Structure-based design leads to the identification of lithium mimetics that block mania-like effects in rodents. Possible new GSK-3β therapies for bipolar disorders

Article abstract of DOI:10.1021/ja068969w

More than two million American adults, or approximately one percent of the population 18 years or older, suffer from bipolar disorder. Current treatments include the so-called "mood stabilizers," lithium and valproic acid. Both are relatively dated drugs that are only partially effective and produce various undesirable side effects including weight gain. Based upon continued efforts to understand the molecular target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3β (GSK-3β) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore, the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent and relatively selective GSK-3β inhibitors. The best ligand in this series (having a K_i value of 4.6 nM against GSK-3β) was studied in a novel mouse model of mania that has recently been validated with several clinically effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3β inhibitor in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become valuable research tools in better defining the role of this multifaceted kinase in both physiological and pathophysiological events.

Full text of DOI:10.1021/ja068969w

Published on Web 06/07/2007
Structure-Based Design Leads to the Identification of Lithium
Mimetics That Block Mania-like Effects in Rodents. Possible
New GSK-3â Therapies for Bipolar Disorders
Alan P. Kozikowski,*,† Irina N. Gaisina,† Hongbin Yuan,† Pavel A. Petukhov,†
Sylvie Y. Blond,† Allison Fedolak,‡ Barbara Caldarone,‡ and Paul McGonigle‡
Contribution from the Drug DiscoVery Program, Department of Medicinal Chemistry and
Pharmacognosy, College of Pharmacy, UniVersity of Illinois at Chicago, 833 South Wood Street,
Chicago, Illinois 60612, and PsychoGenics Inc., 765 Old Saw Mill RiVer Road,
Tarrytown, New York 10591
Received December 14, 2006; E-mail: kozikowa@uic.edu
Abstract: More than two million American adults, or approximately one percent of the population 18 years
or older, suffer from bipolar disorder. Current treatments include the so-called “mood stabilizers,” lithium
and valproic acid. Both are relatively dated drugs that are only partially effective and produce various
undesirable side effects including weight gain. Based upon continued efforts to understand the molecular
target for lithium, it now appears that specific inhibitors of the enzyme glycogen synthase kinase-3â (GSK-
3â) may mimic the therapeutic action of mood stabilizers and might therefore allow for the design of improved
drugs for treating patients with bipolar disorder as well as certain neurodegenerative disorders. Furthermore,
the pro-apoptotic properties of the GSK-3 enzyme suggest the possible use of such inhibitors as
neuroprotective agents. In fact, neuroprotection may contribute to the treatment of mood disorders. The
present chemistry, modeling, and biology efforts have identified 3-benzofuranyl-4-indolylmaleimides as potent
and relatively selective GSK-3â inhibitors. The best ligand in this series (having a Ki value of 4.6 nM against
GSK-3â) was studied in a novel mouse model of mania that has recently been validated with several clinically
effective mood stabilizers. This study presents the first demonstration of the efficacy of a GSK-3â inhibitor
in this mouse model of mania. Selective brain penetrable GSK-3 ligands like those described herein become
valuable research tools in better defining the role of this multifaceted kinase in both physiological and
pathophysiological events.
Introduction
in the pathobiology of mood disorders has recently been
summarized.6 The stimulatory action of GSK-3 inhibition on
On the basis of continued efforts to understand the molecular
target for lithium, it now appears that specific inhibitors of the
enzyme glycogen synthase kinase-3â (GSK-3â) may mimic the
therapeutic action of mood stabilizers and might therefore allow
for the design of improved drugs for treating patients with
bipolar disorder as well as certain neurodegenerative disorders.
GSK-3 is a serine/threonine protein kinase, which was initially
described as a key enzyme involved in glycogen metabolism1,2
but is now known to regulate a diverse array of cell functions.3
GSK-3 phosphorylates and thereby regulates the function of
many metabolic, signaling, and structural proteins.4 GSK-3 also
regulates cell survival, as it facilitates a variety of apoptotic
mechanisms.5 There are two highly homologous forms of GSK-3
in mammals, GSK-3R and GSK-3â.
â-catenin protein levels in the hippocampus is currently believed
to be at the center of the putative therapeutic action of treatments
aimed at moderating mood disorders.7,8 Furthermore, GSK-3â
regulates axon growth and synaptic remodeling under the control
of mood stabilizing drugs.9 In addition, in cultured cells, GSK-
3â modulates brain-derived neurotrophic factor signaling.10
Taken together, these studies have led to speculation on the
role of the GSK-3-related Wnt signaling pathway in mood
disorders.11 Dysfunction of the Wnt pathway has also been
implicated in the pathophysiology of Alzheimer’s disease and
schizophrenia.
