Novel 5-HT1A/1B/1D receptors antagonists with potent 5-HT reuptake inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2008.08.110

Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT_1A/1B/1D receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report desc

Full text of DOI:10.1016/j.bmcl.2008.08.110

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5581–5585
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel 5-HT1A/1B/1D receptors antagonists with potent 5-HT reuptake
inhibitory activity
b
a
c
a
Halina T. Serafinowska a, , Frank E. Blaney , Peter J. Lovell , Giancarlo G. Merlo , Claire M. Scott ,
*
Paul W. Smith a, Kathryn R. Starr a, Jeannette M. Watson a
a Neurosciences CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
b Department of Computational and Structural Chemistry, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
c Neurosciences CEDD, GlaxoSmithKline, Medicines Research Centre, GlaxoSmithKline, Via A. Fleming 4, Verona 37135, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Revised 8 August 2008
Accepted 29 August 2008
Available online 3 September 2008
Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high
affinities for the 5-HT1A/1B/1D receptors coupled with potent 5-HT reuptake inhibitory activity have been
discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinoli-
nyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the
5-HT1A receptor model.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Potent 5-HT1A/1B/1D receptors antagonists
Potent 5-HT reuptake inhibitory activity
6-{2-[4-(2-Methyl-5-quinolinyl)-1-
piperazinyl]ethyl}-2H-1,4-benzoxazin-
3(4H)-one
5-HT transporter model
5-HT1A receptor model
One of the major drawbacks of selective serotonin reuptake
inhibitors (SSRIs) in the pharmacological treatment of depression
is latency in the onset of clinically meaningful effects. It has
been hypothesized that this is associated with 5-HT1A, and pos-
sibly 5-HT1B, autoreceptor activation resulting in a negative con-
The terminal 5-HT1B receptors also control 5-HT release into the
synapse and their blockade has been shown to enhance the effects
of SSRIs on serotonin levels in vivo.10–12
The role of central 5-HT1D receptors is less documented,
although, various reports on combined 5-HT1D antagonist/5-HT
reuptake inhibitors provide increased evidence that they act as
presynaptic autoreceptors.13
We have recently described a potent serotonin reuptake inhib-
itor 2 (SB-649915) incorporating 5-HT1A/1B/1D autoreceptors antag-
onist properties.14,15 SB-649915 was found active in animal models
of anxiety, substantially reducing the latency to onset of anxiolytic
activity.16 Here, we wish to report further studies in this series of
compounds which have led to the discovery of molecule 1 display-
ing a highly increased activity at 5-HT1 autoreceptors17 coupled
with potent inhibition of the 5-HT reuptake site.
Our efforts were focused on modifications of the central 2-eth-
oxypiperidine linker in 2 (Fig. 1) to investigate a correlation
between the potency at the 5-HT reuptake site and affinity for
5-HT1A/1B/1D receptors. The potential binding mode of 2 in a 5-
HT1A receptor model has been previously described.18 While the
primary binding site of the compound’s basic nitrogen is assumed
to be the highly conserved aspartate on TM3, the models did sug-
gest that movement of this aspartate was possible and that some
alternative binding subpockets were accessible which might better
trol
of
serotonergic
neurotransmission.1,2
Consequently,
prolonged dosing of an SSRI is required to desensitize the 5-
HT1 autoreceptors and to bring about restoration of serotonergic
firing rate. A number of strategies have been investigated to ad-
dress this issue.3 In particular, approaches based on inhibition of
serotonin reuptake in conjunction with antagonism of 5-HT1
autoreceptors offer advantages over the current antidepressants
in terms of a faster onset of therapeutic effect and improved effi-
cacy. This is supported by studies demonstrating that the 5-HT1A
antagonism enhances the antidepressant-like effects of SSRIs in
animal models of social interaction, resident-intrude and sche-
dule-induced polydipsia.4–6
In addition, clinical trials using a 5-HT1A receptor ligand pindo-
lol in combination with SSRIs, suggest that improvements in the la-
tency to therapeutic onset can be achieved.7–9
* Corresponding author. Tel.: +44 1279 627683; fax: +44 1279 622790.
