether apomorphine activity at the rodent TAAR1 observed in in vitro studies contributes to its behavioral manifestation in mice. For this purpose, we compared the behavioral effects of a wide range of apomorphine doses in wild type (WT) and TAAR1 knockout (TAAR1-KO) mice. Apomorphine-induced locomotor responses (0.01-4.0 mg/kg) were tested in locomotor activity boxes, and stereotypic behavior at 5 mg/kg was tested by ethological methods. A gnawing test was used to analyze the effects of the highest dose of apomorphine (10 mg/kg). No statistically significant differences were observed between TAAR1-KO and WT mice following inhibitory pre-synaptic low doses of apomorphine. At higher doses (2.0-5.0 mg/kg), apomorphine-induced climbing behavior was significantly reduced in TAAR1 mutants relative to WT controls. Moreover, the lack of TAAR1 receptors decreased certain types of stereotypies (as reflected in by measures of the global stereotypy score, licking but not sniffing or gnawing) that were induced by high doses of apomorphine. These data indicate that apomorphine activity at TAAR1 contributes to some behavioral manifestations, particularly climbing, in rodents following high doses of this drug. The contribution of TAAR1 to apomorphine-induced climbing in rodents should be considered when apomorphine is used as a screening tool in the search for potential antipsychotics.The International Journal of Neuropsychopharmacology 06/2014; 17(10):1683-1693. DOI:10.1017/S1461145714000509 · 5.26 Impact Factor
[Show abstract] [Hide abstract]
- "Apomorphine ( 56 ) , used as an agent in the treatment of Parkinson ' s Disease ( PD ) and closely related to magnoflorine found in Tinospora cordifolia as well as nuciferine , asimilobine and lysicamine obtained from Nelumbo nucifera , shows considerable affinities towards different subtypes of dopamine , serotonine and adrenergic receptors ( Millan et al . , 2002"
ABSTRACT: Food is medicine and vice versa. In Hindu and Ayurvedic medicine, and among human cultures of the Indian subcontinent in general, the perception of the food-medicine continuum is especially well established. The preparation of the exhilarating, gold-coloured Soma, Amrita or Ambrosia, the elixir and food of the 'immortals' - the Hindu pantheon -, by the ancient Indo-Aryans, is described in the Rigveda in poetic hymns. Different theories regarding the botanical identity of Soma circulate, but no pharmacologically and historically convincing theory exists to date.Journal of Ethnopharmacology 06/2014; 155(1). DOI:10.1016/j.jep.2014.05.029 · 3.00 Impact Factor