Differential Actions of Antiparkinson Agents at Multiple Classes of

0022-3565/02/3032-791–804$7.00
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics
JPET 303:791–804, 2002
Vol. 303, No. 2
39867/1021570
Printed in U.S.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
MARK J. MILLAN, LISA MAIOFISS, DIDIER CUSSAC, VALÉRIE AUDINOT, JEAN-A. BOUTIN, and
ADRIAN NEWMAN-TANCREDI
Departments of Psychopharmacology (M.J.M., D.C., A.N.-T.), Statistics (L.M.), and Molecular and Cellular Pharmacology (V.A., J.-A.B.), Institut
de Recherches Servier, Paris, France
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)D1, hD2S,
hD2L, hD3, hD4, and hD5 receptors; human 5-hydroxytryptamine
(5-HT)1A, h5-HT1B, h5-HT1D, h5-HT2A, h5-HT2B, and h5-HT2C receptors; h␣1A-, h␣1B-, h␣1D-, h␣2A-, h␣2B-, h␣2C-, rat ␣2D-, h␤1-,
and h␤2-adrenoceptors (ARs); and native histamine1 receptors. A
correlation matrix (294 pKi 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
hD4 and H1 receptors versus h␣1-AR subtypes. Five percent of
variance was attributable to axis 3, which distinguished drugs with
In Parkinson’s disease, the progressive degeneration of
nigrostriatal dopaminergic pathways is associated with diverse motor symptoms, including rigidity, tremor, bradykinesia, and postural instability (Jenner, 1995). In addition,
patients present, often precociously, sensory and cognitiveattentional deficits together with depressed mood (Jenner,
1995). Despite increasing interest in neuroprotective strategies, Parkinson’s Disease is principally treated by administration of the dopamine (DA) precursor L-dihydroxyphenylalanine (L-DOPA) (Bezard et al., 2001). However, there is
evidence, albeit contentious, that L-DOPA exacerbates damage to dopaminergic neurons (Zou et al., 1999). Furthermore,
L-DOPA displays variable pharmacokinetics, elicits dyskineArticle, publication date, and citation information can be found at
http://jpet.aspetjournals.org.
DOI: 10.1124/jpet.102.039867.
marked affinity for h␤1- and h␤2-ARs versus hD5 and 5-HT2A
receptors. Hierarchical (cluster) analysis of global homology generated a dendrogram differentiating two major groups possessing
low versus high affinity, respectively, for multiple serotonergic and
hD5 receptors. Within the first group, quinpirole, quinerolane, ropinirole, and pramipexole interacted principally with hD2, hD3, and
hD4 receptors, whereas piribedil and talipexole recognized dopaminergic receptors and h␣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 hD2 receptors likely participate in their (contrasting) functional profiles.
sias and autonomic side effects, poorly improves certain motor symptoms, is largely ineffective against cognitive and
mood deficits, and loses efficacy upon prolonged administration (Bezard et al., 2001). Abrupt transitions between “on”
and “off” phases are particularly distressing to patients (Jenner, 1995). In light of these observations, the management of
Parkinson’s Disease by drugs directly stimulating postsynaptic DA receptors is of interest (Jenner, 1995; Montastruc et
al., 1999). Such dopaminergic agents possess neuroprotective
properties, mediated by both dopaminergic (autoreceptor)
and nondopaminergic mechanisms (Zou et al., 1999) and
elicit less marked dyskinesia (Uitti and Ahlskog, 1996; Rascol et al., 2000). Furthermore, they may improve mood and
cognitive function (Weddell and Weiser, 1995; Nagaraja and
Jayashree, 2001). In addition to adjunctive therapy, recent
studies support the long-term efficacy of dopaminergic agonists in monotherapy, thereby delaying the introduction of
ABBREVIATIONS: DA, dopamine; L-DOPA; L-dihydroxyphenylacetic acid; h, human; AR, adrenoceptor; 5-HT, 5-hydroxytryptamine; TL99,
6,7-dihydroxy-N,N-dimethyl-2-ammotetralin; H, histamine; M1, muscarinic; PCA, principle component analysis; PC, principle component.
791
Downloaded from jpet.aspetjournals.org at ASPET Journals on October 2, 2016
Received June 12, 2002; accepted July 22, 2002
792
Millan et al.
L-DOPA
fragmentary data by evaluating the actions of 14 dopaminergic agonists (antiparkinson agents) at multiple classes of
monoaminergic receptor. In addition, actions at muscarinic
(M1) sites and histamine (H)1 sites were evaluated in light of
1) their role in the control of motor behavior, mood, and
cognition (Bacciottini et al., 2001; Brown et al., 2001); 2)
alterations in histaminergic and cholinergic transmission in
Parkinson’s Disease (Jellinger, 1999; Anichtchik et al., 2000);
and 3) the use of anticholinergic agents for management of
refractory tremor (Wilms et al., 1999). The strategy adopted
was as follows. First, using competition binding assays, drug
affinities were determined at recombinant, stably transfected, human receptors as well as at rat ␣2D-ARs1 and at
native H1 receptors. Second, to facilitate analysis of the extensive database and comparisons of drug profiles, a correlation matrix was constructed: data were subjected to principle components analysis (PCA) and then drugs were
classified by hierarchical (cluster) analysis in accordance
with their overall homology. This innovative multivariate
approach to drug comparisons has the advantage that it is
not founded upon specific hypotheses requiring testing via
post hoc, inferential statistics. Rather, by fully and simultaneously exploring total variance, it permits the objective
identification and interpretation of hidden patterns not revealed by visual inspection or drug-by-drug/receptor-by-receptor comparisons (Krzanowski, 2000; Millan et al., 2000a; Carlsson et al., 2001). Third, as described in the accompanying
articles (Newman-Tancredi et al., 2002a,b), efficacies of antiparkinson agents were determined at (the majority of) monoaminergic receptor subtypes incorporated into these multivariate analyses.
Materials and Methods
Determination of Drug Affinities. Procedures used for the
determination of drug affinities have been described in detail previously (Newman-Tancredi et al., 1997; Millan et al., 2001a). They are
summarized in Tables 1, 2, and 3. Isotherms were subjected to
nonlinear regression analysis by use of the program PRISM (GraphPad Software, San Diego, CA) to yield IC50 values. These were
subsequently transformed into Ki values according to the Cheng-
1
Rat ␣2D-ARs are the rodent homolog of human h␣2A-ARs, to which they
show marked differences as concerns affinities of certain drug classes (Hieble
et al., 1995).
TABLE 1
Competition binding conditions at recombinant, human dopaminereceptors
Receptor
Tissue
Radioligand (nM)
Buffer (mM)
pH
Nonspecific (␮M)
Time, temperature
Kd
(nM)
hD1
hD2S
L cells
CHO cells
[3H]SCH23390 (0.3)
125
I]iodosulpride (0.1)
125
]iodosulpride (0.1)
[
hD2L
CHO cells
[
hD3
CHO cells
[125I]iodosulpride (0.2)
hD4a
CHO cells
[3H]spiperone (0.5)
hD5
CH4Cl cells
CHO, Chinese hamster ovary.
a
h4.4. isoform.
3
[ H]SCH23390 (0.3)
Tris-HCl (50), NaCl (120),
(5), CaCl2 (2), MgCl2 (5)
Tris-HCl (50), NaCl (120),
(5), CaCl2 (2), MgCl2 (5)
Tris-HCl (50), NaCl (120),
(5), CaCl2 (2), MgCl2 (5)
Tris-HCl (50), NaCl (120),
(5), CaCl2 (2), MgCl2 (5)
Tris-HCl (50), NaCl (120),
(5), MgCl2 (5), EDTA (1)
Tris-HCl (50), NaCl (120),
(5), MgCl2 (5), EDTA (1)
KCl
7.4
(⫹)Butaclamol (3)
60 min, 25°C
0.53
KCl
7.4
Raclopride (10)
30 min, 22°C
0.45
KCl
7.4
Raclopride (10)
30 min, 22°C
0.45
KCl
7.4
Raclopride (10)
30 min, 22°C
0.98
KCl
7.4
Haloperidol (1)
60 min, 22°C
0.38
KCl
7.4
SCH23390 (10)
60 min, 22°C
0.25
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(Rascol et al., 2000). Nevertheless, “sleep-attacks”,
sedation, and both psychiatric and cardiovascular side effects
complicate utilization of dopaminergic agonists (Friedman
and Factor, 2000).
