Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists

Article abstract of DOI:10.1016/j.bmcl.2008.02.076

A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the bin

Full text of DOI:10.1016/j.bmcl.2008.02.076

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2725–2729
Synthesis and characterization of
1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3.
New potent non-competitive metabotropic glutamate
receptor 2/3 antagonists
Thomas J. Woltering,a,* Jurgen Wichmann,a Erwin Goetschi,a Geo Adam,a
¨
b
b
James N. C. Kew,b, Frederic Knoflach, Theresa M. Ballard,
´ ´
Jo¨rg Huwyler,c,à Vincent Mutelb,§ and Silvia Gattib
aF. Hoffmann-La Roche Ltd., Pharma Discovery Chemistry CNS, CH-4070 Basel, Switzerland
bF. Hoffmann-La Roche Ltd., Pharma Research CNS, CH-4070 Basel, Switzerland
cF. Hoffmann-La Roche Ltd., Pharma Research DMPK, CH-4070 Basel, Switzerland
Received 1 February 2008; revised 28 February 2008; accepted 29 February 2008
Available online 5 March 2008
Abstract—A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists.
Replacement of the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the
binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and
mGluR3. These compounds were able to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the
rat dentate gyrus and in vivo activity could be demonstrated by reversal of the LY354740-induced hypoactivity in mice after oral
administration.
Ó 2008 Elsevier Ltd. All rights reserved.
The family of metabotropic glutamate receptors consists
of eight subtypes, classified into three groups according
to their sequence homology, pharmacology, and second
messenger coupling.1 Group I receptors (mGluR 1 and
5) are positively coupled to phospholipase C, whereas
group II (mGluR2 and 3) and group III (mGluR4, 6,
7 and 8) receptors are negatively coupled to the activity
of adenyl cyclase. Ligands for the different mGluR’s are
under development for the treatment of different CNS
disorders, such as Parkinson’s disease, anxiety and
schizophrenia.2 It was recently shown that while
mGluR2/3 agonists exhibit anxiolytic and antipsychotic
properties, mGluR2/3 antagonists may be useful as anti-
depressants, cognitive enhancers and to inhibit the
growth of malignant gliomas.3,4
We recently reported the discovery of the random screen-
ing hit (8-methyl-4-phenyl-1,3-dihydro-benzo[b][1,4]dia-
zepin-2-one), its characterization as a non-competitive
antagonist at both mGluR2 and mGluR3 and the lead
optimization program to obtain compounds like 3, with
low nanomolar affinity assessed by displacement of
[3H]-LY354740 binding to rat mGluR2 and ability to
reverse LY354740-mediated inhibition of field excitatory
postsynaptic potentials in the rat dentate gyrus in vitro
(Fig. 1).5 The present study describes the optimization
of orally active, brain penetrating, in vivo active com-
pounds, and their pharmacological profiling.
Keywords: Metabotropic glutamate receptors; 1,3-Dihydro-benzo
[b][1,4]diazepin-2-one; mGluR2 antagonist; LY354740; In vivo
activity; Mice.
*
Corresponding author. Tel.: +41 616880407; fax: +41 616888714;
e-mail: thomas.woltering@roche.com
Present address: GlaxoSmithKline, New Frontiers Science Park
North Harlow, Essex CM19 5AW, UK.
The regioselective synthesis of unsymmetrically 7,8-
à
substituted
1,3-dihydro-benzo[b][1,4]diazepin-2-ones
Present address: Fachhochschule Nordwestschweiz Hochschule fur
Life Sciences, Grundenstrasse 40, CH-4132 Muttenz, Switzerland.
¨
¨
has already been described.6,7 Simple condensation of
mono Boc protected 1,2-phenylenediamines 4 and tert-
butyl b-ketoesters 5 in refluxing toluene led to the corre-
§
Present address: Addex Pharmaceuticals SA, 12 Chemin des Aulx,
CH-1228 Plan-les-Ouates, Switzerland.