E-mail address: halina.serafinowska@gsk.com (H.T. Serafinowska).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.08.110

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H. T. Serafinowska et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5581–5585
H
N
O
n
linker
linker
1
2
3
4
1
SB-744185
N
N
(CH2)n
O
1a
1b
1c
Y
CH2
2a X=Me Y=H
2b X=H Y=Me
N
N
O
O
X
n
2
3
3
m
1
1
O
(CH2)m
(CH2)m
3a
3b
3c
(CH2)n
N
H
N
0
O
N
4a
4b
4c
0
1
0
1
1
2
N
(CH2)n
O
O
O
O
5a
5b
0
1
1
1
N
(CH2)n
(CH2)m
N
O
C
2 SB-649915
Figure 1. Linker replacements investigated.
accommodate alternative linker lengths and conformations. Our
desire to increase affinity across all three 5HT1 autoreceptor sub-
types, also suggested that this could be best achieved by binding
the ligands into pockets where the residues were conserved across
these subtypes. To help our understanding of the interactions of
the compounds with the 5-HT reuptake site, a model of the trans-
porter protein was built based on its homology with the leucine
bacterial transporter from aquifex aeolicus.19
reductive amination of the resulting ketone 7 with 6-(4-piperidi-
nylmethyl)-2H-1,4-benzoxazin-3(4H)-one.15 The enantiomers of
2a were separated by chiral chromatography but their absolute
stereochemistry was not determined.
The isomeric 2-substituted analogue 2b was constructed by
coupling of 6 with 1-bromo-2-propanol to give compound 8 which
in turn was used in alkylation of 6-(4-piperidinylmethyl)-2H-1,4-
benzoxazin-3(4H)-one.15
A set of targets was designed to probe the binding pockets with
a range of alternative linkers and to identify structural features
ensuring high affinity at 5-HT1 sites and the 5-HT reuptake site.
The initial study targeted analogues of 2, substituted with a
methyl group at the 1-, or 2-position of the 2-ethoxy sidechain
(Scheme 1). Our previous data15 suggested that similar structural
manipulations were beneficial to affinity for the 5-HT1A receptor.
Compound 2a was prepared by alkylation of 2-methyl-5-hydroxy-
quinoline 6 with 1-bromo-2,2-dimethoxypropane followed by
We also examined a 1,3-di-substituted azetidine system as a
replacement of the piperidine moiety in 2 (Scheme 2). The syn-
thesis of compounds 3a–c involved transformation of 3-azeti-
dinecarboxylic acid
9
into 3-hydroxymethylazetidine 10,
followed by
a
Mitsunobu reaction of 10 or 1120 with
methyl([(4-hydroxy-2-nitrophenyl)oxy]acetate to give products
12 and 13. Subsequent cyclisation of 12 or 13 to the correspond-
ing 3,4-dihydro-2H-benzoxazinone was effected with Pd/C and
ammonium formate. Deprotection of the azetidine nitrogen and
R1
H
OH
N
O
Y
(i)
or (ii)
(iii) or (iv)
N
O
O
X
N
N
O
6
7
R1=
R1=
O
N
2a X=CH3 Y=H
2b X=H Y=CH3
Br
8
O
Scheme 1. Reagents and conditions: (i) 1-bromo-2,2-dimethoxypropane, K2CO3, 2-butanone, 100 °C (53%); (ii) Ph3P, DIAD, 1-bromo-2-propanol, THF, rt (16%); (iii) sodium
triacetoxyborohydride, DCE, acetic acid, 6-(4-piperidinylmethyl)-2H-1,4-benzoxazin-3(4H)-one, rt (29%); (iv), iPr2EtN, 6-(4-piperidinylmethyl)-2H-1,4-benzoxazin-3(4H)-
one, isopropanol (9%).
H
Y
N
O
R
HN
N
N
O
R
O
X
H
N
NO2
N
Y
HN
O
Y
(i) (ii)
(iii)
(iv)
(v)
(vi)
OH
Y
O
O
N
CO2Me
O
10 R=BOC Y=CH2OH
11 R= Bn Y=OH
9
12 R=BOC Y=CH2O
13 R=Bn Y=O
3a X=CH2
3b X=CH2CH2
3c X=CH2CH2
Y=CH2O
Y=CH2O
Y=O
14 Y=CH2O
15 Y=O
Scheme 2. Reagents and conditions: (i) (BOC)2O, THF, NaOH aq, K2CO3 aq; (ii) EtOCOCl, Et3N, LiBH4, THF (45% over two steps, 10); (iii) Ph3P, DIAD, methyl-[(4-hydroxy-2-
nitrophenyl)oxy]acetate, rt (30–62%); (iv) Pd/C, NH4CO2H, MeOH, rt (88–92%); (v) 1 N HCl/Et2O, MeOH or Pd/C, H2, (90% for 14; crude product-15); (vi) 2-methyl-5-
i
bromoethoxyquinoline or 2-methyl-5-bromopropoxyquinoline, Pr2EtN, isopropanol, reflux, 17 h (33–38% for 3a–b; low yield for 3c).