The above-mentioned panoply of desirable and undesirable
actions varies among antiparkinson agents (Uitti and Ahlskog, 1996). Such differences likely reflect contrasting patterns of interactions at sites other than dopamine D2 receptors (Uitti and Ahlskog, 1996). D3 receptors are of particular
interest, although it remains controversial as to whether
their engagement contributes to therapeutic and/or psychiatric and motor side effects (Millan et al., 2000b; Joyce,
2001). Activation of D4 receptors does not, on the other hand,
participate in the improvement of Parkinson’s Disease (Newman-Tancredi et al., 1997; Oak et al., 2000). Although D1
receptor agonists display antiparkinson activity in experimental models, their clinical efficacy upon long-term administration remains uncertain, and their stimulation is not
obligatory for therapeutic activity (Jenner, 1995; Gulwadi et
al., 2001). Furthermore, the relative roles of D1 versus closely
related D5 sites remain unclear (see Discussion).
Inasmuch as 1) Parkinson’s Disease is aggravated by degeneration of locus coeruleus-derived adrenergic and raphederived serotonergic pathways (Brefel-Courbon et al., 1998;
Jellinger, 1999); and 2) adrenergic and serotonergic mechanisms modulate dopaminergic transmission, motor behavior,
mood, and cognitive function (Meneses, 1999; Millan et al.,
2000c), it is important to consider potential actions of antiparkinson agents at adrenoceptors (ARs) and 5-HT receptors.
Although surprisingly little information is available, talipexole and 6,7-dihydroxy-N,N-dimethyl-2-ammotetralin
(TL99) are known to possess agonist properties at native
␣2-ARs (Horn et al., 1982; Meltzer et al., 1989). In contrast,
blockade of ␣2-ARs by piribedil reinforces frontocortical adrenergic, dopaminergic, and cholinergic transmission and favorably influences mood and cognitive-attentional function
(Millan et al., 2000c, 2001a; Maurin et al., 2001; Nagaraja
and Jayashree, 2001; Gobert et al., 2002). In addition to
antagonist actions at ␣2- and ␣1-ARs, bromocriptine reveals
pronounced affinity for 5-HT1A receptors (McPherson and
Beart, 1983; Jackisch et al., 1985; Uitti and Ahlskog, 1996).
Other antiparkinson agents known to recognize 5-HT1A
and/or 5-HT2A receptors are lisuride, terguride, and roxindole (Jackson et al., 1995; Uitti and Ahlskog, 1996).
The purpose of the present studies was to consolidate these
Antiparkinson Drugs and Monoaminergic Receptors
793
TABLE 2
Competition binding conditions at recombinant, human h␣1-, h␣2-, and h␤-adrenoceptors and at rat r␣2-adrenoceptors
Receptor
Tissue
Radioligand (nM)
Buffer (mM)
pH
Nonspecific (␮M)
h␣1A
h␣1B
h␣1D
r␣2D
h␣2A
h␣2B
h␣2C
h␤1
h␤2
CHO cells
CHO cells
CHO cells
Rat cortex
CHO cells
CHO cells
CHO cells
Sf9 cells
Sf9 cells
[3H]Prazosin (0.1)
[3H]Prazosin (0.1)
[3H]Prazosin (0.1)
[3H]RX821,002 (0.4)
[3H]RX821,002 (0.7)
[3H]RX821,002 (0.4)
[3H]RX821,002 (0.6)
[3H]CGP12177 (0.15)
[3H]CGP12177 (0.15)
Tris-HCl (50), EDTA (5)
Tris-HCl (50), EDTA (5)
Tris-HCl (50), EDTA (5)
Tris-HCl (50), EDTA (1), GTP (0.1)
HEPES (50), EDTA (1)
Tris (33), EDTA (1)
HEPES (33), EDTA (1)
Tris-HCl (50), MgCl2 (10) EDTA (2)
Tris-HCl (50), MgCl2 (10) EDTA (2)
7.4
7.4
7.4
7.5
7.5
7.5
7.5
7.4
7.4
Phentolamine (10)
Phentolamine (10)
Phentolamine (10)
Phentolamine (10)
Phentolamine (10)
Phentolamine (10)
Phentolamine (10)
Alprenolol (50)
Alprenolol (50)
Time, temperature
Kd
nM
90
90
90
60
60
60
60
60
60
min,
min,
min,
min,
min,
min,
min,
min,
min,
22°C
22°C
22°C
22°C
22°C
22°C
22°C
27°C
27°C
0.04
0.04
0.04
0.40
0.33
0.43
0.51
0.21
0.22
CHO, Chinese hamster ovary; Sfg, Spodoptera frugiperda.
TABLE 3
Competition binding conditions at recombinant, human serotonin (5-HT) receptors, at recombinant, human hM1 and at native histamine H1
receptors
Receptor
Tissue
Radioligand (nM)
Buffer ingredients (mM)
pH
Time, temperature
Non-specific (␮M)
Kd
h5-HT1A
h5-HT1B
h5-HT1D
h5-HT2A
h5-HT2B
h5-HT2C
H1
CHO cells
CHO cells
CHO cells
CHO cells
CHO cells
CHO cells
Guinea pig
cerebellum
[3H]8-OH-DPAT (0.4)
[3H]GR125,743 (1.0)
[3H]GR125,743 (1.0)
[3H]Ketanserin (0.5)
[3H]Mesulergine (1.0)
[3H]Mesulergine (1.0)
[3H]Pyrilamine (0.5)
HEPES (20), MgSO4 (5)
Tris (50), CaCl2 (4), Asc.Ac. (0.1% w/v)
Tris (50), CaCl2 (4), Asc.Ac. (0.1% w/v)
HEPES (20), EDTA (2), Asc.Ac. (0.1% w/v)
HEPES (20), EDTA (2), Asc.Ac. (0.1% w/v)
HEPES (20), EDTA (2), Asc.Ac. (0.1% w/v)
Na2HPO4/KH2PO4 (50)
7.5
7.7
7.7
7.7
7.7
7.7
7.4
150min,22°C
60 min,25°C
60 min,25°C
40 min,22°C
60 min,22°C
120min,22°C
10 min,25°C
5-HT (10)
5-HT (10)
5-HT (10)
Mianserin (1)
5-HT (10)
Mianserin (1)
Triprolidine (100)
0.65
1.27
0.67
0.22
1.44
0.55
0.37
Asc.Ac., ascorbic acid.
Prussof equation Ki ⫽ IC50/(1 ⫹ L/Kd), where L corresponds to the
radioligand concentration and Kd to its dissociation constant.
Multivariate Analysis: Principal Components Analysis. The
database used for multivariate analysis comprised the affinities (“parameters”) for 14 drugs at (21) separate receptors (“variables”) indicated in Tables 4, 5, and 6. (pKi values of ⬍5.0 were considered as 5.0
for these analyses.) Because all parameters are intrinsically equivalent, they were not transformed (“standardized”): pKi values are the
negative logarithmic expression of affinities. After construction of a
correlation matrix (Pearson product-moment coefficients) across all
parameters (Table 7), the database was subjected to PCA (Krzanowski, 2000) using SPAD-3, a computer program developed by the
Centre International de Statistiques et d’Informatiques Appliquées
(St. Mandé, France). This generates a “multidimensional space” of 21
axes from the database, with all axes mathematically “perpendicular” to each other. The first axis, principal component (PC)1, represents the linear combination of all parameters (affinities) in the data
set that accounts for the maximal possible variance. Correspondingly, loading values (correlation coefficients) in Table 8 indicate the
contribution of individual parameters to PC1. Successive axes (PC2
onwards) account for progressively less variance. PCs 1 to 3, which
accounted for a substantial majority of variance (see Results), were
two-dimensionally represented in scatter diagrams (“biplots”) upon
which drugs were superimposed together with the parameters underlying their dispersion.