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.02.076

2726
T. J. Woltering et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2725–2729
F
Ph
H
N
O
H
N
O
Me
O
H
N
N
N
HO
N
CN
N
N
3
2
1
IC50 = 34 nM
IC50 = 26 nM
IC50 = 6.4 μM
Figure 1. Development of the random screening hit 1 into compounds, like, for example, 2 and 3, with low nanomolar affinity in inhibition of [3H]-
LY354740 binding to rat mGluR2.5
H
N
O
O
O
H
R8
R7
R8
R7
NH2
R8
R7
R3'
N
R3'
a
b
+
O
O
O
NHBoc
N
NHBoc
R3'
4
5
7
6
Scheme 1. Regioselective synthesis of unsymmetrically 7,8-substituted 1,3-dihydro-benzo[b][1,4]diazepin-2-ones 7. Reagents and conditions: (a)
toluene, reflux; (b) TFA [optional anisole], DCM, rt.
Table 1. Structure–activity-relationship of the new 1,3-dihydro-benzo[b][1,4]diazepin-2-ones 7 reported in this study
0
Compound R3
R8
R7
clogP Rat mGluR2
[3H]-LY354740
Rat mGluR2 (1S,3R)-ACPD
inhibition of Forskolin stimulated
bindinga, IC50 (lM) cAMPb, IC50 (lM)
3
1-Imidazolyl
4-FAC6H4AC„CA HO
3.85
4.43
4.62
4.62
4.62
4.78
3.48
3.48
3.66
3.87
4.13
5.04
4.48
4.37
4.90
4.61
4.61
4.77
3.96
3.65
3.50
3.86
2.73
3.89
4.12
5.03
0.026
0.039
0.017
0.012
0.025
0.007
0.022
0.210
0.072
0.043
0.009
0.019
0.017
0.012
0.004
0.031
0.016
0.017
0.466
0.130
0.060
0.092
0.608
0.070
0.038
0.042
0.011
0.027
0.009
0.029
0.007
0.011
0.047
0.024
0.027
nt
7a
7b
7c
7d
7e
7f
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
1-Imidazolyl
Ph
H
4-FAC6H4A
2-FAC6H4A
3-FAC6H4A
2,5-di-FAC6H3A
2-FAC6H4A
cyclo-Propyl
Br
H
H
H
H
HO
0.017
nt
7g
7h
7i
H
nt
H
nt
F3CA
F3CA
H
Me2N
nt
7j
0.052
0.073
0.015
0.019
0.010
0.036
0.037
0.018
nt
7k
7l
F3CA
F3CA
iso-ButylNH
Cl
7m
7n
7o
7p
7q
7r
F3CA
F3CA
Me
Et
1,2,3-Triazolyl 4-FAC6H4A
1,2,3-Triazolyl 2-FAC6H4A
1,2,3-Triazolyl 2,5-di-FAC6H3A
1,2,3-Triazolyl iso-Propyl
1,2,3-Triazolyl Br
H
H
H
H
7s
H
nt
7t
1,2,3-Triazolyl Cl
H
nt
7u
7v
7w
7x
7y
7z
7aa
7ab
7ac
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F2CHA
1,2,3-Triazolyl F3CCH2OA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
1,2,3-Triazolyl F3CA
H
nt
H
nt
H
Me2N
iso-ButylNH
nt
0.184
0.268
0.014
0.116
0.039
0.074
0.034
iso-ButylN(Me) 5.58
Cl
Me
4.47
4.36
3.91
4.44
MeO
EtO
7ad
0
R3 , R7 and R8 refer to the positions of R’s in Scheme 1.
nt, not tested.
a Values are means of at least 2 independent experiments.
b Values are means of 3 independent experiments.

