CJ-1639: A potent and highly selective dopamine D3 receptor full agonist

Article abstract of DOI:10.1021/ml200100t

We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K_i value of 0.50 nM and displays a selectivity of >5000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K_i value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.

Full text of DOI:10.1021/ml200100t

LETTER
pubs.acs.org/acsmedchemlett
CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full
Agonist
Jianyong Chen,† Gregory T. Collins,‡ Beth Levant,|| James Woods,‡ Jeffrey R. Deschamps,^ and
Shaomeng Wang*,‡,§
Departments of †Internal Medicine, ‡Pharmacology, and §Medicinal Chemistry, University of Michigan, 1500 East Medical Center
Drive, Ann Arbor, Michigan 48109, United States
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, United
States
^Center for Biomolecular Science and Engineering, Naval Research Laboratory, 4555 Overlook Avenue, Washington, DC 20375, United
States
S Supporting Information
b
ABSTRACT: We have identified several ligands with high binding affinities to
the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors.
CJ-1639 (17) binds to the D3 receptor with a Ki value of 0.50 nM and displays a
selectivity of >5000 times over D2 and D1 receptors in binding assays using
dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to
human D3 receptor with a Ki value of 3.61 nM and displays over >1000-fold
selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts
to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.
KEYWORDS: Dopamine receptors, ligands, agonists, drug abuse
opamine is an endogenous neurotransmitter in the central
nervous system and exerts its effects through activation of
aqueous solubility as compared to NGB 2904.13 Recently, com-
pound 9 (Figure 1) was reported to be a potent and orally active
D3 antagonist with a 500-fold selectivity over D2 in in vitro
functional assays.14 The in vivo selectivity for compounds 8 and 9
at the D3 receptor over the D2 receptor has not been reported.
In our effort to identify D3 ligands with high selectivity and
good solubility, we have previously reported the design of a set
of new compounds based upon pramipexole (1),15 which included
CJ-1037 (10) and CJ-998 (11) as the two best compounds
(Figure 2). Both 10 and 11 bind to D3 with high affinities and
have a good selectivity for D3 over D2 and excellent aqueous
solubility (>50 mg/mL). Unlike pramipexole, which is a D3 full
agonist, compounds 10 and 11 appear to behave as partial
agonists with low intrinsic agonist activity in rats.15 However,
despite their high binding affinities to D3, both compounds 10
and 11 only show in vivo activity at a very high dose (32 mg/kg),
indicating their poor bioavailability in the brain. Here, we report
further modifications based upon compound 11. These efforts have
now yielded a set of new D3 ligands (Figure 2 and Table 1) that are
highly potent and selective, not only in vitro, but also in vivo.
Newman's group showed that introduction of a hydroxyl
group in the linker region in their D3 ligands improves D3
selectivity and aqueous solubility.13,16 Accordingly, we designed
and synthesized compounds 12 and 13 by placing a hydroxyl
group in the cyclohexane ring of compound 11 to improve its
D
five distinct dopamine receptor subtypes that belong to the G
protein-coupled receptor superfamily. The receptors are grouped
into the D1-like (D1 and D5) and D2-like (D2, D3, and D4) recep-
tor subtypes. Numerous studies have provided strong evidence
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.1ꢀ3 Extensive
efforts have been devoted to the discovery and development
of potent and selective D3 ligands, including agonists, partial
agonists, and antagonists.5,6
Because of the high degree of sequence identity within the trans-
membrane helices between D2 and D3 receptors and the near-
identity of the residues inferred to form the binding site in these
receptors,4 it has been a challenge to design highly selective D3
ligands with excellent aqueous solubility and bioavailability.5,6
Pramipexole (1), quinpirole (2), and 7-hydroxy dipropylamino-
tetralin (7-OH-DPAT, 3), three widely used D3 agonists
(Figure 1), all have modest selectivity (<100-fold) over the D2
receptor based upon their in vitro binding data4 and a narrow
range of selectivity at the D3 receptor over the D2 receptor
in vivo.7,8 SB-277011A (4),9 SB-414796 (5),10 NGB 2904 (6),11
and BP 897(7)12 are four commonly used D3 antagonists
(Figure 1), but they also have a selectivity of 100-fold or less for
D3 over D2. Furthermore, these four ligands have limited aqueous
solubility. R-PG648 (8) (Figure 1), whose design is based upon
the core structure of NGB 2904, is a potent D3 antagonist with a
selectivity of >400-fold over D2 and also has a much improved
Received: April 19, 2011
Accepted: June 19, 2011
Published: June 28, 2011
r
2011 American Chemical Society
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Figure 1. Chemical structures of representative known D3 agonists (1ꢀ3) and antagonists (4ꢀ9).