Hyperactive GSK-3 may be an early contributory factor in
apoptosis and neuronal death. Since GSK-3 inhibition exerts a
dramatic neuroprotective action, it has been proposed that the
The line of evidence leading to the proposal that GSK-3 plays
(6) Jope, R. S.; Bijur, G. N. Mol. Psychiatry 2002, 7, 35.
(7) Gould, T. D.; Chen, G.; Manji, H. K. Neuropsychopharmacology 2004,
29, 32.
an important role in the action of mood stabilizers and possibly
† University of Illinois at Chicago.
(8) Madsen, T. M.; Newton, S. S.; Eaton, M. E.; Russell, D. S.; Duman, R. S.
Biol. Psychiatry 2003, 54, 1006.
‡ PsychoGenics Inc.
(1) Woodgett, J. R. EMBO J. 1990, 9, 2431.
(9) Hall, A. C.; Brennan, A.; Goold, R. G.; Cleverley, K.; Lucas, F. R.; Gordon-
Weeks, P. R.; Salinas, P. C. Mol. Cell Neurosci. 2002, 20, 257.
(10) Mai, J.; Sameni, M.; Mikkelsen, T.; Sloane, B. F. Biol. Chem. 2002, 383,
1407.
(2) Welsh, G. I.; Proud, C. G. Biochem. J. 1993, 294, 625.
(3) Cohen, P.; Frame, S. Nat. ReV. Mol. Cell. Biol. 2001, 2, 769.
(4) Dominguez, I.; Green, J. B. DeV. Biol. 2001, 235, 303.
(5) Kim, L.; Kimmel, A. R. Curr. Opin. Genet. DeV. 2000, 10, 508.
(11) Gould, T. D.; Manji, H. K. Neuroscientist 2002, 8, 497.
9
8328
J. AM. CHEM. SOC. 2007, 129, 8328-8332
10.1021/ja068969w CCC: $37.00 © 2007 American Chemical Society

Lithium Mimetics That Block Mania-like Effects
A R T I C L E S
Figure 1. Binding of 3-(benzofuran-3-yl)-4-(indol-3-yl)maleimides to GSK-3â as determined from docking studies: (a) compound 2b docked to the ATP-
binding site of GSK-3â; (b) another rendering of 2b in complex with GSK-3â in which the protein surface inside the binding site is colored by lipophilic
potential (blue ) hydrophilic, brown ) lipophilic).
positive action of mood stabilizers on cell survival and adult
neurogenesis may underlie the therapeutic behavioral effects
of these drugs. The small molecule GSK-3 inhibitor AR-
A014418 has been shown to protect N2A neuroblastoma cells
against cell death mediated by inhibition of the PI3K/PKB
survival pathway.12 Moreover, a robust body of data suggested
a role for GSK-3â in the mechanism of action of lithium, by
showing that lithium noncompetitively inhibits the phosphory-
lation activity of GSK-3â, thus regulating neuronal plasticity
through an axonal remodeling and an increasing of synaptic
proteins levels. The inhibition of GSK-3â may thus provide the
mechanism by which lithium lengthens and stabilizes the period
of biological rhythms, an effect which has been linked to its
therapeutic efficacy and to its specific action on illness periodic-
ity in mood disorders.13 These ideas have led in turn to variants
of GSK-3â and other components of the molecular clock being
considered as possible endophenotypes for bipolar disorder.14
Klein has recently shown that lithium is able to modulate certain
behaviors in mice in a fashion that is paralleled by mice lacking
one copy of GSK-3â.15 Moreover, the molecular changes linked
to the inhibition of GSK-3 are observed in vivo in both the
lithium-treated and GSK-3â( mice. These data provide further
genetic support for the hypothesis that lithium affects mouse
behaviors through direct inhibition of GSK-3â. In summation,
there is a reasonable body of information to support the action
of lithium in bipolar disorder as working through the inhibition
of GSK-3â. Moreover, in light of the accumulating data showing
that substantive neuroprotective effects can be achieved through
the inhibition of GSK-3, it is likely that properly designed
inhibitors will find use not only in the treatment of bipolar
disorders, but also neurodegenerative diseases including Alzhe-
imer’s disease, Huntington’s disease, Parkinson’s disease,
schizophrenia, and even stroke.
academic researchers. These compounds are largely ATP
competitive inhibitors whose kinase activity has been determined
in vitro; in many cases their true kinase selectivity profiles and
their in vivo action remain to be established. As there have been
no significant new therapies for treating bipolar disorders in
decades, the design of efficacious GSK-3 inhibitors offers
promise in fulfilling this unmet medical need.