T. J. Woltering et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2725–2729
2727
sponding b-ketoamides 6. We found that the tert-butyl
b-ketoester was superior to the corresponding ethyl ester
in this condensation reaction, probably due to its ability
of reacting through a ketene mechanism. Deprotection
and concomitant cyclization were achieved by treatment
with TFA yielding the unsymmetrically 7,8-substituted
1,3-dihydro-benzo[b][1,4]diazepin-2-ones 7 (Scheme 1).
while maintaining a small molecule size we kept the 8-
(trifluoromethyl) group and attached additional small
alkyl, alkoxy, and alkylamino groups as well as Cl in
the adjacent 7-position. Overall, a significant enhance-
ment in activity was observed (ꢀ2- to 9-fold for 7j–n ver-
sus 7i and ꢀ2- to 13-fold for 7x–ad versus 7u).
In conclusion the (2-aryl)-ethynyl-moiety in the 8-posi-
tion could most effectively be replaced by a 2-fluoro-
phenyl group or the combination of a trifluoromethyl
group in 8-position together with a small alkyl or alkoxy
group in 7-position.
We reported that 5-membered heterocycles were suitable
replacements for the cyano group, especially the
employment of 1-imidazoles and 1,2,3-triazoles lead to
very potent mGluR2/3 antagonists.5b Although these
modifications improved the physico-chemical properties
of the compounds they remained quite lipophilic (2:
clogP 4.44; calculated log(coctanol/cwater); 3: clogP
3.85). Therefore we sought for further alteration of the
substituents enabling the in vivo evaluation of com-
pounds from this class in an mGlu2 receptor-mediated
behavioral test. Our main focus was the search for a
suitable—preferably smaller—replacement for the (2-
aryl)-ethynyl-moiety in 8-position.
The closest derivative to 3 and most polar compound 7f
(clogP 3.48) was not suitable for in vivo evaluation,
since it revealed high clearance in rat microsomes
(ꢀ100 mL/min/kg, MAB ꢀ20%), whereas 7c and 7p
are metabolically stable compounds (MAB 93% and
100%). Therefore only the reduction in size could be
achieved but not in lipophilicity (7c: clogP 4.62; 7p:
clogP 4.61; 7n: clogP 4.90; 7ab: clogP 4.36; 7ad: clogP
4.44).
Omitting the acetylene linker and using fluorinated phe-
nyl groups produced compounds 7a–f, which proved to
be equipotent to 3 (Table 1). In the cases of simple
halides, Br (7h and 7s) appeared to be less effective than
Cl (7t). Employing alkyl groups like cyclopropyl (7g)
and isopropyl (7r) resulted in ꢀ10- to 20-fold loss of
affinity. Interestingly, introducing fluorinated alkyl
groups a remarkable ꢀ7-fold advantage of trifluoro-
methyl over difluoromethyl was observed (7u versus
7v). The 2,2,2-trifluoroethoxy group was also tolerated
(7w). In order to increase the potency of the compounds
The pharmacological properties of these compounds
were consistent with a mechanism of non-competitive
antagonism at both mGluR2 and mGluR3 as previously
described demonstrated by partial inhibition of the
binding of the selective agonist [3H]-LY354740 to rat
mGluR2, full blockade of the effect of LY354740,
(1S,3R)-ACPD and L-glutamate in both GTPcS and
cAMP assays and inhibition of the glutamate-induced
GIRK current. Table 1 summarizes the IC50 values cal-
culated for each compound in affinity studies (partial
displacement of 10 nM [3H]-LY354740) and concentra-
tion dependent blockade of (1S,3R)-ACPD (10 lM-
EC90) induced inhibition on intracellular cAMP levels
(Forskolin 10 lM, n:3 for each value) in the experimen-
tal conditions described earlier.5 In this chemical series
the effect of all the tested compounds does not seem to
vary depending on the mGluR2 agonist under study.
Table 2. IC50 values for GIRK current inhibition by selected
compounds in CHO cells expressing mGluR2 and mGluR3 receptors
Compound
Rat mGluR2
GIRK inhibition
IC50 (lM)
Rat mGluR3
GIRK inhibitiona,
IC50 (lM)
a
,
3
0.024
0.299
0.011
0.035
0.022
nt
7b
7c
7f
7p
0.017
0.033
0.122
0.042
For representative compounds we have determined the
IC50s for the GIRK inhibition at both rat mGluR2
and mGluR3 (Table 2). The concentration response
curves of the antagonistic properties of 7c (a) and 7p
(b) are shown in Figure 2. All compounds were potent
a Values are means of 3–5 independent experiments, (nt = not tested).