Table 1. Binding Affinities at the D1-Like, D2-Like, and D3 Receptors in Binding Assays Using Rat Braina
Ki ( SEM (nM)
selectivity
ligand
D3 ([3H]-R(+)-7-OH-DPAT)
D2-like [3H]spiperone
D1-like [3H]SCH23390
D2-like/D3
D1-like/D3
1
11
12
13
14
15
16
17
0.45 ( 0. 034
0.80 ( 0.05
1.6 ( 0.25
39 ( 4
92 ( 9
>10000
87
115
>10000
>5000
7373
>5000
1628 ( 234
3549 ( 421
584 ( 72
564 ( 52
725 ( 45
2568 ( 302
11557 ( 996
14057 ( 1095
6125 ( 271
3058 ( 198
1616 ( 167
10127 ( 1002
1039
3816
1416
1627
1827
5136
0.93 ( 0.094
0.41 ( 0.038
0.35 ( 0.019
0.40 ( 0.087
0.50 ( 0.080
15115
14848
8822
4074
20254
a Binding affinities for all of the compounds in this table were evaluated under the assay conditions as described in the Supporting Information.
solubility and also to explore the effect of this hydroxyl group for
binding and selectivity at the D3 receptor (Figure 2). Compound
12 with a cis-hydroxycyclohexyl group and compound 13, the
corresponding trans isomer, have Ki values of 1.6 and 0.9 nM to D3,
respectively, in our in vitro binding assays using dopamine receptors
expressed in the native rat brain tissues. Thus, they are as potent as
compound 11, indicating that introduction of a hydroxyl group at
the bridge carbon atom of the cyclohexyl group is not detrimental to
D3 binding. Both compounds 12 and 13, however, have a reduced
binding affinity to D2 as compared to pramipexole. As a result, 12
and 13 display a selectivity of >1000 times and >3000 times,
respectively, for D3 over D2.
We next synthesized compounds 14 and 15 with a four-membered
ring in the linker region to replace the six-membered ring in
compound 11. Compound 14, with a trans-cyclobutyl group, has a
Ki value of 0.41 nM to D3 and is thus two times more potent than 11.
Compound 14 binds to D2 with a Ki value of 584 nM and is six times
less potent than 11. Hence, compound 14 is a highly potent D3 ligand
and displays >1000-fold selectivity for D3 over D2. Compound 15
with a cis-cyclobutyl group in the linker region binds to D3 with a Ki
value of 0.35 nM, very similar to that for compound 14. Compound
15 also shows a >1000-fold selectivity for D3 over D2. Hence,
replacement of the trans-cyclohexyl group in compound 11 with
either a trans- or a cis-cyclobutyl group improves both the binding
affinity for D3 and the selectivity over D2.
Encouraged by the promising binding and selectivity data
observed for compounds 12ꢀ15, we next synthesized com-
pounds 16 and 17, in which a hydroxyl group is introduced to
the bridge carbon atom of the four-membered ring in compounds
14 and 15, respectively. Compound 16 binds to D3 with a Ki
value of 0.40 nM and displays a selectivity of 1827 times over D2.
Compound 17 binds to D3 with a Ki of 0.50 nM and displays a
selectivity of >5000 times over D2. In addition to their high
binding affinities to D3 and excellent selectivity over D2,
compounds 16 and 17 also have excellent aqueous solubility
(>100 mg/mL) in their HCl salt form.
The syntheses of compounds 12 and 13 were outlined in
Scheme 1. Basically, 2-naphthoyl chloride was reacted with
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Figure 2. Chemical structures of two previously reported D3 ligands, 10 and 11, and designed new analogues 12ꢀ17.
trans-4-aminocyclohexanol in the presence of triethylamine, followed
by oxidation with PCC in DCM to give ketone 18. Ketone 18 was
treated with allylmagnesium bromide at ꢀ78 ꢀC to afford cis-
cyclohexanol 20 and trans-cyclohexanol 21. Compounds 20 and
21 were separated by silica gel chromatography (hexane:ethyl
acetate = 1:1). cis-Aldehyde 22 was obtained by the treatment of
cis-cyclohexanol 20 with osmium tetraoxide followed by sodium
periodate. trans-Aldehyde 23 was obtained in a similar manner.