Multivariate Analysis: Hierarchical Cluster Analysis. After
PCA, and likewise exploiting SPAD-3, drugs were hierarchically
(“cluster”) classified in accordance with their overall homology to
yield a binary dendrogram (Krzanowski, 2000). Using an “agglomeration” algorithm, the array of drugs was progressively (“hierarchically”) fused into subclusters and clusters until it comprised a single
group. With the formation of each successive cluster, the loss of
“objective function value” (information) was constrained as much as
possible, that is, the intragroup compared with intergroup variance
was minimized. The length of bars between pairs of drugs in the
two-dimensional dendrogram reflects their dissimilarity, that is, the
shorter the distance, the more closely related the pairs of drugs.
TABLE 4
Affinities (pKi values) of antiparkinson agents at recombinant, human dopamine receptors
Data are pKi values (minus log Ki values) and, unless indicated, are expressed as means ⫾ S.E.M. values of at least three independent determinations carried out in triplicate.
a
b
Ligand
hD1
hD2S
hD2L
hD3
hD4
hD5
Apomorphine
Bromocriptine
Cabergoline
Lisuride
Pergolide
Piribedil
Pramipexole
Quinelorane
Quinpirole
Ropinirole
Roxindole
Talipexole
Terguride
TL99
6.43 ⫾ 0.05
6.16 ⫾ 0.09
6.67 ⫾ 0.12
7.19 ⫾ 0.09
6.47 ⫾ 0.04
⬍5
⬍5
⬍5
⬍5
⬍5
6.33 ⫾ 0.13
⬍5
7.55 ⫾ 0.03
5.57 ⫾ 0.09
7.46 ⫾ 0.05
8.30 ⫾ 0.08
9.21 ⫾ 0.06
9.47 ⫾ 0.11
7.50 ⫾ 0.11
6.88 ⫾ 0.03
6.02 ⫾ 0.02
6.50 ⫾ 0.13
6.05 ⫾ 0.05
6.17 ⫾ 0.03
8.55 ⫾ 0.15
6.21 ⫾ 0.02
9.09 ⫾ 0.11
7.22 ⫾ 0.10
7.08 ⫾ 0.01
7.83 ⫾ 0.08
9.02 ⫾ 0.04
9.18 ⫾ 0.04
7.59 ⫾ 0.06
6.76 ⫾ 0.07
5.77 ⫾ 0.05
6.15 ⫾ 0.04
5.84 ⫾ 0.02
6.03 ⫾ 0.06
8.63 ⫾ 0.10
6.01 ⫾ 0.03
8.94 ⫾ 0.07
7.17 ⫾ 0.11
7.59 ⫾ 0.07
8.17 ⫾ 0.04
9.10 ⫾ 0.04
9.55 ⫾ 0.07
8.26 ⫾ 0.11
6.63 ⫾ 0.05
7.98 ⫾ 0.05
8.27 ⫾ 0.05
7.38 ⫾ 0.07
7.43 ⫾ 0.13
8.93 ⫾ 0.08
7.17 ⫾ 0.03
9.00 ⫾ 0.06
8.60 ⫾ 0.13
8.36 ⫾ 0.07
6.43 ⫾ 0.11
7.25 ⫾ 0.11
8.34 ⫾ 0.07a
7.23 ⫾ 0.09a
6.52 ⫾ 0.10
6.89 ⫾ 0.13
7.72 ⫾ 0.16a
7.47 ⫾ 0.05
6.07 ⫾ 0.06a
8.23 ⫾ 0.06
6.48 ⫾ 0.03
8.09 ⫾ 0.09a
7.24 ⫾ 0.18
7.83 ⫾ 0.11
6.27 ⫾ 0.05
7.65 ⫾ 0.08
8.45 ⫾ 0.04
7.48 ⫾ 0.21
⬍5
⬍5
⬍5
⬍5
⬍5
6.72 ⫾ 0.26b
5.46 ⫾ 0.11
7.63 ⫾ 0.05
7.11 ⫾ 0.08
Mean ⫾ range, n ⫽ 2.
Newman-Tancredi et al., 1997.
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nM
794
Millan et al.
Nodes on the dendrogram therefore represent the consecutive aggregation of two individual elements (drugs or drug clusters).
Radar Plots. “Radar” representations of binding profiles at certain key receptors were constructed to further visualize similarities
and differences in drug binding profiles.
Drugs. Pramipexole dihydrochloride, piribedil hydrochloride, and
ropinirole were synthesized by Institut de Recherches Servier (Paris,
France). Lisuride maleate and terguride were donated by Schering
(Berlin, Germany); bromocriptine, (⫺)-quinpirole, pergolide, and
TL99 were purchased from Sigma/RBI (Natick, MA); apomorphine
hydrochloride was purchased from Sigma (St. Quentin Fallavier,
France); and roxindole was donated by Merck (Darmstadt, Germany)
and talipexole (BHT-920) by Boehringer Ingelheim GmbH (Ingelheim, Germany). Cabergoline was obtained from Farmitalia Carlo
Erba (Rueil-Malmaison, France). Quinelorane dihydrochloride was a
gift from Eli Lilly & Co. (Indianapolis, IN).
Results
2
A more detailed discussion of the actions of drugs at hD2S, hD2L, hD3, and
hD4 receptors, multiple classes of ␣1- and ␣2-AR and multiple subtypes of 5-HT
receptor is to be found in the accompanying articles, which document drug
efficacies at these sites.
TABLE 5
Affinities (pKi values) of antiparkinson agents at recombinant human h␣1-, h␣2-, and h␤-adrenoceptors and at native, rat r␣2D-ARs
Data are pKi values (minus log Ki values) and, unless indicated, are expressed as means ⫾ S.E.M. values of at least three independent determinations carried out in triplicate.
Ligand
h␣1A
h␣1B
h␣1D
Apomorphine
Bromocriptine
Cabergoline
Lisuride
Pergolide
Piribedil
Pramipexole
Quinelorane
Quinpirole
Ropinirole
Roxindole
Talipexole
Terguride
TL99
5.70 ⫾ 0.19
8.38 ⫾ 0.08
6.54 ⫾ 0.06
8.26 ⫾ 0.13
5.98 ⫾ 0.11
6.09 ⫾ 0.08
⬍5
⬍5
⬍5
⬍5
8.59 ⫾ 0.09
⬍5
8.45 ⫾ 0.03
⬍5
6.17 ⫾ 0.06
8.86 ⫾ 0.13
7.22 ⫾ 0.06
7.78 ⫾ 0.01
6.16 ⫾ 0.08
5.21 ⫾ 0.07
⬍5
⬍5
⬍5
⬍5
8.55 ⫾ 0.11
5.41 ⫾ 0.13
7.46 ⫾ 0.01
⬍5
7.19 ⫾ 0.06
8.95 ⫾ 0.08
6.78 ⫾ 0.07
8.53 ⫾ 0.03
6.53 ⫾ 0.19
6.66 ⫾ 0.11
⬍5
⬍5
⬍5
⬍5
8.87 ⫾ 0.03
5.90 ⫾ 0.06
8.41 ⫾ 0.05
⬍5
a
Mean ⫾ range, n ⫽ 2.
