Design, synthesis, and evaluation of potent and selective ligands for the dopamine 3 (D3) receptor with a novel in vivo behavioral profile

Article abstract of DOI:10.1021/jm800471h

A series of compounds structurally related to pramipexole were designed, synthesized, and evaluated as ligands for the dopamine 3 (D₃) receptor. Compound 12 has a K_i value of 0.41 nM to D₃ and a selectivity of > 30000- and 800-fold over the D₁-like and D ₂ receptors, respectively. Our in vivo functional assays showed that this compound is a partial agonist at the D₃ receptor with no detectable activity at the D₂ receptor.

Full text of DOI:10.1021/jm800471h

J. Med. Chem. 2008, 51, 5905–5908
5905
Design, Synthesis, and Evaluation of Potent
and Selective Ligands for the Dopamine 3
(D3) Receptor with a Novel in Vivo
Behavioral Profile
Jianyong Chen,† Gregory T. Collins,‡ Jian Zhang,†
Chao-Yie Yang,† Beth Levant,| James Woods,‡ and
Shaomeng Wang*,†,‡,§
Departments of Internal Medicine, Pharmacology, and Medicinal
Chemistry, UniVersity of Michigan, 1500 East Medical Center
DriVe, Ann Arbor, Michigan 48109, Department of Pharmacology,
Toxicology, and Therapeutics, UniVersity of Kansas Medical Center,
Kansas City, Kansas 66160
Figure 1. Chemical structures of representative D3 ligands.
ReceiVed April 23, 2008
Abstract: A series of compounds structurally related to pramipexole
were designed, synthesized, and evaluated as ligands for the dopamine
3 (D3) receptor. Compound 12 has a Ki value of 0.41 nM to D3 and a
selectivity of >30000- and 800-fold over the D1-like and D2 receptors,
respectively. Our in vivo functional assays showed that this compound
is a partial agonist at the D3 receptor with no detectable activity at the
D2 receptor.
Dopaminergic neurotransmission is mediated by five dopam-
ine receptors (D1-D5), which can be grouped into the D1-like
a
(D1 and D5) and D2-like (D2, D3, and D4 ) receptor subtypes.
Recent studies have suggested that the D3 receptor is a promising
therapeutic target for a variety of conditions, including drug
abuse, restless legs syndrome, schizophrenia, Parkinson’s
disease, and depression.1-6 Considerable effort has been devoted
in recent years to the discovery and development of potent and
selective D3 ligands.6-22
Figure 2. New analogues structurally related to pramipexole.
Despite intense research efforts, design of truly selective D3
ligands with good solubility and bioavailability remains a
challenge. Compound 1 (pramipexole) is a potent D3-preferring
agonist but has limited selectivity over the D2 receptor in vitro23
and in vivo.24,25 Compound 2 was initially reported as a D3
partial agonist and has a 67-fold selectivity over the D2 receptor.2
A number of potent and selective D3 ligands, such as 3, have
been designed based upon the core structure of 2.17 Our
laboratory has reported the design of 4 as a potent and selective
D3 ligand using the hexahydropyrazinoquinoline as the core
structure.21 Despite its relatively high affinity and excellent
selectivity for D3 over other dopamine receptor subtypes, 4 has
a poor aqueous solubility, which limits its in vivo evaluations
(Figure 1). The poor aqueous solubility is also a major limitation
for many recently described potent and selective D3 ligands and
an obstacle for evaluation of these novel agents in behavioral
models in animals and their therapeutic potential.
Among them, the core structure in 1 has a number of very
attractive features. First, 1 itself is a very potent D3 ligand and
has a Ki value of 0.78 nM to D3 in our binding assay (Table 1).
Second and importantly, 1 has an excellent aqueous solubility.
Third, pramipexole dihydrochloride has been approved for the
treatment of Parkinson’s disease and restless legs syndrome and
has an excellent pharmacological and toxicological profile in
humans and in animals. Hence, 1 represents a particularly
attractive template for the design of potent and selective D3
ligands with desirable physiochemical and pharmacological
properties (Figure 2). Of note, although 1 has been widely used
as a D3 preferring ligand, it potently binds to the high affinity
state of the D2 receptor with a Ki value of 3.1 nM in our binding
assays (Table 1), thus displaying only a 4-fold selectivity for
the D3 receptor over the D2 receptor.
Recently, the crystal structures for the human ꢀ2 adrenergic
(ꢀ2AD) G-protein coupled receptor (GPCR) were solved.26,27
We have modeled the human D3 receptor structure based upon
the high-resolution crystal structures of ꢀ2AD receptor because
these two proteins belong to the same GPCR subfamily28 and
share close sequence homology. Because the crystal structure
of ꢀ2AD receptor was solved with an inverse agonist bound to
it, our modeled D3 structure likely represents the conformational
state bound to either antagonists or inverse agonists. Hence,
care must be taken when using the structure to model the
interactions of the D3 receptor with its ligands with different
intrinsic functions. Nevertheless, we reasoned the modeled
To overcome this major limitation, we investigated other core
structures for the design of potent and selective D3 ligands.
* To whom correspondence should be addressed. Phone: 734-615-0362.
Fax: 734-647-9647. E-mail: shaomeng@umich.edu.
†
Department of Internal Medicine, University of Michigan.
Department of Pharmacology, University of Michigan.
Department of Medicinal Chemistry, University of Michigan.
Department of Pharmacology, Toxicology, and Therapeutics, University
‡
§
|
of Kansas Medical Center.
a Abbreviations: D1-5, dopamine 1-5 receptor subtypes; ꢀ2AD, the
human ꢀ2 adrenergic receptor; GPCR, G-protein coupled receptor.
10.1021/jm800471h CCC: $40.75
2008 American Chemical Society
Published on Web 09/12/2008

