Design, synthesis and structure-activity relationship studies of hexahydropyrazinoquinolines as a novel class of potent and selective dopamine receptor 3 (D3) ligands

Article abstract of DOI:10.1016/j.bmcl.2005.01.037

A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D₃ ligand with a moderate binding affinity to the D₃ receptor (K_i = 304 nM) but no selectivity over the D ₁-like and D₂-

Full text of DOI:10.1016/j.bmcl.2005.01.037

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1701–1705
Design, synthesis and structure–activity relationship studies of
hexahydropyrazinoquinolines as a novel class of potent and
selective dopamine receptor 3 (D3) ligands
Min Ji,a Jianyong Chen,a Ke Ding,a Xihan Wu,a Judith Varady,a
Beth Levantb and Shaomeng Wanga,*
aDepartments of Internal Medicine and Medicinal Chemistry, University of Michigan, CCGC/3316,
1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA
bDepartment of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City,
KS 66160-7417, USA
Received 8 July 2004; revised 14 January 2005; accepted 18 January 2005
Abstract—A hexahydropyrazinoquinoline (compound 5c) was previously discovered as a novel D3 ligand with a moderate binding
affinity to the D3 receptor (Ki = 304 nM) but no selectivity over the D1-like and D2-like receptors. In this study, we wish to report the
design, synthesis and structure–activity relationship studies of a series of novel hexahydropyrazinoquinolines. Our efforts resulted in
new compounds with improved binding affinity and selectivity. Among them, compound 12d has a Ki value of 2.6 nM for its binding
affinity to the D3 receptor and has >2000- and 99-fold selectivity over the D1-like and D2-like receptors, respectively, representing a
potent and selective D3 ligand.
Ó 2005 Elsevier Ltd. All rights reserved.
The dopamine 3 (D3) subtype receptor has been impli-
cated in several neurological conditions and potent
and selective D3 ligands may have the therapeutic poten-
tial for the treatment of drug addiction, ParkinsonÕs dis-
ease and schizophrenia.1–5 Design and development of
highly potent and selective D3 ligands is currently a very
active research area.6–12
in vivo pharmacological properties. To this end, we have
employed a novel computational three-dimensional
(3D) database screening strategy to discover novel D3
ligands.14 Our efforts led to the identification of several
classes of new D3 ligands.14
Among those new D3 ligands we have discovered,14
compound 5c contains hexahydropyrazinoquinoline as
the basic core structure, which was not found in previ-
ously reported D3 ligands. Hence, compound 5c repre-
sents a promising initial lead compound with a novel
core structure for further design and optimization.7–13
Structurally, compound 5c may be viewed as a conform-
ationally constrained analogue of BP 897.
Although several classes of D3 ligands have been de-
signed and synthesized in the last decade, many of the
previously reported D3 ligands were based upon a very
limited number of basic core structures.7 Indeed, the
majority of those recently reported potent and selective
D3 ligands8–13 were based upon the core structure of BP
897.6 Hence, we believe that D3 ligands with novel
chemical core structures or scaffolds would have consid-
erable value to increase the chemical diversity in D3
ligand design and may lead to the development of potent
and highly selective D3 ligands with unique in vitro and
The initial lead compound 5c has a Ki value of 304 nM to
the D3 receptor and no selectivity over the D1-like and
D2-like receptors. Hence, its potency and selectivity need
to be significantly improved. In this paper, we wish to re-
port our design, synthesis and preliminary structure–
activity relationship studies for this class of D3 ligands.
Keywords: Dopamine receptor
Hexahydropyrazinoquinolines.
*
3
subtype; Novel ligands;
Based upon its chemical structure, compound 5c may be
divided into three regions, the tricyclic hexahydropyraz-
inoquinoline core structure as the ÔheadÕ, the phenyl ring
Corresponding author. Tel.: +1 734 615 0362; fax: +1 734 647
9647; e-mail: shaomeng@umich.edu
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.037

1702
M. Ji et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1701–1705
Head (core structure)
Linker
Tail
N
O
N
OCH3
O
N
N
N
H
F
5c (initial lead)
BP 897
as the ÔtailÕ and the linker between the ÔheadÕ and the
ÔtailÕ groups. Our current study provides initial struc-
ture–activity relationship with modifications made on
each of the three regions for this class of compounds
aiming at improving both its binding affinity to the D3
receptor and its selectivity over other closely related
dopamine receptor subtypes.
playing an excellent selectivity between the D2 and D3
receptor subtypes is likely to be highly selective over
other dopamine receptors. Hence, in this study, all the
new compounds were evaluated for their binding affini-
ties at the D1-like, D2-like and D3 receptors using previ-
ously established methods.15–17 Because the affinities of
compounds at the dopamine receptor subtypes have
been shown to vary depending on the in vitro assay con-
ditions used and the source of receptors (i.e., human or
rat and the expression system used),18 the assay condi-
tions were designed to favour agonist binding and used
receptors expressed in their native tissue, brain.