Results and Discussion
Identification of 3-(Benzofuran-3-yl)-4-(indol-3-yl)-
maleimides as Potent GSK-3â Inhibitors: Docking Studies.
To date, we have identified some 3-indolyl-4-indazolylmale-
imides (1), high potency GSK-3â inhibitors that emerged from
our SAR studies of staurosporine (Scheme 1).16 In continuation
of this work, we found that certain benzofuranyl bearing
maleimides such as 2a (a 200 nM PKC inhibitor)17 show very
good inhibitory activity toward GSK-3. As benzofurans are more
lipophilic than their indazole counterparts, we believed that these
relatively unexplored molecules might well serve as better drug
development candidates for reasons of blood-brain barrier
penetrability. As an aside we note that the related indazoles
failed to show any behavioral effects in animal studies. It was
our plan to optimize the selectivity of this series by using two
approaches: (1) design compounds that would fit “sterically”
into the catalytic site of GSK-3 and not into other homologous
kinases using the 3D structural features that are unique to GSK-
3; and (2) design compounds that are able to bind to amino
acids residues that are unique (so-called “selectivity residues”)
for the ATP binding site of GSK-3 and the areas surrounding
it compared to that of other homologous kinases. The closest
human homologues of GSK-3â and their alignments were
identified using the BLAST search in ExPASy database and
these are shown in the Supporting Information. The presence
of the phenylalanine (Phe80 in CDK2 corresponds to Leu132
in GSK-3â) residue found in CDK2 as well as CDK3, 7, MAK,
and the ICK kinases makes the binding site of these kinases
slightly smaller and “hilly” and restricts the entrance of bulkier,
more demanding ligands into the catalytic site.12 From our
A number of synthetic GSK-3 inhibitors are now currently
available,3 but many of these have not been fully characterized
in a battery of biological tests nor are they readily available to
(12) Bhat, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormo, M.; Nilsson, Y.; Radesater,
A. C.; Jerning, E.; Markgren, P. O.; Borgegard, T.; Nylof, M.; Gimenez-
Cassina, A.; Hernandez, F.; Lucas, J. J.; Diaz-Nido, J.; Avila, J. J. Biol.
Chem. 2003, 278, 45937.
(13) Klemfuss, H. Pharmacol. Ther. 1992, 56, 53.
(16) Kozikowski, A. P.; Gaisina, I. N.; Petukhov, P. A.; Sridhar, J.; King, L.
T.; Blond, S. Y.; Duka, T.; Rusnak, M.; Sidhu, A. ChemMedChem 2006,
1, 256.
(17) Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst,
S. A.; Keech, E.; Turner, S. E. J. Med. Chem. 1992, 35, 177.
(14) Lenox, R. H.; Gould, T. D.; Manji, H. K. Am. J. Med. Genet. 2002, 114,
391.
(15) O’Brien, W. T.; Harper, A. D.; Jove, F.; Woodgett, J. R.; Maretto, S.;
Piccolo, S.; Klein, P. S. J. Neurosci. 2004, 24, 6791.
9
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A R T I C L E S
Kozikowski et al.