5906 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
Letters
Table 1. Binding Affinities at the D1-like, D2, and D3 Receptors in Binding Assays Using Rat Braina
Ki ( SEM (nM)
selectivity
ligand
D3 [3H]PD128907
D2 [3H]Spiperone
D1-like [3H]SCH23390
D2-like/D3
4.0
D1-like/D3
1
0.78
3.1 ( 0.3 (h)
6400 ( 1700 (l)
>10000
>100000
>100000
4
5
5.7 ( 0.4
0.043 ( 0.006
>50000
11000 ( 500
>1000
>5000
>100000
2.7 ( 0.4 (h)
6700 ( 1500 (l)
307 ( 38
55 ( 12 (h)
1300 ( 180 (l)
345 ( 33
1200 ( 170
670 ( 140
68 ( 4.6
330 ( 69
62
6
7
0.40 ( 0.057
0.74 ( 0.083
3400 ( 300
5400 ( 500
763
74
>7000
>7000
8
9
10
11
12
2.2 ( 0.10
23 ( 2.7
7.6 ( 0.87
0.51 ( 0.10
0.41 ( 0.031
13000 ( 1000
4400 ( 800
64000 ( 7000
4900 ( 600
13000 ( 1700
157
53
88
133
800
>5000
194
>8000
>9000
>30000
a Data represent the mean ( SEM of 3-5 independent determinations. For compounds producing a two-site fit in competition with [3H]-spiperone, Ki
values are presented for the high and low affinity components and are indicated by the designation “(h)” or “(l)”. All other Ki values are based on a
single-site model.
state of the D2 receptor with a Ki value of 2.7 nM, thus
displaying a 62-fold selectivity for the D3 receptor over the D2
receptor. Similar to 1, 5 has a weak affinity to the D1-like
receptors and has a Ki value of 11000 nM. Hence, although 5
has a very high affinity to the D3 receptor, its selectivity over
the D2 receptor is modest.
In our previous design of 4, we have shown that introduction
of a trans-cyclohexyl group into the linker region yielded new
ligands with much improved selectivity for the D3 receptor over
the D2 receptor as compared to a linear 4-carbon linker.21 We
have thus designed compound 6 to investigate if introduction
of this rigid cyclohexyl group into 5 may also improve the
selectivity. Compound 6 binds to the D3 and D2 receptors with
Ki values of 0.40 and 307 nM, respectively. Hence, 6 is a potent
D3 ligand and displays an excellent selectivity of 763-fold for
the D3 receptor over the D2 receptor.
Figure 3. Predicted binding model of compound 1 to the human D3
receptor. For protein, carbon atoms of human D3 are shown in white,
oxygen atoms in red, and nitrogen atoms in blue. Side chains of crucial
residues in the binding site are shown as stick and labeled. Hydrogen
bonds between 1 and D3 are depicted in dotted line in yellow. Figures
were generated by Pymol.
We next designed and synthesized compounds 7-10 to
investigate the importance of the n-propyl group in 6 for binding
and selectivity. Compound 7 with an n-butyl group has a slightly
weaker affinity for the D3 receptor than 6 and exhibited a two-
site competition curve at the D2 receptor, with roughly 10-fold
less selectivity for the D3 receptor over the D2 receptor with
the high affinity binding component. Compound 8 with an