r␣2D
h␣2A
6.49 ⫾ 0.15 6.85 ⫾ 0.05
7.17 ⫾ 0.14 7.96 ⫾ 0.14
8.44 ⫾ 0.24 7.92 ⫾ 0.11
9.10 ⫾ 0.16 10.26 ⫾ 0.04
5.93 ⫾ 0.29 7.30 ⫾ 0.09
6.36 ⫾ 0.07 7.05 ⫾ 0.19
5.26 ⫾ 0.04 5.77 ⫾ 0.19
⬍5
⬍5
⬍5
⬍5
5.35 ⫾ 0.15 5.73 ⫾ 0.09
7.56 ⫾ 0.05 8.21 ⫾ 0.18
6.79 ⫾ 0.06 7.43 ⫾ 0.06
8.83 ⫾ 0.07 9.53 ⫾ 0.12
7.33 ⫾ 0.07 7.38 ⫾ 0.28a
h␣2B
h␣2C
h␤ 1
h ␤2
7.18 ⫾ 0.18
7.46 ⫾ 0.05
7.14 ⫾ 0.14
9.87 ⫾ 0.05
7.49 ⫾ 0.08
6.54 ⫾ 0.02
6.20 ⫾ 0.08
⬍5
5.60 ⫾ 0.05
6.12 ⫾ 0.04
8.34 ⫾ 0.11
7.09 ⫾ 0.05
9.35 ⫾ 0.07
7.28 ⫾ 0.13a
7.44 ⫾ 0.10
7.55 ⫾ 0.11
7.65 ⫾ 0.15
9.87 ⫾ 0.06
7.17 ⫾ 0.01
7.16 ⫾ 0.12
⬍5
⬍5
⬍5
5.92 ⫾ 0.14
8.75 ⫾ 0.20
7.37 ⫾ 0.04
9.12 ⫾ 0.14
8.22 ⫾ 0.17a
⬍5
6.23 ⫾ 0.13a
⬍5
7.17 ⫾ 0.11a
⬍5
⬍5
⬍5
⬍5
⬍5
⬍5
5.57 ⫾ 0.10a
⬍5
6.18 ⫾ 0.14a
⬍5
⬍5
6.13 ⫾ 0.01a
⬍5
8.10 ⫾ 0.03a
⬍5
⬍5
⬍5
⬍5
⬍5
⬍5
6.03 ⫾ 0.10a
⬍5
7.70 ⫾ 0.04a
⬍5
Downloaded from jpet.aspetjournals.org at ASPET Journals on October 2, 2016
General Comments. In view of the large number of drugs
and binding sites examined, a detailed text description of all
(⬃300) interactions cannot be presented below. Full data are
shown in Tables 4 to 7.
Dopamine hD2S, hD2L, hD3, and hD4 Receptors. There
was a substantial (5000-fold) range in drug affinities at hD2S
receptors (Table 4).2 For example, the affinity of cabergoline
was very pronounced compared with that of pramipexole. At
hD2L receptors (which possess a 29 amino acid insert in the
third intracellular loop), affinities of drugs likewise varied
broadly and were similar to those at hD2S sites. There was
likewise marked (⬃1000-fold) variability in drug affinities at
hD3 sites. The ratio of drug affinities at hD3 compared with
hD2L and hD2S sites differed considerably from modest (e.g.,
cabergoline and pergolide) to pronounced (e.g., pramipexole).
The variation in drug affinities at hD4 receptors was also
striking (⬃400-fold). Certain drugs displayed considerably
higher affinities at hD4 versus hD2S/hD2L sites (such as apomorphine), whereas others showed modest differences (such
as piribedil) or a marked preference for hD2S/hD2L sites (such
as bromocriptine).
Dopamine hD1 and hD5 Receptors. Drug affinities for
hD1 sites were substantially lower than for hD2S and hD2L
receptors: apomorphine and cabergoline showed the least
and most pronounced difference, respectively (Table 4).
There was ⬃200-fold variability in drug affinities at hD1 sites
with certain agents, including pramipexole, displaying negligible affinity. For all drugs manifesting significant affinity
for hD1 receptors, affinities were higher at hD5 receptors.
This difference was mild for certain drugs, such as bromocriptine, and pronounced for others, such as pergolide.
h␣1A-, h␣1B-, and h␣1D-ARs. For each drug, affinities at
h␣1A-, h␣1B-, and h␣1D-ARs were similar (Table 5). Affinities
varied over a ⬃10,000 range from negligible (e.g.,
pramipexole) through intermediate (e.g., apomorphine) to
pronounced (e.g., bromocriptine).
r␣2D-, h␣2A-, h␣2B-, and h␣2C-ARs. There was considerable (⬎10,000) variability in drug affinities for h␣2A- and
r␣2D-ARs, ranging from quinerolane (negligible) to lisuride
(very high), with piribedil, talipexole, and several other drugs
showing intermediate values (Table 5). Only cabergoline revealed (slightly) higher affinity for r␣2D- versus h␣2A-ARs.
No drug clearly differentiated h␣2-AR subtypes, although
pramipexole showed negligible affinity for h␣2C- versus h␣2Aand h␣2B-ARs. Bromocriptine and roxindole were the only
drugs to show similar or weaker affinities at h␣2A- compared
with h␣1-AR subtypes.
h␤1- and h␤2-ARs. Only four ligands (lisuride, terguride,
bromocriptine, and roxindole) displayed significant affinity
for h␤1-ARs (Table 5). Bromocriptine and roxindole showed
similar affinity at h␤2-ARs, whereas lisuride and terguride
revealed higher affinity for h␤2- compared with h␤1-ARs.
Compared with h␣2-ARs, affinities at h␤1- and h␤2-ARs were
relatively weak for all drugs, and only lisuride and terguride
approached affinities seen at h␣1-ARs.
h5-HT1A Receptors. There was substantial (10,000-fold)
variation in drug affinities at h5-HT1A receptors varying
from quinerolane (⬍5.0) to roxindole (9.9) (Table 6). Several
other agents, such as bromocriptine and apomorphine,
showed marked affinity for h5-HT1A sites although others,
such as piribedil and talipexole, showed only modest affinities.
h5-HT1B and h5-HT1D Receptors. Several drugs, including piribedil and talipexole, failed to recognize h5-HT1B receptors, although others, such as cabergoline and pergolide,
displayed modest affinities (Table 6). At structurally related
h5-HT1D receptors, affinities were generally elevated com-
795
Antiparkinson Drugs and Monoaminergic Receptors
TABLE 6
Affinities (pKi values) of antiparkinson agents at serotonin h5-HT1 and h5-HT2 receptor subtypes and at native histamine H1 receptors
Data are pKi values (minus log Ki values) and, unless, indicated, are expressed as means ⫾ S.E.M. values of at least three independent determinations carried out in
triplicate.