In view of the numerous dopamine receptors at which
binding affinity can be determined for these compounds,
we have designed our screening protocol to make the
most important comparison (i.e., D2-like/D3) as well as
comparison between the major subclasses of dopamine
receptors (i.e., D1-like/D2-like and D1-like/D3) in our
initial investigation. Because of the relatively low se-
quence homology between the D1 and D3 receptors,
many of the previously reported D3 ligands were shown
to have an excellent selectivity over the D1 receptor.7 In
contrast, the D2 and D3 receptors have close sequence
homology. Until very recently, most of the previously
reported D3 ligands also displayed good affinities to
the D2 receptor.7 Hence, a high-affinity D3 ligand dis-
First, compounds 5a–d were designed and synthesized to
determine the optimal length of the linker. As can be
seen from Table 1, compounds 5a and 5b with either a
1- or 2-carbon linker are 26- and 9-times less potent than
compound 5c with a 3-carbon linker. In comparison,
compound 5d with a 4-carbon linker has a similar bind-
ing affinity to the D3 receptor as compound 5c, indicat-
ing either a 3- or a 4-carbon linker is optimal for binding
to the D3 receptor.
Table 1. Binding affinities at the D1-like, D2-like and D3 receptors in binding assays using rat brain
Compounds
Ki SEM (nM)
Selectivity
D1-like [3H]SCH 23390
D2-like [3H]spiperone
D3 [3H]PD 128907
D1-like/D3
D2-like/D3
5a
5b
7947 597
8893 568
904 100
3887 664
3643 459
243 30
7487 591
2755 475
304 53
1.1
3.2
0.5
1.3
0.8
2.2
>4
5c
5d
3.0
6.5
2467 303
>100,000
356 47
852 49
381 59
22,967 6846
2523 692
9a
9b
>100,000
906 190
220 21
>4
0.1
0.34
10
9c
258 52
22
6
12
0.7
10a
10b
10c
12a
12b
12c
12d
BP 897
1218 145
152,567 17,284
791 187
1389 111
2443 403
1568 338
762 51
1650 424
1535 81
18 2.4
0.8
1
10
44
87
4602 287
>250,000
5.8 1.3
244 59
793
>1000
130
>2000
578
131
>1000
25
>250,000
1125 207
258 41
5802 422
6051 570
636 103
45
7
2.6 0.4
1.1 0.2
99
147
162 48
Data represent the mean SEM of three to five independent determinations. [3H]SCH 23390 binding assays for D1-like dopamine receptors were
performed as previously described in detail17 using membranes prepared from the caudate-putamen of adult male Sprague–Dawley rats (Harlan,
Indianapolis, IN). All compounds were dissolved in 100% EtOH at a concentration up to 5 mM. The assay buffer was 50 mM Tris–HCl, 5 mM KCl,
2 mM MgCl2 and 2 mM CaCl2, pH 7.4 at 23 °C; the concentration of [3H]SCH 23390 (73 Ci/mmol; Amersham) was 0.3 nM; and nonspecific binding
was determined in the presence of 1 lM (+)-butaclamol. SigmaPlot was used to determine Ki values using the KD value for [3H]SCH 23390 of
0.3 nM.17 [3H]spiperone binding assays for D2-like dopamine receptors were performed as previously described in detail and as described for
[3H]SCH 23390 except the concentration of [3H]spiperone (24 Ci/mmol; Amersham) was 0.2 nM.15,17 Ki values were determined using the KD value
for [3H]spiperone of 0.1 M.15 [3H]PD 128907 binding assays D3-like dopamine receptors were performed as previously described in detail16,17 using
ventral striatal (nucleus accumbens and olfactory tubercles) membranes prepared in assay buffer (50 mM Tris, 1 mM EDTA; pH 7.4 at 23 °C). The
concentration of [3H]PD 128907 was 0.3 nM (116 Ci/mmol; Amersham, Arlington Heights, IL) and nonspecific binding was defined by 1 lM
spiperone. Ki values were determined using the KD value for [3H]PD 128907 of 0.3 nM.16

M. Ji et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1701–1705
1703
Compounds 9a–c were designed to investigate if a much
longer biphenyl can be used to replace the 4-flurophenyl
ring in compound 5c as the tail. Consistent with the data
obtained for compound 5b, compound 9a with a 2-car-
bon linker only has a weak affinity (Ki = 23 lM) to the
D3 receptor. In contrast to 5c and 5d, compounds 9b
and 9c with a 3-carbon and 4-carbon linker, have very
different affinities to the D3 receptor. While compound
9b has a relatively weak binding affinity (Ki = 2.5 lM)
to the D3 receptor, compound 9c is a potent D3 ligand
(Ki = 22 nM). Interestingly, compound 9b has higher
affinities at the D1-like and D2-like receptors than at
the D3 receptor. In contrast, compound 9c has a higher
affinity at the D3 receptor than at the D1-like and D2-
like receptors, thus displaying a selectivity of 12- and
10-fold.