Reductive amination of pramipexole 1with 22 and 23 gave designed
compounds 12 and 13, respectively. Details of the synthesis of
compounds 12ꢀ17 are provided in the Supporting Information.
The stereochemistry of cis-conformation of compound 12 was
confirmed by X-ray crystallographic analysis of key intermediate
20 (Figure 3). The stereochemistry of cis-conformation of com-
pound 16 was confirmed by X-ray crystallographic analysis of a
key intermediate (see the Supporting Information).
Our previous studies have shown that the induction of
yawning by D2-like agonists is a sensitive and well-validated
measure of agonist activity at the dopamine D3 receptor,7,8,17
whereas the inhibition of yawning and induction of hypothermia
by D2-like agonists are indicative of an agonist activation at the
D2 receptor.17ꢀ19 We have evaluated compounds 16 and 17 for
their in vivo function in the yawning and hypothermia assays in
the rat and included pramipexole as the reference compound in
the evaluations. The results are shown in Figure 4.
at higher doses (Figure 4A,D). The data are consistent with its
full agonist activity profile at the D3 and D2 receptors and a
narrow in vivo selectivity at the D3 receptor.7,8 Like pramipexole,
both 16 and 17 produced a dose-dependent increase in yawning
(Figure 4A). Unlike pramipexole, which induced yawning over a
very narrow dose range, compound 16 and 17 produced increases
in yawning over a very wide range of doses, with significant increases
in yawning observed at a dose range of 0.1ꢀ10.0 mg/kg for
compound 16 (CJ-1638) and 0.01ꢀ10.0 mg/kg for compound
17 (CJ-1639) (Figure 4A). Although both compounds have very
similar binding affinities to D3 based upon our in vitro binding data,
our yawning assay showed that compound 17 is more active than 16
in activation of the D3 receptor in the rat and has a significant
yawning activity at a dose of 0.01 mg/kg. These data suggest that
compound 17 has a better bioavailability in the brain than com-
pound 16. Both compounds produced peak levels of yawning at a
dose of 1.0 mg/kg (Figure 4A).
Because 17 is more potent in vivo in the yawning assay, we
focused our further evaluation on this compound. Consistent
with previous reports, significant decreases in core body tem-
perature were observed with doses of 0.32 and 1.0 mg/kg
pramipexole (Figure 4D). In comparison, compound 17 had
no significant effect on core body temperature at 3.2 mg/kg and
had a significant but a modest effect at 10 mg/kg (Figure 4D).
These data suggest that compound 17 readily crosses the bloodꢀ
brain barrier and functions as a highly selective, full efficacy agonist
at the D3 receptor.
Pramipexole produced dose-dependent increases in yawning
atlowdosesandinhibitionofyawningandinductionofhypothermia
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Scheme 1. Synthesis of Compounds 12 and 13a
a Conditions and reagents: (i) 2-Naphthoyl chloride, trans-4-aminocyclohexanol, triethylamine, DCM. (ii) PCC, DCM, room temperature, 12 h.
(iii) Allylmagnesium bromide, THF, ꢀ78 ꢀC, 2 h. (iv) OsO4, NaIO4, THFꢀH2O, room temperature, 30 min. (v) Compound 22, NaBH(OAc)3,
CH3CO2H, DCM. (vi) Compound 23, NaBH(OAc)3, CH3CO2H, DCM.
Figure 3. Crystal structure of intermediate 20.
The in vivo profiles of activity for compound 17 and prami-
pexole were assessed by the antagonist interaction studies with
the known D3 antagonist SB-277011A9 and the D2 antagonist
L-741,62620 in both yawning and hypothermia assays. The
selective D3 antagonist SB-277011A effectively inhibited the
induction of yawning by both 0.1 and 0.32 mg/kg of pramipexole
and 1 and 10 mg/kg of 17 (Figure 4B,C). In comparison,
although the selective D2 antagonist L-741,626 failed to modulate
the yawning effect induced by the lower doses of pramipexole
and 17 (0.1 and 1.0 mg/kg, respectively), a significant increase in
the yawning effect was observed when L-741,626 was adminis-
tered prior to the higher doses of pramipexole and 17 (0.32 and
10.0 mg/kg, respectively; Figure 4B,C). These data further
confirm the agonist activity for pramipexole and compound 17
at the D3 receptor and suggest that D2 agonist effects may be
observed with high doses of pramipexole (∼1.0 mg/kg) and 17
(∼10.0 mg/kg). In the hypothermia assay, although the D2
antagonist L-741,626 significantly reversed the hypothermia
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Figure 4. Functional evaluations of the D3 and D2 activity of pramipexole and compounds 16 and 17 in yawning and hypothermia assays in rats. *,
P < 0.05; **, P < 0.005; and ***, P < 0.001.