Apomorphine
Bromocriptine
Cabergoline
Lisuride
Pergolide
Piribedil
Pramipexole
Quinelorane
Quinpirole
Ropinirole
Roxindole
Talipexole
Terguride
TL99
a
h5-HT1A
h5-HT1B
h5-HT1D
h5-HT2A
h5-HT2B
h5-HT2C
H1
6.93 ⫾ 0.12
7.89 ⫾ 0.04
7.70 ⫾ 0.17
9.83 ⫾ 0.05
8.72 ⫾ 0.13
6.35 ⫾ 0.01
6.16 ⫾ 0.02
⬍5
5.77 ⫾ 0.10
6.54 ⫾ 0.07
9.94 ⫾ 0.24
5.77 ⫾ 0.04
8.46 ⫾ 0.11
5.42 ⫾ 0.06
5.53 ⫾ 0.06
6.45 ⫾ 0.12
6.32 ⫾ 0.09
7.73 ⫾ 0.11
6.55 ⫾ 0.10
⬍5
5.08 ⫾ 0.05
⬍5
⬍5
⬍5
5.84 ⫾ 0.13
⬍5
6.59 ⫾ 0.09
⬍5
5.91 ⫾ 0.15
7.97 ⫾ 0.03
8.06 ⫾ 0.08
9.01 ⫾ 0.05
7.88 ⫾ 0.11
⬍5
5.78 ⫾ 0.10
⬍5
⬍5
5.86 ⫾ 0.07
7.20 ⫾ 0.11
⬍5
7.79 ⫾ 0.15
5.71 ⫾ 0.03
6.92 ⫾ 0.06
6.97 ⫾ 0.15
8.21 ⫾ 0.08
8.56 ⫾ 0.03
8.08 ⫾ 0.06
⬍5
⬍5
⬍5
⬍5
⬍5
8.18 ⫾ 0.01
⬍5
8.32 ⫾ 0.12
5.63 ⫾ 0.07
6.88 ⫾ 0.15
7.25 ⫾ 0.07
8.93 ⫾ 0.01a
8.88 ⫾ 0.05
8.15 ⫾ 0.04
5.92 ⫾ 0.06
⬍5
⬍5
⬍5
5.42 ⫾ 0.15
7.51 ⫾ 0.05
⬍5
8.15 ⫾ 0.10
5.69 ⫾ 0.26a
6.99 ⫾ 0.07
6.13 ⫾ 0.04
6.16 ⫾ 0.02
8.18 ⫾ 0.02
6.53 ⫾ 0.06
⬍5
⬍5
5.58 ⫾ 0.12
⬍5
⬍5
6.51 ⫾ 0.05
⬍5
7.32 ⫾ 0.07
5.64 ⫾ 0.21
⬍5
⬍5
5.86 ⫾ 0.14
7.46 ⫾ 0.04
5.77 ⫾ 0.13a
⬍5
⬍5
5.98 ⫾ 0.05
5.98 ⫾ 0.01
5.53 ⫾ 0.03
6.89 ⫾ 0.07a
⬍5
6.47 ⫾ 0.15a
6.11 ⫾ 0.20a
Mean ⫾ range, n ⫽ 2.
21 to a “subspace” of three axes preserved almost the entire
variance in the data. This permitted the construction of bidimensional “biplots” (1/2, 1/3, and 2/3) upon which both the
drugs and the variables that contributed to their dispersion
could be projected (Figs. 1–3).
The majority of variance (76.3%) could be attributed to PC1.
Upon projection of drugs onto the biplot, they distributed along
its entire length with lisuride and terguride defining one extremity and quinerolane, quinpirole, pramipexole, and ropinirole the other. (Note that orthogonal dispersion along PC2 is not
relevant to the notion of clustering along PC1.) TL99, piribedil,
and talipexole migrated close to the latter group, whereas roxindole, cabergoline, bromocriptine, and pergolide were located
near to lisuride and terguride. Superimposition of the 21 variables upon PC1 revealed that all were situated on, and contributed to, its leftward extension. This observation is in line with
the high degree of correlation among pKi values (Table 8) and
indicates that PC1 is a composite axis to which numerous variables cojointly contribute. Accordingly, the “loading values”
(correlation coefficients) for the majority of variables onto PC1
were generally high, with hD2S/hD2L and hD1 receptors yielding the most pronounced values (Table 8). Consistent with the
relatively low correlation coefficients of hD4 and H1 receptors to
other variables, their participation in PC1 was minor. This is
indicated in Table 8 by their comparatively modest loading
values onto PC1. In line with the absence of negative correlation
coefficients in the correlation matrix, no variables were located
at the opposite extremity of PC1 (Figs. 4 and 5). This contribution of multiple variables to PC1 explains the important role of
lisuride and terguride in its determination inasmuch as they
presented high affinities for all receptors. In contrast, drugs
located at the opposite extremity displayed modest or low affinities. Accordingly, other drugs were situated between the two
limits of PC1 as a function of the magnitude of their overall
affinities.
Axis PC2 accounted for 6.5% of variance. In line with the
comparatively low correlation coefficients of hD4 and H1 sites
versus h␣1-AR subtypes (Table 7), they defined its two extremes. Accordingly, hD4/H1 sites and h␣1-AR subtypes displayed, respectively, positive and negative loading values for
this axis (Table 8). The location of bromocriptine at one limit
of PC2 (Figs. 1 and 3) corresponds to its ⬃1,000-fold lower
affinity at H1 and D4 receptors versus ␣1-AR subtypes.
Quinelorane and TL99 were dissociated from bromocriptine
Downloaded from jpet.aspetjournals.org at ASPET Journals on October 2, 2016
pared with h5-HT1B receptors, notably for cabergoline and
pergolide, whereas these sites were not recognized by piribedil and talipexole.
h5-HT2A, h5-HT2B, and h5-HT2C Receptors. For closely
related h5-HT2A, h5-HT2B, and h5-HT2C receptors, binding
profiles were generally comparable (Table 6). However, certain agents, including cabergoline and pergolide, showed
substantially lower affinity for h5-HT2C versus h5-HT2A and
h5-HT2B receptors. No drug clearly differentiated h5-HT2A
from h5-HT2B sites. There was marked (⬎100-fold) variability in drug affinities at h5-HT2A, h5-HT2B, and h5-HT2C
receptors in each case: piribedil, talipexole, and pramipexole,
for example, showed low affinities compared with apomorphine, bromocriptine, and, in particular, cabergoline and pergolide.
H1 Receptors. Affinities of drugs at H1 receptors varied
from negligible (for example, apomorphine, bromocriptine,
piribedil, and pramipexole) to modest (for example, terguride
and lisuride) (Table 6).
Interrelationship among Binding Sites: Correlation
Matrix. An important and general feature of the correlation
matrix was the lack of negative correlation coefficients, that
is, in no case was high affinity at one receptor associated with
low affinity at a second site (Table 7). This feature was
reflected in numerous statistically significant correlation coefficients among pairs of receptors (Table 8). Some were
unsurprising, such as between hD2S and hD2L receptors,
among h␣1-AR and h␣2-AR subtypes and between h5-HT2A
and h5-HT2C receptors. More notably, there were high correlation coefficients between affinities at hD2S and hD2L
receptors on the one hand, and h5-HT2A, h5-HT2B, and h5HT2C receptors on the other. Furthermore, hD5, h5-HT2C,
and h5-HT2A sites were well correlated. Similarly, high correlation coefficients were observed between hD2 receptors
and ␣1- and ␣2-AR subtypes. On the other hand, affinities at
hD4 receptors were poorly correlated with affinities at hD2S,
hD2L, and hD3 receptors, as well as other sites with the
exception of H1 receptors. H1 receptors were themselves distinguished by relatively poor (and, in certain cases, nonsignificant) correlation coefficients with other receptor types.