Scheme 1. Synthesis of 3-(Benzofuran-3-yl)-4-(indol-3-yl)maleimides
modeling studies (Figure 1), a lipophilic pocket in GSK-3 exists
in the vicinity of the 5-position of the indole ring system (made
up of the lipophilic portions of Leu130, Leu132, Va110, Met101,
Phe201, and Cys199), one that can be nicely filled by a halogen,
an acetylenic unit, a methoxy group, or a small ring, like
cyclopropyl. Additionally, Tyr-134 in GSK-3 appears to offer
the opportunity for locating H-bond acceptor groups within the
locus of the 5-position of the heterocyclic ring. In contrast, this
site in CDK2 is occupied by Phe82, lacking an OH group. Thus,
again this residue may serve as a useful selectivity determi-
nant.18,19 A library of compounds was designed following
recommendations for lead-likeness,20 oral bioavailability,21 and
Lipinski’s “rule of five”.22,23 Solubility and cell-permeability
properties of potential inhibitors were verified using molecular
spreadsheet capabilities, ClogP, and the Volsurf24 modules in
Sybyl.25
Synthesis and Screening of 3-(Benzofuran-3-yl)-4-(indol-
3-yl)maleimides. Novel 3-(benzofuran-3-yl)-4-(indol-3-yl)ma-
leimides were readily prepared by condensation26 of 3-indolylg-
lyoxylic acid esters and the appropriately substituted benzofuranyl-
3-acetamides (Scheme 1). N-Alkylation of indoles 3 with various
alkyl halides in the presence of sodium hydride followed by
acylation of the resulting indoles 4 with oxalyl chloride and
then ester formation afforded the precursors 5. The required
reaction partners, benzofuranyl-3-acetamides 10, were prepared
starting from the appropriately substituted anisoles 6.27 An
acylation of 6 catalyzed by AlCl3, followed by cyclization of
aryl ketones 7 in methanolic solution of sodium acetate at
elevated temperature yielded 3-benzofuranones 8. Wittig reac-
tion of 8 with (carboxymethylene)triphenylphosphorane afforded
ethyl (1-benzofuran-3-yl)acetates, which were subsequently
converted into the corresponding acetamides 10. All new
compounds were screened for their potency to inhibit GSK-3â.
As presented in Table 1, the Ki values vary from moderate (1100
nM) to excellent (4.6 nM). Among the variety of compounds
we have synthesized and tested to date, the presence of a halogen
atom or an acetylenic group in position 5 and a hydroxy group
in position 6 of the indole ring turned out to be the best, which
supports our strategy for structural modification of the lead
scaffold. Compounds 2b,c and the indazole-based compound 1
(Scheme 1) were tested against a panel of 22 kinases, and these
results are shown in the Supporting Information. The lead
compound 2b shows a very significant improvement in selectiv-
ity against all the off-target kinases as compared to the
structurally related indazole.
Behavior Results. Amphetamine/Chlorodiazepoxide-
Induced Hyperactivity. While the in vitro data are compelling,
the most important measure of success must derive from the
animal studies. Animal models for bipolar disorder/mania are
scarce and hyperactivity models are often used to mimic the
mania associated with bipolar disorder. It was found that a
combination of the anxiolytic chlorodiazepoxide (CDP) and the
psychostimulant amphetamine (Amph) produces an increase in
locomotor activity that is greater than the increase produced by
amphetamine alone, and this hyperactivity can be blocked by
theputativemood-stabilizerslithium,valproate,andlamotrigine.28-31
Our best benzofuran-based ligand 2b was studied in a novel
(18) Shen, M.; Beguin, C.; Golbraikh, A.; Stables, J. P.; Kohn, H.; Tropsha, A.
J. Med. Chem. 2004, 47, 2356.
(19) Zhang, K. Y.; Card, G. L.; Suzuki, Y.; Artis, D. R.; Fong, D.; Gillette, S.;
Hsieh, D.; Neiman, J.; West, B. L.; Zhang, C.; Milburn, M. V.; Kim, S.
H.; Schlessinger, J.; Bollag, G. Mol. Cell 2004, 15, 279.
(20) Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D. J. Chem. Inf.
Comput. Sci. 2001, 41, 1308.
(21) Martin, Y. C. J. Med. Chem. 2005, 48, 3164.
(22) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. AdV. Drug
DeliVery ReV. 1997, 23, 3.
(23) Lipinski, C. A. J. Pharmacol. Toxicol. Methods 2000, 44, 235.
(24) Cruciani, C.; Crivori, P.; Carrupt, P. A.; Testa, B. J. Mol. Struct. 2000,
503, 17.
(25) SYBYL, version 7.0; Tripos Inc.: St. Louis, 2004.
(26) Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. Tetrahedron Lett. 1999,
40, 1109.
(27) Deshpande, A. R.; Paradkar, M. V. Indian J. Chem., Sect. B: Org. Chem.
Incl. Med. Chem. 1992, 31, 526.