100
80
60
40
20
0
a100
80
b
60
40
20
0
1
10
100
10
100
1000
[compound 7c] (nM)
[compound 7p] (nM)
Figure 2. Concentration-response curves for the inhibition of GIRK currents by 7c and 7p in CHO cells stably expressing GIRKs and transiently
transfected with rat mGluR2 (s) and rat mGluR3 (d) and stimulated with L-glutamate (10 lM). (a) 7c: mGluR2 IC50 = 11 nM, mGluR3
IC50 = 33 nM. (b) 7p: mGluR2 IC50 = 22 nM, mGluR3 IC50 = 42 nM.

2728
T. J. Woltering et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2725–2729
group II mGluR antagonists, with a slight preference for
the mGluR2.
a 120
110
100
90
80
70
60
50
40
30
20
10
0
We also assessed in vitro the selectivity of 7p on group I
and group III mGluRs, respectively: rat mGluR1a,
mGluR5a (using a Ca2+ mobilization functional assay)
and rat mGluR8a (displacement studies with [3H]-L-
AP4) (with 7p tested at 30 lM final concentration). In
addition 7p was devoid of any affinity at ionotropic glu-
tamate receptors and GABAA receptors (data not
shown).
Using compounds 7c and 7p we could also demonstrate
antagonism at native group II metabotropic glutamate
receptors by reversal of LY354740-mediated inhibition
of fEPSPs in the dentate gyrus in vitro (Fig. 3).8 Com-
plete reversal was observed in the case of 7c while only
partial reversal could be measured in the case of 7p. This
is possibly related to the poor solubility of 7p in the
experimental conditions used for this study and it does
not correspond to the observations in other functional
assays where it always exhibited complete blockade of
the effects of the mGluR2/3 agonists.
0
20 40 60 80 100 120 140 160 180 200 220 240
Time (min)
b
100
90
80
70
60
50
40
30
20
10
0
To evaluate the drug-drug-interaction (DDI) potential
we measured the binding to cytochrome P450 3A4 iso-
enzyme. Not surprisingly 7c and 7f—bearing the well-
known 1-imidazolyl pharmacophore for CYP450
3A4—were strong inhibitors with an IC50 ꢀ 1 nM,
whereas 7p showed only weak activity (IC50 = 4.3 lM).
0
20 40 60 80 100 120 140 160 180 200 220 240
Time (min)
For compounds 7c and 7p a single dose pharmacoki-
netic (SDPK) assessment in rats at 10 mg/kg p.o. was
performed and plasma and brain concentration mea-
surements after 1.5 h revealed for 7c 2656 ng/mL and
1344 ng/mL (brain/plasma 0.5) and for 7p 1423 and
1060 ng/mL, respectively (brain/plasma 0.9, CSF/plasma
0.5%) (4 animals/group).9
Figure 3. Reversal of mGluR2-mediated inhibition of synaptic trans-
mission (fEPSP) evoked by stimulation of the medial perforant path
input to the dentate gyrus mid-moleculare by 7c (0.1 lM) and by 7p
(0.1 lM) in presence of the mGluR2/3 agonist LY354740 (1 lM). (a)
. . .., 7c (0.1 lM), —– LY354740 (1 lM),
mean SE, n = 6. (b) . . .. 7p (0.1 lM), —– LY354740 (1 lM), – –
wash-out period; mean SE, n = 3.
– – wash-out period;
a
8000
b
8000
7000
7000
#
##
*
##
6000
5000
4000
3000
2000
1000
0
6000
5000
*
4000
3000
2000
1000
0
***
veh
7c (30)
veh
7c (3) 7c (10) 7c (30)
veh
7p (30)
vehicle
veh
7p (3) 7p (10) 7p (30)
vehicle
+ LY354740 (15 mg/kg i.p.)