Principle Components Analysis. Application of PCA to
the pKi values revealed that almost 90% of variance could be
accounted for by three axes: PC1, PC2, and PC3 (Figs. 1, 2,
and 3; Table 8). That is, a reduction of “dimensionality” from
h5-HT1A
h5-HT1B
h5-HT1D
h5-HT2A
h5-HT2B
h5-HT2C
hD1
hD2S
hD2L
hD3
hD4
hD5
h␣1A-AR
h␣1B-AR
h␣1D-AR
r␣2-AR
h␣2A-AR
h␣2B-AR
h␣2C-AR
H1
h␤1-AR
h␤2-AR
1.00
0.85
0.87
0.90
0.86
0.76
0.81
0.81
0.83
0.63
0.46
0.68
0.85
0.83
0.85
0.66
0.77
0.82
0.74
0.57
0.68
0.69
h5-HT1A
1.00
0.96
0.89
0.91
0.86
0.88
0.87
0.85
0.73
0.45
0.79
0.77
0.77
0.76
0.74
0.82
0.81
0.71
0.56
0.82
0.79
h5-HT1B
h5-HT1B
1.00
0.92
0.93
0.79
0.87
0.89
0.88
0.79
0.35
0.78
0.78
0.82
0.75
0.74
0.79
0.78
0.70
0.52
0.73
0.69
h5-HT1D
h5-HT1D
1.00
0.97
0.87
0.96
0.93
0.94
0.78
0.59
0.88
0.78
0.81
0.80
0.77
0.80
0.82
0.77
0.57
0.60
0.64
h5-HT2A
h5-HT2A
1.00
0.83
0.93
0.94
0.95
0.72
0.47
0.86
0.75
0.77
0.77
0.79
0.80
0.78
0.76
0.49
0.59
0.61
ht-HT2B
h5-HT2B
1.00
0.93
0.85
0.83
0.76
0.75
0.91
0.70
0.67
0.73
0.75
0.79
0.85
0.78
0.64
0.74
0.77
h5-HT2C
h5-HT2C
1.00
0.92
0.92
0.76
0.63
0.91
0.77
0.75
0.78
0.82
0.84
0.87
0.79
0.54
0.67
0.74
hD1
hD1
1.00
0.99
0.80
0.53
0.84
0.85
0.85
0.83
0.91
0.87
0.83
0.84
0.59
0.71
0.73
hD2S
hD2S
1.00
0.80
0.53
0.84
0.85
0.83
0.81
0.90
0.88
0.84
0.86
0.62
0.67
0.71
hD2L
hD2L
1.00
0.60
0.72
0.61
0.62
0.49
0.70
0.64
0.65
0.60
0.77
0.61
0.65
hD3
hD3
1.00
0.63
9.40
0.35
0.42
0.41
0.38
0.50
0.42
0.66
0.38
0.50
hD4
hD4
1.00
0.54
0.59
0.61
0.78
0.78
0.81
0.79
0.50
0.52
0.55
hD5
hD5
1.00
0.93
0.95
0.75
0.81
0.80
0.76
0.52
0.82
0.82
h␣1A
h␣1A
0.94
0.94
0.71
0.74
0.72
0.71
0.40
0.72
0.66
h␣1B
h␣1B
r␣2D
1.00
0.95
0.89
0.93
0.54
0.69
0.74
r␣2D
h␣1D
1.00
1.00
0.74
0.81
0.80
0.78
0.36
0.75
0.73
h␣1D
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h5-HT1A
Values are Pearson product-moment correlation coefficients (r). All values were positive; values except those indicated in bold were not statistically significant.
1.00
0.97
0.95
0.52
0.78
0.81
h␣2A
h␣2A
1.00
0.93
0.58
0.78
0.84
h␣2B
h␣2B
1.00
0.55
0.68
0.71
h␣2C
h␣2C
H1
1.00
0.60
0.68
H1
TABLE 7
Correlation matrix of the interrelationship between drug affinities (pKi values) at multiple classes of dopamine receptor, adrenoceptor, serotonin receptor, and at H1 receptors
1.00
0.95
h␤1
h ␤1
1.00
h␤2
h ␤2
796
Millan et al.
Antiparkinson Drugs and Monoaminergic Receptors
TABLE 8
Loading values for individual variables onto principal components (PC)
1, 2, and 3.
Note that these values correspond to those illustrated in Figs. 1 through 3. High
positive and negative loading values indicate a major contribution to the respective
PCs, whereas values close to zero indicate a minor contribution.
Loading Factor
Receptor
PC2
PC3
⫺0.89
⫺0.92
⫺0.91
⫺0.94
⫺0.92
⫺0.91
⫺0.95
⫺0.96
⫺0.96
⫺0.80
⫺0.58
⫺0.85
⫺0.88
⫺0.85
⫺0.87
⫺0.89
⫺0.92
⫺0.93
⫺0.88
⫺0.81
⫺0.83
⫺0.65
⫺0.13
⫺0.04
⫺0.09
0.08
0.00
0.27
0.11
⫺0.01
0.01
0.37
0.65
0.29
⫺0.32
⫺0.34
⫺0.37
⫺0.06
⫺0.17
⫺0.05
⫺0.10
⫺0.17
⫺0.05
0.49
⫺0.05
⫺0.04
⫺0.17
⫺0.27
⫺0.34
0.00
⫺0.18
⫺0.12
⫺0.15
0.04
0.12
⫺0.32
0.19
⫺0.03
0.03
0.01
0.06
0.10
0.02
0.48
0.50
0.42
at the other extreme in line with their more pronounced
affinity for H1 and hD4 versus h␣1-AR subtypes. The other
drugs were distributed in accordance with this schema.
PC3 contributed 5.1% of variance to the data. The projections of variables indicate that h␤2/h␤1-ARs and H1 receptors
on the one hand, and hD5, h5-HT2A, and h5-HT2B receptors
on the other, primarily underlay distribution of drugs along
this axis. Correspondingly, the loading values of h␤2/h␤1-ARs
and H1 receptors onto PC3 were ⬃0.4 and positive, whereas
those of h5-HT2A and hD5 receptors were similar but negative (Table 8). The location of cabergoline and pergolide at
one limit of the axis (Figs. 2 and 3) reflects, thus, their
markedly (⬎100-fold) higher affinity for h5-HT2A and hD5
sites compared with H1 receptors and h␤1/h␤2-ARs. The position of lisuride at the opposite extreme, on the other hand,
reflects its comparatively more pronounced affinity for h␤1and h␤2-ARs as well as H1 receptors.
Hierarchical (Cluster) Analysis of Global Drug Homology. From the dendrogram of overall drug homology generated
by analysis of the total database, several drug clusters not
apparent from inspection of the biplots could be recognized (Fig.
4). It is pragmatic to comment the dendrogram in a direction
opposite to that of its mathematical construction, and the most
striking separation between drugs was at the first “node”,
which yielded two major subdivisions.
The first major group comprised quinpirole, quinelorane,
ropinirole, pramipexole, piribedil, and talipexole, whereas
the second comprised lisuride, terguride, roxindole, bromocriptine, cabergoline, pergolide, TL99, and apomorphine.
Compared with drugs in the second group, drugs in the first
group displayed low affinities for multiple classes of 5-HT
receptor, and low affinities for hD5 compared with hD2S/hD2L
receptors. Drugs in this first cluster also showed low affinity
for hD1 and H1 receptors and negligible affinity for h␤1- and
h␤2-ARs, although this feature was also seen in certain drugs
in the second major cluster. Within the first group, a marked
similarity was apparent between quinelorane and quinpirole,
and between pramipexole and ropinirole, which comprised
two closely related subclusters. The other two agents,
piribedil and talipexole, could be distinguished by their
more pronounced affinities at h␣1-AR subtypes as well as
at h␣2A-ARs, h␣2C-ARs, and, less markedly, h␣2B-ARs.
Within the second major subdivision, lisuride and terguride revealed high affinities at all sites, notably, at h5HT2A and h5-HT2C receptors, all subtypes of dopamine receptor and h␤1- and h␤2-ARs. Roxindole and bromocriptine
constituted a closely related subcluster showing a similar
overall pattern of affinities, notably sharing high affinity for
h␣1-AR subtypes. Overall, roxindole showed higher affinities,
although this difference was only marked for hD4 receptors.
An additional pair of ligands displaying similar receptor
binding profiles was formed by cabergoline and pergolide,
with the former showing higher affinities at most sites. Both
revealed low affinities for H1 receptors and h␤1- and h␤2ARs. The final couple of closely related drugs was TL99 and
apomorphine, which showed less pronounced affinities at
most sites than other drugs in this division.
Radar Plots. The radar representations of Fig. 5 complement the dendrogram in exemplifying similarities and differences among various drugs at specific receptor types discussed above.