isopentyl group is five times less potent than 6 to the D3 receptor
but has a similar binding affinity to the D2 receptor. Compound
9 with a bulky cyclohexylethyl group is 55 times less potent
than 6 to the D3 receptor but is only three times less potent
than 6 to the D2 receptor. Compound 10 with a hydrogen atom
at this site has a Ki value of 7.6 nM to the D3 receptor, being
19 times less potent than 6, but their binding affinities to the
D2 receptor are essentially the same. Therefore, our binding data
clearly showed that the substitution on this nitrogen atom has
a major effect on the binding to the D3 receptor but modest
influence on the binding to the D2 receptor. Our data also
showed that the n-propyl group in 6 enhances the binding
affinity to the D3-receptor by 19-fold as compared to a hydrogen
atom in 10.
We next investigated the influence of the naphthyl group in
6 for binding and selectivity. Compound 11, in which the
naphthyl group is replaced by a 2-benzofuran, binds to the D3
receptor with the same affinity (Ki ) 0.51 nM) as 6, but its
selectivity over the D2 receptor is decreased to 133-fold due to
its increased binding affinity to the D2 receptor. Compound 12,
in which a cinnamyl group is used to replace the naphthyl,
retains a high binding affinity for the D3-receptor (Ki ) 0.41
nM) and displays 800- and >30000-fold selectivity over the
human D3 structure based upon the very first human GPCR
structure could be useful to guide the design of novel D3 ligands.
To this end, we modeled the binding of 1 to the D3 receptor
structure through computational docking, followed by extensive
refinement (Supporting Information). The predicted model
(Figure 3) showed that the primary amino group in the thiazol
ring of 1 forms a hydrogen bonding network with the
hydroxyl groups of Ser192 and Ser193. The thiazol ring in 1
is parallel to the imidazole ring in His349, making favorable
π-π stacking interaction. The protonated nitrogen in 1 forms
a salt bridge with the negatively charged Asp110. The n-propyl
group in 1 inserts into a hydrophobic channel formed by Cys114,
Phe345, Phe346, Trp342, and Try373.
The predicted model of 1 in complex with the D3 receptor
suggested that there is ample room available to accommodate
a much larger hydrophobic group where the n-propyl group in
1 binds. Interestingly, in the adjacent area, there is another well-
defined but smaller hydrophobic cavity formed by Cys114,
Phe197, and Trp342 residues. We have thus designed and
synthesized compound 5 to explore the interactions with these
two pockets.
Compound 5 was tested for its binding affinities to the
dopamine receptors using the same methods as described
previously (Table 1).21 It was found that 5 has a Ki value of
0.043 nM to the D3 receptor, being 18 times more potent than
1. Compound 5, however, also potently binds to the high affinity