effect induced by 0.32 mg/kg of pramipexole, it did not have a
significant effect on the modest hypothermia induced by 10 mg/kg
of compound 17 (Figure 4E). Of note, both pramipexole at
0.32 mg/kg and compound 17 at 10 mg/kg produced similar
modest decreases in core body temperature (approximately 0.75 ꢀC)
with pretreatment of L-741,626 at 1 mg/kg (Figure 4E). Taken
together, these in vivo data show that 17 functions as a potent,
highly selective, full efficacy agonist at the D3 receptor, with the
onset of modest D2 agonist activity observed at 10 mg/kg for
compound 17 and at 0.32 mg/kg for pramipexole. Pramipexole
was one of the most selective D3 agonists identified to date7 and
has been extensively used in in vitro and in vivo studies. The
profiles of activity obtained in the current studies have shown
that compound 17 functions as a full agonist at the D3 receptor
at a dose of 0.01 mg/kg but has minimal D2 activity at a dose of
10.0 mg/kg, displaying not only higher potency but also much
better selectivity than pramipexole.
To further assess the binding affinity, selectivity, and func-
tional activity of compound 17, we evaluated this compound in
the Addiction Treatment Discovery Programs of the National
Institute on Drug Abuse (NIDA) using cloned human dopamine
receptors (Supporting Information). Compound 17 binds to
human D3 receptor with a Ki value of 3.61 ( 0.53 nM and to
human D2 receptor with a Ki value of >4000 nM. Furthermore,
17 shows no detectable binding to human D1 receptor at 10000
nM. Functional testing using a mitogenesis functional assay
for the D3 receptor in CHO cells showed that 17 is a potent
and full agonist with an EC50 value of 1.70 ( 0.53 nM and
103.4% of maximum stimulation of quinpirole as the standard D3
agonist control. Therefore, compound 17 is also a highly potent
D3 full agonist in the functional assays using the cloned human
D3 receptor and displays a >1000-fold selectivity for D3 over D2
and D1 in the binding assays using cloned human dopamine
receptors.
In summary, through exploration of the linker region of our
previously reported D3 ligand 11, we have identified a number of
new D3 ligands with high binding affinities to the D3 receptor and
a selectivity of >1000 times over the D2 and D1 receptors based
upon our in vitro binding data. Compound 17 binds to D3 with a
Ki value of 0.50 nM and shows a selectivity of >5000 times over
D2 and >10000 over D1 in our binding assays using rat brain.
The high binding affinity and selectivity of 17 for the D3 receptor
were further confirmed using cells transfected with cloned
human dopamine receptors. Our in vivo functional evaluation
demonstrated that compound 17 is a highly potent and selective
D3 full agonist. While it is active at the D3 receptor at doses as
low as 0.01 mg/kg, it has a minimal activity at the D2 receptor in
the rat at doses as high as 10 mg/kg. Its full agonist profile at the
D3 receptor was also confirmed using cells transfected with
cloned human D3 receptor in the mitogenesis assay. To the best
of our knowledge, compound 17 is the most active and selective
D3 full agonist reported to date. Furthermore, compound 17 also
has good aqueous solubility. Taken together, our data show that
compound 17 (CJ-1639) is an excellent pharmacological tool with
which to elucidate the role of the D3 receptor in different neuro-
logical conditions in animal models. Extensive in vivo studies are in
progress to evaluate its therapeutic potential for the treatment of drug
abuse and other neurological conditions in which the D3 receptor
may play a role, and the results will be reported in due course.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details of chemical
b
synthesis, chemical data, X-ray crystallographic analysis, and in
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LETTER
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Corresponding Author
*Tel: 734-615-0362. Fax: 734-647-9647. E-mail: shaomeng@
umich.edu.
Funding Sources
This work was supported by a grant from the NIDA, NIH
(R01DA020669). Crystallographic studies were supported by a
grant from NIDA under contract Y1-DA-1101. We are grateful to
the Addiction Treatment Discovery Programs at the NIDA,
NIH, for evaluation of CJ-1639 for its binding affinities and
functional activity in cells transfected with cloned human dopamine
receptors under the contract NIDA Y1-DA-0101, performed by
Dr. Aaron Janowsky at the Oregon Health & Science University
(Portland, Oregon).
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