pound 12b with the 8-methoxyl substituent on the phen-
yl ring has a Ki value of 244 nM at the D3 receptor, 13-
time less potent than 10c. However, compound 12b was
found to be completely inactive at the D1-like and D2-
like receptors at the highest concentration tested
(250 lM). Hence, 12b is a moderately potent D3 ligand
but has an excellent selectivity over the D1-like and
D2-like receptors. Compound 12c with the 9-methoxyl
substituent on the phenyl ring has a Ki value of 45 nM
at the D3 receptor, 130-fold selectivity over the D1-like
receptors and 25-fold selectivity over the D2-like recep-
tors. Thus, 9-methoxyl substituent on the phenyl ring
has a marginal influence on both the binding affinity
and selectivity. Compound 12d with the 10-methoxyl
substituent on the phenyl ring has a Ki value of
2.6 nM at the D3 receptor, >2000-fold selectivity over
the D1-like receptors and 99-fold selectivity over the
D2-like receptors. Hence, 10-methoxyl substituent on
the phenyl ring of 10c improves the binding affinity by
seven times at the D3 receptor and selectivity more than
45-fold between the D3-like receptor and the D2-like
receptors. Compound 12d is a potent D3 ligand with
an excellent selectivity over the D1-like receptors and a
good selectivity over the D2-like receptors.
Previously, it was shown that a naphthyl ring can be
used as the tail in D3 ligands to improve binding affinity
and/or selectivity. Accordingly, compounds 10a–c were
designed and synthesized. Consistent with the data ob-
tained for compounds 9a and 9b, compounds 10a and
10b with either a 2- or 3-carbon linker only has a weak
affinity to the D3 receptor. Similar to 9c, compound 10c
with
a 4-carbon linker is a potent D3 ligand
(Ki = 18 nM). But 10c is more selective than 9c and
has a selectivity of 44- and 87-fold over the D1-like
and D2-like receptors. These data indicate that a bulky
naphthyl tail and a 4-carbon linker afford compound
(10c) with a potent binding affinity to the D3 receptor
(Ki = 18 nM) and a good selectivity over both the D1-
like and the D2-like receptors.
To directly compare 12a and 12d with other known D3
ligands, we have evaluated BP 897, a known selective
D3 ligand,6 in our assay conditions and the results are
provided in Table 1. As can be seen, BP 897 has Ki val-
ues of 1.1 nM at the D3 receptor, 162 nM at the D2-like
receptors, and 636 nM at the D1-like receptors, respec-
tively. These values are in good agreement with the re-
ported Ki values of 0.92 nM at the D3 receptor, 61 nM
at the D2 receptor and 3 lM at the D1 receptor, respec-
tively, using the CHO cells expressing recombinant hu-
man D1, D2 and D3 receptors.6 Of note, although it is
known that assay conditions can have a significant influ-
ence on the binding affinity of a ligand at the D3 recep-
tor and the selectivity over other dopamine subtype
receptors,18 our results on BP 897 indicate that our as-
says using membranes prepared from rat brains and as-
says using CHO cells expressing recombinant human
D1, D2 and D3 appear to produce quite consistent re-
sults in both binding affinity and selectivity. Based upon
our data, compound 12d and BP 897 have similar bind-
ing affinities at the D3 receptor (2.6 vs 1.1 nM for their
Ki values). Compound 12d has a better selectivity than
BP 897 over the D1-like receptors (>2000-fold vs 578-
fold) and has a slightly worse selectivity than BP 897
(99- vs 147-fold). Taken together, our data indicate that
compound 12d represents a promising new lead com-
pound for further optimization towards our goal of
obtaining highly potent D3 ligands with outstanding
selectivity over the D1-like and D2-like receptors.