Letters
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19 5907
concurrent with deceases in yawning. These data showed that
5 functions as a full agonist at the D3 and D2 receptors in vivo,
consistent with the two-site competition curve observed in the
[3H]spiperone binding assay for 1 and 5 (Supporting Informa-
tion). Furthermore, the in vivo data suggested that 5 is
bioavailable.
Unlike 1 and 5, the dose-response curves for 6 and 12
induced yawning were relatively flat and failed to reach
significance during the initial 30 min observation period. While
significant levels of yawning induced by 6 and 12 were observed
after 60 min, the dose-response curves for both compounds
remained relatively flat. Moreover, 6 and 12 failed to induce
changes in body temperature over the initial hour of observation,
an effect that is indicative of D2 agonist activity. Together, the
low levels of yawning, combined with the absence of any
hypothermic effect, suggested two possibilities: (1) 6 and 12
function as weak partial agonists at the D3 receptor, with no
detectable agonist activity at the D2 receptor, or (2) they are
simply not bioavailable.
To investigate these two possibilities, we next evaluated the
ability of 12 to alter compound 1-induced yawning and
hypothermia and the data are shown in Figure 4. Similar to the
effects of 12 alone, but unlike the effects of D3-selecitve
antagonists,24,25 low levels of yawning were observed during
the initial 30 min after administration of either 10.0 or 32.0
mg/kg of 12. Interestingly, this effect appeared to persist upon
administration of low doses of 1 as significant increases in
yawning were observed when rats were pretreated with 12 (10.0
or 32.0 mg/kg). However, 12 resulted in a dose-dependent
decrease in the amount of yawning observed following the
maximally effective dose of 1 at 0.1 mg/kg. No significant
effects of 12 were observed at higher doses of 1 (0.32 and 1
mg/kg). These data suggested that 12 is capable of antagonizing
the D3-mediated effects of 1. However, the profile of activity
for 12 is different from that observed for selective D3 antago-
nists, which generally produce selective rightward and/or
downward shifts of the ascending limb of the yawning
dose-response curve for D3-preferring agonists without increas-
ing the amount of yawning observed at low doses.24,25 In fact,
the effects of 12 alone, and in combination with 1, suggest that
it is more similar to the partial agonist, aripiprazole,34 than an
antagonist. Moreover, 12 failed to alter the induction of
hypothermia by 1, an effect that is indicative of D2 agonist
activity, which can be reliably blocked by both selective and
nonselective D2 antagonists.32,33 Together, our data provide
evidence that 12 is a partial agonist at the D3 receptor with no
detectable agonist or antagonist activity at the D2 receptor, thus
possessing a novel in vivo functional profile.
Figure 4. Functional evaluations of the D3 and D2 activity of pra-
mipexole and compounds 5, 6, and 12 in yawning and hypothermia
assays in rats. Top and middle panels: induction of yawning or
hypothermia by D3 ligands. Bottom panels: interactions between
pramipexole and compound 12 in yawning and hypothermia assays.
D2 and D1-like receptors. These data suggested that the
modifications of the naphthyl group can have a significant effect
on the selectivity, and this region should be further investigated
for the design of potent and selective D3 ligands.
The synthesis of compounds 5-12 is provided in the
Supporting Information.
Compounds 5, 6, and 12 were found to have good aqueous
solubility. For example, the dihydrochloride salt form of 6 has
an aqueous solubility greater than 100 mg/mL. Their excellent
aqueous solubility provided us with an opportunity to evaluate
their in vivo functional profiles in animals.
Another challenge in the development of selective D3 ligands
was that the current in vitro functional assays for the D3 receptor
are not predictive of the in vivo function of D3 ligands.6
Furthermore, there was also the lack of a robust in vivo
functional assay for the D3 receptor. To addresses these
challenges, we have recently validated in vivo functional assays
for the D3 and D2 receptors.24,25 Our studies showed that
yawning in rats provides a sensitive measure of in vivo agonist
activity at the dopamine D3 receptor,24,25 while the induction
of hypothermia has been shown to be mediated by agonist
activity at the D2 receptor.32,33 Employing these well-validated
assays, we evaluated 5, 6, and 12 for their in vivo functional
activity at the D3 and D2 receptors. Compound 1, a known D3
and D2 agonist, was used as a control in our evaluations. The
results are shown in Figure 4.
In summary, a series of enantiomerically pure pramipexole
derivatives have been designed, synthesized, and evaluated for
their binding and selectivity to the D3, D1-like, and D2 receptor.
This led to the identification of several potent and highly
selective D3 ligands with excellent aqueous solubility. Our in
vivo functional evaluations showed that while 5 functions as a
full D3 agonist, 12 behaves as a selective D3 partial agonist with
no activity at the D2 receptor. Further in vivo studies are
underway to evaluate the therapeutic potential of 12 for the
treatment of drug abuse and other indications. The results will
be reported in due course.
Consistent with the data obtained in previous studies,24,25
increases in yawning were observed over low doses (0.01 to
0.1 mg/kg) of 1 with inhibition of yawning and the induction
of hypothermia occurring at higher doses. These data indicate
that 1 functions as a preferential D3 agonist in vivo and a D2
agonist at higher doses.
Compound 5 induced yawning and produced an inverted
U-shaped dose-response curve. The maximum levels of yawn-
ing induced by 5 are very similar to that induced by 1.
Furthermore, hypothermia was induced by 5 at higher doses,
Acknowledgment. This work was supported by a grant from
the National Institute of Drug Abuse, National Institutes of
Health (R01DA020669).

5908 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 19
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