+ LY354740 (15 mg/kg i.p.)
Figure 4. Spontaneous locomotor activity in C57BL/6J mice (total horizontal activity counts in 30 min): reversal of LY354740-induced hypoactivity
by compounds 7c and 7p. Dose–response measurements of 7c (a) and 7p (b) suspension prepared in 0.3% Tween 80 v/v saline (at 3, 10 and 30 mg/kg
p.o.) revealed for 7c (a) an ED50 = 12.5 mg/kg p.o. (n = 8 mice/group; ANOVA p < 0.0001; *p < 0.05, ***p < 0.001 versus veh. + veh.; ##p < 0.01
versus veh. + LY354740) and for 7p (b) an ED50 = 3.3 mg/kg p.o. (n = 8 mice/group; ANOVA p < 0.01; *p < 0.05 versus veh. + veh.; #p < 0.05 versus
veh. + LY354740).

T. J. Woltering et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2725–2729
2729
Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38,
1431.
Consistent with the in vivo exposure and the brain pene-
tration data are the in vivo antagonistic properties of
both 7c and 7p when administered per os by gavage in
mice (Fig. 4).9 The mGluR2/3 agonist LY354740 pro-
duces a dose-dependent decrease of the horizontal activ-
ity after intraperitoneal administration (1–30 mg/kg,
30 min prior to testing) in mice. The experimental condi-
tions of this test have been validated for the contribution
of mGluR2 using mGluR2 null mutant mice.3,10 The
p.o. administration of either 7c or 7p 1 h prior to the
mGluR2/3 agonist (15 mg/kg i.p.) was able to block
completely the hypoactivity caused by the administra-
tion of LY354740. It should be noted that neither 7c
nor 7p caused a significant increase in locomotor activity
when administered alone.
´
2. (a) Recasens, M.; Guiramand, J.; Aimar, R.; Abdulka-
rim, A.; Barbanel, G. Current Drug Targets 2007, 8,
651; (b) Swanson, C. J.; Bures, M.; Johnson, M. P.;
Linden, A.-M.; Monn, J. A.; Schoepp, D. D. Nature
Reviews. Drug Discovery 2005, 4, 131; (c) Higgins, G.
A.; Miczek, K. A. Psychopharmacology 2005, 179, 1; (d)
Mutel, V. Expert Opinion on Therapeautic Patients 2002,
12, 1845.
3. (a) Spinelli, S.; Ballard, T.; Gatti-McArthur, S.; Richards,
G. J.; Kapps, M.; Woltering, T.; Wichmann, J.; Stadler,
H.; Feldon, J.; Pryce, C. R. Psychopharmacology 2005,
179, 292; (b) Higgins, G. A.; Ballard, T. M.; Kew, J. N. C.;
Richards, J. G.; Kemp, J. A.; Adam, G.; Woltering, T.;
Nakanishi, S.; Mutel, V. Neuropharmacology 2004, 46,
907.
4. Nicoletti, F.; Battaglia, G.; Storto, M.; Ngomba, R. T.;
Iacovelli, L.; Arcella, A.; Gradini, R.; Sale, P.; Rampello,
L.; De Vita, T.; Di Marco, R.; Melchiorri, D.; Bruno, V.
Psychoneuroendocrinology 2007, 32, S40.
5. (a) Woltering, T. J.; Adam, G.; Alanine, A.; Wichmann,
J.; Knoflach, F.; Mutel, V.; Gatti, S. Bioorganic &
Medicinal Chemistry Letters 2007, 17, 6811; (b) Woltering,
T. J.; Adam, G.; Wichmann, J.; Goetschi, E.; Kew, J. N.
C.; Knoflach, F.; Mutel, V.; Gatti, S. Bioorganic &
Medicinal Chemistry Letters 2008, 18, 1091.