Finally, based upon the potent binding affinity activity
of BP 897 to the D3 receptor and its good selectivity over
the D1 and D2 receptors, it appears that a methoxyl sub-
stituent on the phenyl ring in the hexahydropyrazino-
quinoline core structure may further improve the
binding and/or selectivity of compound 10c. This idea
is supported by our modeling studies on 10c (data not
shown), which suggests that a methoxyl substituent on
the phenyl ring may form hydrogen bonding interaction
with one of the three serine residues, namely Ser192,
Ser193 and Ser196 in the D3 receptor. To explore the
influence of a methoxyl substituent on binding affinity
and selectivity, compounds 12a–d were synthesized and
tested.
Compound 12a with the 7-methoxyl substituent on the
phenyl ring has a Ki value of 5.8 nM at the D3 receptor,
793-fold selectivity over the D1-like receptors and 131-
fold selectivity over the D2-like receptors. The 7-meth-
oxyl substituent on the phenyl ring improves the binding
affinity by three-fold at the D3 receptor as compared to
10c. Furthermore, the 7-methoxyl substituent improves
the selectivity by 18 times between the D3 receptor and
the D1-like receptors as compared to 10c. This improved
selectivity over the D1-like receptors is the combination
of an increased binding affinity at the D3 receptor and a
decreased binding affinity at the D1-like receptors. The
selectivity of 12a between the D3 receptor and the D2-
like receptors is only improved marginally by 1.5-fold
as compared to that of 10c (131-fold vs 87-fold). Com-
The synthetic route for compounds 5a–d is outlined in
Scheme 1. The key intermediate 4 was synthesized using
known methods with some modifications.19–21 Briefly,
condensation of 2-quinoline-carboxaldehyde 1 with
ethanolamine generated the SchiffÕs base, which was
reduced to 2-substituted aminomethylquinoline 2 with
NaBH4.19,20 Reduction of 2 with nickel–aluminium
alloy in aqueous KOH readily produced 2-substituted

1704
M. Ji et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1701–1705
i
ii
H
N
H
N
R
R
R
N
CHO
N
OH
N
H
OH
1a: R=H;
2a: R=H;
3a: R=H;
1b: R=5-OCH3;
1c: R=6-OCH3;
1d: R=7-OCH3;
1e: R=8-OCH3;
2b: R=5-OCH3;
2c: R=6-OCH3;
2d: R=7-OCH3;
2e: R=8-OCH3;
3b: R=5-OCH3;
3c: R=6-OCH3;
3d: R=7-OCH3;
3e: R=8-OCH3;
iii
iv
R
R
N
O
N
N
NH
(CH2)n
4a: R=H;
4b: R=7-OCH3;
4c: R=8-OCH3;
4d: R=9-OCH3;
4e: R=10-OCH3;
5a: R=H, n= 1;
5b: R=H, n= 2;
5c: R=H, n= 3;
5d: R=H, n= 4;
F
Scheme 1. Synthesis of important intermediates 4a–e and compounds 5a–d. Reagents and conditions: (i) a. 1.1 equiv ethanolamine, benzene, under
N2, reflux, overnight; b. 3.5 equiv NaBH4, absolute ethanol, under N2, reflux, overnight; (ii) ca. 5 g nickel–aluminium alloy/1 g substrate, 1 M KOH,
methanol, rt, overnight; (iii) 3 equiv P2O5, xylenes, under N2, reflux, overnight; (iv) 1.2 equiv p-FC6H4CO(CH2)n(n=1,2,3,4)–I, 2 equiv Cs2CO3,
CH3CN, under N2, reflux, overnight.