H. T. Serafinowska et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5581–5585
5583
Table 1
alkylation of the resulting intermediates 14 and 15 with 2-
5-HT1 receptor bindinga,b affinities, SerT potency and IAd
methyl-5-bromoalkoxyquinolines15 furnished target compounds
3a–c in 33–38% overall yield.
Compoundc
Affinity (pKi)
IA 1A/1B/1Dd
To explore further the chemical space occupied by the basic
nitrogen, a selection of piperidine and piperazine templates was
investigated (Scheme 3). The key intermediates, quinolines linked
to the 4-position of a piperidine moiety via an oxygen atom (17)
or a methyloxy group (18) were prepared from 6 by a sequence
of coupling, displacement and deprotection methods.
Subsequent reductive alkylation of 17 or 18 with 3-oxo-3,4-
dihydro-2H-1,4-benzoxazine-6-carbaldehyde provided target
compounds 4a, 4b. Reaction of 17 with mesylate 27, which was
prepared as shown in Scheme 4, gave 23. Cyclisation of 23 to the
corresponding 3,4-dihydro-2H-benzoxazinone 4c was achieved
by reduction of the 2-nitro group (Scheme 3).
5-HT1A
5-HT1B
5-HT1D
SerT
1
9.6
8.6
9.2
6.2
8.6
7.3
7.0
6.4
7.3
7.1
6.8
<5.0
<5.8
6.5
<5.0
6.3
9.3
7.3
8.2
<5.0
8.0
7.4
7.0
6.7
7.3
6.5
9.7
8.0
7.9
6.9
8.8
6.6
6.3
7.1
8.1
6.8
6.6
5.9
5.9
8.2
5.7
6.6
8.4
7.6
8.2
6.1
8.1
NDe
ND
6.6
7.2
ND
ND
6.7
7.5
7.0
ND
6.1
0.2/0.1/0
0/0.1/0
1a
1b22
1c22
2
0.1/0.5/0.5
0.3/0.5/0.5
2af
2ag
2b
3a
3b
3c
4a
4b
4c
6.4
<5.6
<5.0
7.6
<5.3
6.2
Alkylation of 17 or 18 with 6-chloroacetyl-3,4-dihydro-2H-ben-
zoxazinone afforded the keto analogues 5a, 5b.
5a
5b
The synthesis of title compounds 1 and 1a entailed a prior
preparation of 5-piperazine-2-methylquinoline 20. Thus, reaction
of 16 with bromine in the presence of aluminium chloride gave
the desired 5-bromo isomer 19 in 30% yield. A palladium cata-
lysed cross-coupling of 19 with piperazine afforded intermediate
20 which was then converted into 1 or 1a employing the syn-
thetic sequence described already for the preparation of 4c.
Mesylates 27 and 28, used in the displacement reactions were
obtained by a three-step synthesis (Scheme 4) which involved a
cross-coupling reaction21 of 24 with tri-n-butylvinyltin or tri-
a
All values represent the mean of at least three determinations, with each
determination lying within 0.3 log unit of the mean.
b
Receptors and radioligands used in binding assays; 5-HT1A (human cloned
receptors in CHO cells, [3H]-5-HT; 5-HT1B (human cloned receptors in CHO cells,
[3H]-5-HT; 5-HT1D (human cloned receptors in CHO cells, [3H]-5-HT; [3H]-5-HT
uptake into rat cortical synaptosomes.
c
All new compounds gave satisfactory NMR and LC/MS data.
IA, intrinsic activity.
d
e
ND, not done.
f
Enantiomer 1, unknown stereochemistry.