In summary, by replacement of the (2-aryl)-ethynyl-moi-
ety in 8-position with smaller less lipophilic substituents
we were able to develop a series of in vivo active 1,3-
dihydro-benzo[b][1,4]diazepin-2-one derivatives. These
compounds are selective, non-competitive antagonists
at recombinant (inhibiting the binding of [3H]-
LY354740 to rat mGluR2 with low nanomolar affinity)
and native (reversal of LY354740-mediated inhibition of
fEPSPs in the dentate gyrus) group II metabotropic glu-
tamate receptors, they are orally active and brain pene-
trating and also exhibit in vivo activity by reversal of the
LY354740-induced hypolocomotion in mice.
6. Hemstapat, K.; Da Costa, H.; Nong, Y.; Brady, A. E.;
Luo, Q.; Niswender, C. M.; Tamagnan, G. D.; Conn, P. J.
The Journal of Pharmacology and Experimental Therapeu-
tics 2007, 322, 254.
7. (a) Adam, G.; Alanine, A., Goetschi, E.; Mutel, V., J.;
Woltering, T. J. World Patent WO01/29011, 2001;
Chem. Abstr. 2001, 134, 311234; (b) Adam, G.; Alanine,
A., Goetschi, E.; Mutel, V., J.; Woltering, T. J. World
Patent WO01/29012, 2001; Chem. Abstr. 2001, 134,
311235; (c) Adam, G.; Goetschi, E.; Mutel, V.; Wich-
mann, J.; Woltering T. J. World Patent WO02/083652,
2002; Chem. Abstr.2002, 137, 325447; (d) Adam, G.;
Goetschi, E.; Mutel, V.; Wichmann, J.; Woltering T. J.
World Patent WO02/083665, 2002; Chem. Abstr.2002,
137, 325438.
Acknowledgments
We cordially thank G. Achermann, J. Beck, N. Bene-
detti, D. Buchy, S. Chaboz, M. Dellenbach, N. Gross-
mann, R. Haab, A. Maier, A. Nilly, P. Oberli, M.-C.
Pflimlin, P. Reindl , H. Scha¨r, M. Weber and R. Wyler
for their skilful technical assistance.
8. Kew, J. N. C.; Ducarre, J.-M.; Pflimlin, M.-C.; Mutel, V.;
Kemp, J. A. Neuropharmacology 2001, 40, 20.
References and notes
9. The experimental procedures used in the present investi-
gation received prior approval from the City of Basel
Cantonal Animal Protection Committee based on adher-
ence to federal and local regulations.
10. (a) Spooren, W.; Gasparini, F.; van der Putten, H.; Koller,
M. I. S.; Nakanishi, S.; Kuhn, R. European Journal of
Pharmacology 2000, 397, R1; (b) Ballard, T. M.; Kew, J.
N. C.; Richards, J. G.; Woltering, T. J.; Adam, G.;
Nakanishi, S.; Kemp, J. A.; Mutel, V.; Higgins, G. A.
Abstract of Papers, 31st Annual Meeting of the Society for
Neuroscience, San Diego, CA; Society for Neuroscience,
Washington, DC, 2001; Abstract 705.11.
1. Reviews (a) Gasparini, F.; Spooren, W. Current Neuro-
pharmacology 2007, 5, 187; (b) Monn, J. A.; Johnson, M.
P.; Schoepp, D. D. In Handbook of Contemporary
Neuropharmacology; Sibley, D. R., Ed.; John Wiley &
Sons, Inc.: Hoboken, 2007; Vol. 1, pp 421–464; (c)
Neugebauer, V. Handbook of Experimental Pharmacology
2007, 177, 217; (d) Oswald, R. E.; Ahmed, A.; Fenwick,
M. K.; Loh, A. P. Current Drug Targets 2007, 8, 573; (e)
Ossowska, K. Dopamine and Glutamate in Psychiatric
Disorders 2005, 117; (f) Ferraguti, F.; Shigemoto, R. Cell
& Tissue Research 2006, 326, 483; (g) Schoepp, D. D.;