aminomethyl-1,2,3,4-tetrahydro-quinoline 3 in good
yield.19 The key intermediate 4 was prepared by reflux
of 3 with P2O5 in xylenes.19,20 Alkylation of 4 with dif-
ferent alkyl iodides in the presence of Cs2CO3 in aceto-
nitrile afforded compounds 5a–d.20
The synthetic route for compounds 12a–d is shown in
Scheme 3. Briefly, compounds 11a–d were obtained by
treatment of the important intermediates 4b–e obtained
in Scheme 1 with N-(4-bromobutyl)-phthalimide in
CH3CN followed by hydrazine. Acylation with 2-naph-
thoyl chloride in the presence of N,N-diisopropylethyl-
amine afforded the target compounds 12a–d in good
yield (>90%).
The synthetic route for compounds 9a–c and 10a–c is
provided in Scheme 2. Briefly, phthalimido-protected
1-bromoalkylamines 6a–c were reacted with 4 to pro-
duce 7a–c. Deprotection of 7a–c with hydrazine generated
amines 8a–c. Amidation of 8a–c using 4-biphenyl-
carbonyl chloride or 2-naphthoyl chloride afforded
compounds 9a–c and 10a–c, respectively.21
In summary, compound 5c was previously identified as a
novel D3 ligand with a moderate binding affinity to the
D3 receptor (Ki value = 304 nM) but no selectivity over
the D1-like and D2-like receptors. Our present study
O
O
+
Br
N
N
i
( )n
N
N
N
( )n
O
NH
7a n=2
7b n=3
7c n=4
6a n=2
6b n=3
6c n=4
O
4a
N
N
H
N
N
( )n
iii
ii
N
9a n=2
9b n=3
9c n=4
O
NH2
( )n
N
iv
8a n=2
8b n=3
8c n=4
H
N
N
( )n
O
10a n=2
10b n=3
10c n=4
Scheme 2. Synthesis of compounds 9a–c and 10a–c. Reagents and conditions: (i) 1.2 equiv phthalimido-1-bromoalkylamines (6a–c), 2 equiv Cs2CO3,
CH3CN, under N2, reflux, overnight, yield 75–88%; (ii) 2 equiv hydrazine, EtOH, reflux, 2 h, yield 82–87%; (iii) 1.2 equiv 4-biphenylcarbonyl
chloride, 3 equiv triethylamine, 0 °C, 4 h, yield 31–48%; (iv) 1.2 equiv 2-naphthoyl chloride, 3 equiv triethylamine, 0 °C, 4 h, yield 83–87%.

M. Ji et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1701–1705
1705
iii
i,ii
R
R
R
N
N
N
O
NH
N
N
NH2
N
H
4b: R=7-OCH3;
4c: R=8-OCH3;
4d: R=9-OCH3;
4e: R=10-OCH3;
12a: R=7-OCH3;
12b: R=8-OCH3;
12c: R=9-OCH3;
12d: R=10-OCH3;
11a: R=7-OCH3;
11b: R=8-OCH3;
11c: R=9-OCH3;
11d: R=10-OCH3;
Scheme 3. Synthesis of compounds 12a–d. Reagents and conditions: (i) N-(4-bromobutyl)-phthalimide, Cs2CO3, CH3CN, reflux, 3 h; (ii) NH2NH2,
EtOH, reflux, 2 h; (iii) 2-naphthoyl chloride, N,N-diisopropylethylamine, CH2Cl2, rt, 2 h.
8. Robarge, M. J.; Husbands, S. M.; Kieltyka, A.; Brodbeck,
R.; Thurkauf, A.; Newman, A. H. J. Med. Chem. 2001, 44,
3175–3186.
9. Bettinetti, L.; Schlotter, K.; Hubner, H.; Gmeiner, P. J.
Med. Chem. 2002, 45, 4594–4597.
10. Hackling, A.; Ghosh, R.; Perachon, S.; Mann, A.; Holtje,
H.-D.; Wermuth, C. G.; Schwartz, J.-C.; Sippl, W.;
Sokoloff, P.; Stark, H. J. Med. Chem. 2003, 46, 3883–3899.
11. Leopoldo, M.; Berardi, F.; Colabufo, N. A.; De Giorgio,
P.; Lacivita, E.; Perrone, R.; Tortorella, V. J. Med. Chem.
2002, 45, 5727–5735.