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Lithium Mimetics That Block Mania-like Effects
A R T I C L E S
Table 1. GSK-3â Inhibition by Substituted
3-(Benzofuran-3-yl)-4-(indol-3-yl)maleimidesa
IC50
Ki
compd
X
Y
R
(nM)
(nM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
H
H
H
5-F
H
CH3
CH3
CH3
CH3
CH3
H
35.0 ( 9.0
7.0 ( 3.0
15.0 ( 3.0
14.0 ( 3.0
9.6 ( 4.0
670.0 ( 40.0
550.0 ( 20.0
180.0 ( 15.0
360.0 ( 40.0
26.0 ( 6.0
42.0 ( 8.0
125.0 ( 35.0
23
5-Br
6-OH
6-OH
5-CtCH
H
H
H
5-F
5-F
4.6
10
9.3
6.4
446
366
120
240
17
5-F
5-Br
7-OCH3 CH3
H
H
5-F
H
H
H
H
H
5-F
H
H
CH3
H
2j
2k
2l
CH3
CH3
CH3
H
5-Cl
5-OCH3
28
83
2m 5-OBn
1650.0 ( 200.0 1100
500.0 ( 60.0
2n
2o
2p
2q
2r
2s
5-OBn
5-OBn
6-OBn
6-OBn
7-OBn
5-cyclo-propane
5-OH
CH3
333
146
600
107
146
156
(CH2)3OH 220.0 ( 30.0
CH3
CH3
CH3
CH3
CH3
CH3
900.0 ( 80.0
160.0 ( 35.0
220.0 ( 45.0
235.0 ( 15.0
690.0 ( 100.0 460
55.0 ( 8.0 36
2t
2u
H
H
7-OH
a The concentration of the inhibitor producing a 50% inhibition of the
enzyme (IC50) was determined experimentally and used to calculate the
apparent equilibrium dissociation constant Ki, by using the Chen-Prusoff
equation shown here in its simplified form: Ki ) IC50/(1 + (S/Km)), where
S is the substrate (ATP) concentration used in the assays (10 µM) and Km
is the Michaelis constant of the substrate for the enzyme (20 µM for ATP).
mouse model of mania that has recently been validated with
several clinically effective mood stabilizers.31,32 In this study,
male C57BL/6J mice were pretreated with compound 2b (50
mg/kg) for 5 min and then injected with amphetamine or a
mixture of amphetamine and chlordiazepoxide and locomotor
activity was monitored for 60 min (Figure 2). Pretreatment with
2b inhibited the hyperactivity produced by the combination of
amphetamine/chlordiazepoxide, with minimal effects on baseline
activity. A 30 min pretreatment with the mood stabilizer
valproate (400 mg/kg) produced a similar reduction in admphet-
amine/chlordiazepoxide-induced hyperactivity. These results
clearly demonstrate that our newly synthesized GSK-3â inhibitor
2b has a profile similar to known mood stabilizers like valproate
in the amphetamine/chlordiazepoxide mania model.32
Figure 2. Inhibition of chlordiazepoxide (CDP) and amphetamine (Amph)
induced hyperactivity in C57BL/6J mice by 2b and valproate. (a) Mice
were pretreated with either compound 2b (50 mg/kg), valproate (400 mg/
kg), or 1% Tween vehicle. After 5 min or 30 min (valproate group) mice
were injected with either water vehicle, amphetamine (4 mg/kg) alone
(Amph), or a mixture of amphetamine (4 mg/kg) and chlordiazepoxide (2.5
mg/kg) (Amph + CDP). Locomotor activity was automatically recorded
every 5 min for a 60 min period in a square locomotor activity chamber
surrounded by infrared beams. (b) Locomotor activity was quantified for a
period of 60 min as indicated in the bottom line of the x-axis. Each column
represents the mean ((SEM) total distance traveled (cm) for at least eight
mice. The mixture of Amph + CDP produced greater locomotor activity
than Amph alone (∧, p < 0.05 1% Tween-Amph + CDP vs 1% Tween-
Amph (Fisher’s PLSD). Pretreatment with 2b and valproate normalized
the locomotor activity produced by the Amph + CDP mixture (/, p < 0.05
2b-Amph + CDP vs 1% Tween-Amph + CDP (Fisher’s PLSD)).
Conclusion
Recent biological studies support the idea that bipolar
disorders and other mood disorders may be remedied by
targeting the enzyme GSK-3. Although it has been conjectured
that because of the ubiquitous expression of this enzyme, GSK-3
inhibition may produce side-effects,33 the fact that known GSK-3
inhibitors such as lithium and valproic acid are not only effective
in the treatment of bipolar disorder but are also relatively well
tolerated suggests that the development of selective GSK-3
inhibitors may lead to novel and better therapies for mood
disorders.