Discussion
hD2S and hD2L Receptors. Although benzamides display
contrasting affinities at hD2L compared with hD2S receptors,
other classes of antagonist show similar affinity; likewise, all
agonists examined to date (including several antiparkinsonian agents) revealed comparable affinities for these sites
(Leysen et al., 1993). The present observations extend such
reports in demonstrating similar affinities of numerous antiparkinson drugs at hD2S versus hD2L sites. Such information is important because 1) D2S versus D2L sites present
differential patterns of post-translational processing, coupling, regulation, and localization; 2) D2S autoreceptors modulate DA release and may contribute to neuroprotective properties of antiparkinson agents; and 3) postsynaptic D2S and
(predominant) hD2L sites, perhaps via contrasting interactions with D1 receptors, differentially control motor function
(Zou et al., 1999; Usiello et al., 2000).
hD3 and hD4 Receptors. Comparisons of affinities at hD3
versus hD2 sites should be made cautiously in the light of
multiple affinity states of the latter (Mierau et al., 1995;
Coldwell et al., 1999; Perachon et al., 1999). Nevertheless,
the high potency of all agents for hD3 sites underscores their
potential relevance to beneficial and/or undesirable properties of antiparkinson drugs (Millan et al., 2000b; Joyce,
2001). The modest correlation coefficients of hD4 to hD2S/
hD2L/hD3 receptors indicate distinctive structure-activity relationships, in line with the discovery of many selective hD4
receptor antagonists. Bromocriptine and piribedil displayed
modest affinity, and antagonist properties (Newman-Tancredi et al., 2002a), at hD4 receptors indicating, as discussed
elsewhere, that their stimulation is not mandatory for clinical efficacy (Rondot and Ziegler, 1992; Jenner, 1995; Newman-Tancredi et al., 1997). Indeed, blockade of D4 receptors
Downloaded from jpet.aspetjournals.org at ASPET Journals on October 2, 2016
h5-HT1A
h5-HT1B
h5-HT1D
h5-HT2A
h5-HT2B
h5-HT2C
hD1
hD2S
hD2L
hD3
hD4
hD5
h␣1A
h␣1B
h␣1D
r␣2D
h␣2A
h␣2B
h␣2C
h␤1-AR
h␤2-AR
H1
PC1
797
798
Millan et al.
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Fig. 1. Principle component analysis of drug interactions at multiple binding sites examined herein: axes (principal components) 1 and 2. The database
(pKi values) comprised 14 drugs and 21 binding sites indicated in Tables 4 to 6. These values (a total of 294) were simultaneously analyzed in a
“polydimensional” space, as described under Materials and Methods. Top (scatter diagram), plots the distribution of each parameter (specific binding
sites) as a function of its contribution to the first two principle components (axes), which accounted for 76.27 and 6.53% of variance, respectively.
Reflecting extensive, positive “covariance” indicated in Table 8, all parameters (vectors) clustered in the same direction along axis 1. Within the plot,
the “circle of correlation” is depicted. The degree of correlation among specific parameters is revealed by projection of vectors onto this circle, and by
the angle between pairs of vectors, which is inversely correlated to their degree of correlation (Table 8). For example, in the bottom left quadrant, all
three ␣1-AR subtypes are highly intercorrelated, whereas they are poorly correlated to hD4 receptors located in the upper quadrant (Table 8). The tips
of the vectors, when vertically or horizontally projected onto PC1 and PC2, respectively, yield loading values indicated in Table 8. Bottom, drugs are
superimposed upon PCs 1 and 2. S, 5-HT.
Antiparkinson Drugs and Monoaminergic Receptors
799
may improve cognitive-attentional processing (Oak et al.,
2000).
hD1 and hD5 Receptors. Surprisingly, affinities were
well correlated between hD1 and hD2S/hD2L sites, suggesting that structure-activity relationships are less distinct
than might be imagined. Joint D1/D2 receptor stimulation
may improve therapeutic efficacy for drugs such as apomorphine and pergolide (Jenner, 1995; Markham and Benfield, 1997; Perachon et al., 1999; Aizman et al., 2000).
Functional interactions among (partially colocalized) D1
and D3 receptors are also of importance in the actions of
L-DOPA and other antiparkinson agents (Karasinska et
al., 2000; Joyce, 2001). Nevertheless, the low affinities of
clinically effective drugs, such as pramipexole and ropinirole, at hD1 sites support the notion that their engagement
is not requisite for therapeutic efficacy. Although we corroborate the preference of apomorphine for hD5 versus hD1
sites (Sunahara et al., 1991; Demchyshyn et al., 2000), we
found (⬃5-fold) higher affinities of apomorphine, bromocriptine, lisuride, and pergolide at hD5 receptors com-
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Fig. 2. Principle component analysis of
drug affinities at multiple binding sites
examined herein: axes (principal components) 1 and 3. Top, distribution of each
parameter (specific binding sites) as a
function of principle components (axes) 1
and 3, which accounted for 76.27 and
5.4% of variance, respectively. Bottom,
drugs are superimposed upon PCs 1 and
2. See the legend to Fig. 4 and Results for
further details. S, 5-HT
800
Millan et al.
pared with these studies. One factor underlying this difference may be the use of Chinese hamster ovary versus
COS-7 cells. Indeed, Kimura et al. (1995) (using GH4C1
cells) similarly concluded that the cell line confers distinctive binding properties to hD1 and hD5 receptors. D5 sites
are of significance in several respects: 1) multivariate
analyses revealed that hD5 affinities discriminate antiparkinson agents; 2) D5 receptors are situated on striatal
dopaminergic, cholinergic, and GABAergic neurons (Ciliax
et al., 2000); and 3) antisense probes against D5 and D1
receptors potentiated and inhibited, respectively, induction of rotation by D1/D5 agonists in unilateral substantia
nigra-lesioned rats (Dziewczapolski et al., 1998). Differential modulation of motor function is supported by the contrasting phenotypes of mice lacking D5 versus D1 receptors
and their distinctive patterns of localization (Sibley, 1999;
Ciliax et al., 2000).
h␣2 and h␣1-ARs. The observations herein amplify isolated studies (Uitti and Ahlskog, 1996) of antiparkinson
agents at r␣1- and r␣2-ARs in demonstrating that many
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Fig. 3. Principle component analysis of
drug affinities at multiple binding sites
examined herein: axes (principal components) 2 and 3. Top, distribution of each
parameter (specific binding sites) as a
function of principle components (axes) 2
and 3, which accounted for 6.53 and 5.4%
of variance, respectively. Bottom, drugs
are superimposed upon PCs 2 and 3. See
the legend to Fig. 4 and Results for further details. S, 5-HT.
Antiparkinson Drugs and Monoaminergic Receptors
801
Fig. 4. Hierarchical (cluster) classification of overall drug homology based
upon binding profiles at all receptors.
The database (pKi values) exploited
for generation of the dendrograms is
given in Tables 4 to 6. Note that the
distance between two individual drugs
is inversely proportional to their overall homology. That is, drugs situated
adjacently present very similar binding profiles, whereas those widely separated show substantially different
binding profiles. The chemical class of
each drug is indicated.