12. Campiani, G.; Butini, S.; Trotta, F.; Fattorusso, C.;
Catalanotti, B.; Aiello, F.; Gemma, S.; Nacci, V.; Novel-
lino, E.; Stark, J. A.; Cagnotto, A.; Fumagalli, E.;
Carnovali, F.; Cervo, L.; Mennini, T. J. Med. Chem.
2003, 46, 3822–3839.
13. Campiani, G.; Butini, S.; Fattorusso, C.; Catalanotti, B.;
Gemma, S.; Nacci, V.; Morelli, E.; Cagnotto, A.; Mere-
ghetti, I.; Mennini, T.; Carli, M.; Minetti, P.; Di Cesare,
M. A.; Mastroianni, D.; Scafetta, N.; Galletti, B.; Stasi,
M. A.; Castorina, M.; Pacifici, L.; Vertechy, M.; Serio, S.
D.; Ghirardi, O.; Tinti, O.; Carminati, P. J. Med. Chem.
2004, 47, 143–157.
shows that the 4-flurophenylkentone group can be suc-
cessfully replaced by other hydrophobic groups and
the optimal length of the ÔlinkerÕ between the ÔheadÕ
and the ÔtailÕ is 4-carbon. Furthermore, introduction of
a methoxyl group to the phenyl ring in the hexahydropy-
razinoquinoline core structure can significantly improve
the binding affinity and/or selectivity. Our preliminary
SAR study has thus led to potent and selective D3 li-
gands. Of which, compound 12d is a potent D3 ligand
(Ki = 2.6 nM) and displays an excellent selectivity of
>2000-fold between the D3 receptor and the D1-like
receptors and a good selectivity of 99-fold between the
D3 receptor and the D2-like receptors. Based upon com-
pound 12d, extensive modifications are being performed
towards achieving novel D3 ligands with high binding
affinity and outstanding binding selectivity and the
results will be reported in due course.
References and notes
14. Varady, J.; Wu, X.; Fang, X.; Ji, M.; Hu, Z.; Levant, B.;
Wang, S. J. Med. Chem. 2003, 46, 4377–4392.
15. Levant, B.; Grigoriadis, D. E. J. Pharmacol. Exp. Ther.
1992, 262, 929–935.
16. Bancroft, G. N.; Morgan, K. S.; Flietstra, R. J.; Levant, B.
Neuropsychopharmacology 1998, 18, 305–316.
17. Levant, B. Characterization of dopamine receptors. In
Current protocols in pharmacology; Ferkany, J., Enna, S.
J., Eds.; John Wiley & Sons: New York, 1998; pp 1.6.
1–1.6.16.
1. Joyce, J. N. Pharmacol. Ther. 2001, 90, 231–259.
2. Luedtkea, R. R.; Mach, R. H. Curr. Pharm. Des. 2003, 9,
643–671.
3. Prasad, S.; Semwal, P.; Deshpande, S.; Bhatia, T.;
Nimgaonkar, V. L.; Thelma, B. K. J. Biosci. 2002, 27
(1. Suppl 1), 35–52.
4. Crocg, M. A.; Mant, R.; Asherson, P.; Williams, J.; Hode,
Y.; Shimohama, S.; Sawada, H.; Kitamura, Y.; Taniguchi,
T. Trends Mol. Med. 2003, 9, 360–365.
5. Volkow, N. D.; Fowler, J. S.; Wang, G. J. Behav.
Pharmacol. 2002, 13, 355–366.
18. Levant, B. Pharmacol. Rev. 1997, 49, 231–252.
19. Rabjohn, N. Org. React. 1976, 24, 261–415.
20. Vliet, L. A.; Rodenhuis, N.; Djikstra, D.; Wikstrom, H. J.
Med. Chem. 2000, 43, 2871–2882.
6. Pilla, M.; Perachon, S.; Sautel, F.; Garrido, F.; Mann, A.;
Wermuth, C. G.; Schwartz, J. C.; Everitt, B. J.; Sokoloff,
P. Nature 1999, 400, 371.
21. Robarge, J. M.; Husbands, M. S.; Kieltyka, A.; Brodbeck,
R.; Thurkauf, A.; Newman, H. A. J. Med. Chem. 2001, 44,
3175–3186.
7. For a recent review on novel D3 ligands, please see:
Hackling, A. E.; Stark, H. ChemBioChem 2002, 3, 946–
961.