The Wnt signaling pathway blocks GSK-3 phosphorylation
of â-catenin leading to its translocation to the nucleus with the
subsequent transcription of genes needed for neuronal growth
and neuronal plasticity and ultimately to behavioral changes
beneficial to the treatment of mood disorders.5 In the absence
of Wnt, the GSK-3 mediated phosphorylation of â-catenin leads
to its degradation by the proteasome. Many of the components
found in the Wnt signaling pathway are overexpressed or
mutated in several types of cancers. Many colon cancers are
known to come about from an initiating mutation in APC or
mutations in â-catenin that make it resistant to degradation.
Consequently, GSK-3 inhibitors have been considered to
possibly mimic the Wnt signaling pathway and to be potentially
oncogenic. GSK-3 is also known to phosphorylate the transcrip-
tion factors c-JUN and c-MYC, and thus the GSK-3-inhibitor-
(28) Poitou, P.; Boulu, R.; Bohuon, C. Experientia 1975, 31, 99.
(29) Aylmer, C. G.; Steinberg, H.; Webster, R. A. Psychopharmacology 1987,
91, 198.
(30) Vale, A. L.; Ratcliffe, F. Psychopharmacology 1987, 91, 352.
(31) Hanania, T.; Dillon, G. M.; Malekiani, S. A.; Manzano, M. L.; Leahy, E.
Soc. Neurosci. Abstr. 2005, 108.9.
(32) Arban, R.; Maraia, G.; Brackenborough, K.; Winyard, L.; Wilson, A.;
Gerrard, P.; Large, C. BehaV. Brain Res. 2005, 158, 123.
(33) Woodgett, J. R. Curr. Drug Targets Immune Endocr. Metabol. Disord.
2003, 3, 281.
9
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A R T I C L E S
Kozikowski et al.
promoted dephosphorylation of these proto-oncogenes might be
anticipated to lead to their activation. However, in spite of these
concerns, it is well-known that lithium, which has been used
for many years for the treatment of bipolar disorder, is not
known to be associated with an increased risk of cancer. The
administration of the GSK-3 inhibitor CHIR 99021 in ZDF rats
for up to 20 h was found not to cause an observable increase in
â-catenin or cyclin D1 mRNA in brain, liver, lung, adipose
tissue, or colon. The effects of GSK-3 inhibition by lithium were
studied in the APC multiple intestinal neoplasia mouse model,
a model of tumorigenesis. Chronic lithium treatment in this
model did not increase the number of tumors indicating that
GSK-3 inhibitors may not exacerbate intestinal polyp formation
and may pose a low risk for the tumor development.34 Other
studies suggest that stabilization of â-catenin in the CNS does
not result in brain tumors.35 Moreover, lithium actually increases
survival rates of patients with adenocarcinomas.36 Thus, perhaps,
the inhibition of GSK-3 by itself may be unable to elevate
â-catenin levels in primary cells; such elevations may require
that the cell lines have already undergone some prior transform-
ing events. While these results would suggest that the GSK-3
inhibitors may be free of oncogenic effects, it is clear that longer
term studies employing a wide variety of GSK-3 inhibitors
possessing diverse chemical scaffolds should be undertaken to
completely eliminate such concerns as well as to ascertain
whether some chemical scaffolds are problematic for reasons
relating to their off-target activity.
Using structure-based design methods, we have designed and
synthesized a new series of 3-benzofuranyl-4-indolylmaleimides
as potent and relatively selective GSK-3â inhibitors. This study
presents the first demonstration of the efficacy of a GSK-3â
inhibitor in this novel mouse model of mania. Future studies
will determine if these behavioral effects generalize to other
mania models such as enhancement of prepulse inhibition. As
more than 2 million people per year experience bipolar disorders
in the United States, the present work may eventually lead to
desperately needed improved therapies.
Acknowledgment. This work was supported in part by NIH
(Grant 1R01 MH072940-01, A.P.K.).
Supporting Information Available: Methods of biological
assay and detailed experimental procedures with spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
(34) Gould, T. D.; Gray, N. A.; Manji, H. K. Pharmacol. Res. 2003, 48, 49.
(35) Kratz, J. E.; Stearns, D.; Huso, D. L.; Slunt, H. H.; Price, D. L.; Borchelt,
D. R.; Eberhart, C. G. BMC Cancer 2002, 2, 33.
(36) Johnson, C. D.; Puntis, M.; Davidson, N.; Todd, S.; Bryce, R. Br. J. Surg.
2001, 88, 662.
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