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Fig. 5. “Radar” representations of the binding profiles of (closely related) pairs of drugs at certain receptor types. In each radar plot, the two drugs
depicted show broadly similar profiles. Affinities are indicated in pKi values. Thus, the greater the distance from the central node of the radar plot,
the higher the drug affinity for a specific binding site. Plots of quinpirole and quinelorane are not shown for reasons of space: they presented very
similar profiles close to those of pramipexole and ropinirole.
recognize h␣1- and h␣2-AR subtypes. The present data thus
complement reports of the weak (agonist) interaction of
pramipexole with r␣2-ARs (Mierau et al., 1995) and of actions
of apomorphine and bromocriptine at hippocampal r␣2-ARs
(Jackisch et al., 1985). Furthermore, the high affinity of TL99
for h␣2-AR subtypes amplifies observations with native r␣2ARs (Martin et al., 1983). Of particular interest, whereas
talipexole behaves as an agonist at ␣2-ARs (Meltzer et al.,
1989), piribedil manifests antagonist properties. Correspondingly, in contrast to talipexole, piribedil reinforces corticolimbic adrenergic and cholinergic transmission (Millan et al.,
2000c, 2001a; Gobert et al., 2002), actions contributing to its
favorable influence upon cognitive function and mood
(Brefel-Courbon et al., 1998; Bezard et al., 2001; Maurin et
al., 2001; Nagaraja and Jayashree, 2001). Extending work
with native ␣1-ARs, bromocriptine, lisuride, terguride, and
802
Millan et al.
mon functional effects distinguishable from those of cabergoline and roxindole and from older agents such as bromocriptine and apomorphine. As regards piribedil and talipexole,
which likewise recognized dopaminergic but not serotonergic
receptors, it is important to emphasize their opposite antagonist and agonist properties at ␣2-ARs, respectively; indeed,
piribedil seems to be unique in simultaneously activating
D2/D3 receptors and blocking ␣2-ARs without markedly interacting with 5-HT receptors (Newman-Tancredi et al.,
2002a,b). On the contrary, among ligands with pronounced
serotonergic properties, cabergoline and roxindole were remarkably similar to pergolide and bromocriptine, respectively. Terguride and TL99, on the other hand, closely resembled lisuride and apomorphine, respectively. Certain closely
related drugs possess similar structures, for example, pergolide and cabergoline. However, ropinirole/pramipexole and
piribedil/talipexole presented similar binding profiles despite
their chemical distinctiveness. Thus, chemical structure does
not provide a satisfactory basis for prediction of receptor
binding profiles.
Principal Component Analysis. The compound nature
of PC1, which accounted for 76% variance, reflects marked
correlation among receptors. That is, with the exception of
hD4 and H1 receptors, all receptor types made a pronounced
contribution to PC1 (Table 8). In accordance with its generally high affinity, lisuride defined one extremity of PC1 in
distinction to drugs of modest affinity, such as quinpirole,
which migrated at the opposite limit. PC2 and PC3, nevertheless, proved discriminant in dissociating bromocriptine
from TL99 based on low and high affinities, respectively, for
H1/hD4 receptors versus ␣1-ARs. Furthermore, cabergoline
was located at one limit of PC3 on the basis of higher affinity
for hD5 and h5-HT2A versus h␤1/h␤2-ARs and H1 receptors,
whereas lisuride (high affinity at ␤1/␤2-ARs and H1 receptors) defined the opposite extremity. Thus, PCA identified
several receptors contributing to diversity in the binding
profiles of antiparkinson agents. Within this framework,
PCA also provided insights into relationships among the
drug themselves as a function of their affinities at abovementioned and other sites. For example, reflecting their pronounced affinities for virtually all sites, lisuride and terguride comprised a subset of drugs (clustered together) when
projected onto PC1, PC2, and PC3, whereas piribedil and
talipexole were likewise adjacent to each other across all
PCs, corresponding to their mixed dopaminergic-adrenergic
profiles in the absence of serotonergic affinities.
General Discussion. Several general features of this
novel multivariate approach should be evoked. First, although multivariate techniques have been used for evaluation of biochemical abnormalities in schizophrenia (Carlsson
et al., 2001) and characterization of drug pharmacokinetic
profiles (Ette et al., 2001), this is their first systematic utilization for characterization of drug receptor-binding profiles.
Whereas pairwise drug/drug and site/site comparisons can be
misleading, multivariate strategies simultaneously analyze
the entire database in a multidimensional space permitting
hypothesis-free exploration of similarities and differences as
a function of overall binding profiles. Although both drugs
and variables must be selected, substantial databases (as
herein) minimize the risk that an involuntary “bias” may
distort analyses. Second, a precondition for multivariate procedures is a homogeneous and extensive database incorpo-
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roxindole displayed high affinities at h␣1-AR subtypes
(McPherson and Beart, 1983; Uitti and Ahlskog, 1996). Potent blockade of ␣1-ARs may interfere with the influence of
antiparkinson agents upon motor performance and perturb
cardiovascular function (Hieble et al., 1995; Millan et al.,
2000).
h␤1 and h␤2-ARs. The finding that several drugs recognize h␤1- and h␤2-ARs is of interest. First, ␤1/␤2-ARs are
excitatory to corticostriatal glutamatergic afferents (Niittykoski et al., 1999). Second, they activate dopaminergic, adrenergic, and serotonergic pathways in cortex and nucleus
accumbens (Millan et al., 2000; Tuinstra and Cools, 2000).
Third, stimulation of ␤1/␤2-ARs enhances cognitive function
and improves mood (O’Donnell et al., 1994). Fourth, stimulation and blockade of central ␤1/␤2-ARs elicits and blocks
tremor, respectively (Wilms et al., 1999).
h5-HT Receptors. Although all ligands showed some affinity for h5-HT1A receptors, extending studies of native sites
(Uitti and Ahlskog, 1996), marked differences among antiparkinson agents were seen at 5-HT2 receptor subtypes. High
affinities of lisuride, terguride, cabergoline, and pergolide at
h5-HT2A (and h5-HT2C) receptors underpin studies showing
that ergot-related compounds interact with native “5-HT2”
receptors (Beart et al., 1986; Uitti and Ahlskog, 1996;
Markham and Benfield, 1997; Fariello, 1998). Interestingly,
their marked serotonergic affinities were mimicked by the
structurally distinct roxindole and apomorphine (Uitti and
Ahlskog, 1996; Newman-Tancredi et al., 1999). Actions of
antiparkinson drugs at 5-HT2A/2C sites may, as discussed in
the accompanying article (Newman-Tancredi et al., 2002b),
influence motor function and mood.
H1 and Muscarinic Receptors. Lisuride interacts with
rat H1 sites (Beart et al., 1986), an observation extended here
to a further species and other drugs. Such actions at H1
receptors are of potential importance. First, H1 receptors
modulate motor function, and inhibit and enhance striatal
dopaminergic and cholinergic transmission, respectively
(Bacciottini et al., 2001; Brown et al., 2001). Second, they
influence arousal and cognition (Brown et al., 2001). Third,
H1 receptor blockade encourages sleep and elicits sedation, a
troublesome symptom of treated and untreated parkinsonian
patients (Brown et al., 2001; Friedman and Factor, 2000).
Fourth, rats sustaining 6-hydroxydopamine lesions of the
substantia nigra and Parkinson’s Disease patients show an
increase in striatal histaminergic innervation (Anichtchik et
al., 2000). Reflecting functional interplay among dopaminergic and cholinergic networks in basal ganglia, muscarinic
antagonists suppress tremor and dyskinesias provoked by
L-DOPA, although side effects compromise their utilization
(Wilms et al., 1999; Bezard et al., 2001). However, antiparkinson agents tested herein did not occupy cloned, human M1
receptors (for all drugs, pKi values of ⬍6.0).
Hierarchical (Cluster) Analysis. High versus low affinities at multiple 5-HT and hD5 receptors underpinned a
major subdivision of agents into two groups. This association
is intriguing because “selective” hD1/hD5 receptor ligands
show pronounced affinity for h5-HT2A and h5-HT2C receptors
(Millan et al., 2001b). Of drugs not interacting with serotonergic receptors, the data support experimental use of quinpirole and quinelorane as selective D2-like receptor agonists.
Furthermore, inasmuch as the receptor profiles of ropinirole
and pramipexole were very similar, they should display com-
Antiparkinson Drugs and Monoaminergic Receptors
Acknowledgments
We thank M. Soubeyran for secretarial assistance, and V. Pasteau, L. Verrièle, L. Marini, C. Chaput, M. Touzard, and V. Dubreuil
for technical assistance.
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