Enantiomer 2, unknown stereochemistry.
g
H
R1
R2
N
O
linker
R1=OH
(i)or(ii)
(iii) or (iv)
O
N
N
6
R1=OH
17 R2=
16 R1=H
O
NH
N
18 R2=
R1=H
(v)
OCH2
NH
linker
O
N
4a
4b
5a
5b
R1=Br
19
OCH2
N
(vii)
27
(vi)
20 R1=
N
NH
O
N
(vii)
27or 28
O
H
N
OCH2
N
NO2
O
O
linker
linker
O
CO2Me
(viii)
O
N
N
linker
linker
1
N
N
N
N
N
N
21
1a
4c
N
O
22
N
O
N
23
N
Scheme 3. Reagents and conditions: (i) NaH/1-BOC-piperidine-4-mesylate, DMF, rt then 1 N HCl/Et2O, MeOH, rt (75%, 17); (ii) Ph3P, DIAD, 1-BOC-4-hydroxymethylpiper-
idine, rt then 1 N HCl/Et2O, MeOH, rt (51%, 18); (iii) 17 or 18, 3-oxo-3,4-dihydro-2-1,4-benzoxazine-6-carbaldehyde, sodium triacetoxyborohydride, DCE, rt (50–55%, 4a–b);
i
(iv) 17 or 18, 6-chloroacetyl-2H-1,4-benzoxazin-3(4H)-one, Pr2EtN, isopropanol, reflux, 4 h (71–59%, 5a–b); (v) Br2, AlCl3, DCE (30%, 19); (vi) piperazine, Pd(AcO)2, BINAP,
i
Cs(CO3)2, dioxane, 100 °C, 2.5 days (49%, 20); (vii) 27 or 28, Pr2EtN or K2CO3, NaI, DMF, 80 °C (13–69%, 21–23); (viii) iron, acetic acid, (23–71%, 1, 1a, 4c).
MsO
NO2
O
Br
NO2
O
X
NO2
O
X
(iii)
(ii)
(i)
CO2Me
CO2Me
CO2Me
25 X=
26 X=
27 X=CH2
28 X=CH2CH2
24
Scheme 4. Reagents and conditions: (i) tri-n-butylvinyltin or tri-n-butylallyltin, Pd(Ph3P)4, toluene, rt (34–64%), (ii) BH3/THF, 5 °C followed by sodium perborate
tetrahydrate, rt (23–46%); (iii) MesCl, Et3N, CH2Cl2 (87%).

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H. T. Serafinowska et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5581–5585
n-butylallyltin, hydroboration of 25–26 followed by mesylation of
the resulting alcohols.
mental to 5-HT1 affinities. Thus, compounds 4a, 4b and 5a were
inactive, whereas the analogous 4c and 5b showed highly re-
duced potency at the 5-HT1A receptor. In contrast, potency at
the 5-HT reuptake site was less affected by these modifications,
as the methoxy linked compound 4c and its oxygen analogue 4b
displayed respectable inhibitory activities with pKi values of 7.5
and 7.0, respectively.
The breakthrough modification was identified when the 2-
ethoxypiperidine fragment in 2 was replaced with a piperazine
system. Compound 1 (SB-744185) showed outstanding affinity
for the 5-HT1A/1B/1D receptors, excellent 5-HT reuptake inhibitory
activity and high selectivity over a range of monoamine recep-
tors (5-HT2A pKi 5.9, 5-HT2B pKi 6.5, 5-HT6 pKi <5, 5-HT2C pKi
5.4 and D2 pKi 6.5). The distance between the quinoline ring
and the 3,4-dihydro-2H-benzoxazinone moiety seemed crucial
for the potency. Thus, a three carbon analogue 1a showed a con-
siderable reduction in affinity for all 5-HT1 receptors but a smal-
ler decrease in affinity for the 5-HT reuptake site. Rather
surprisingly, the four carbon linker compound 1b22 provided a
All compounds prepared were evaluated using published proce-
dures.14,15 Data expressed as pKi are shown in Table 1.
Introduction of a methyl group into the 1- or 2-position of the
2-ethoxy sidechain in 2 resulted in more than a 10-fold reduction
in potency at 5-HT1A/1B/1D receptors and the 5-HT reuptake site.
Interestingly, the individual enantiomers of 2a possessing the
methyl group at the 1-position had similar activity profiles at 5-
HT1 receptors whereas compound 2b as a racemic mixture, con-
taining the methyl group at the 2-position, showed good potency
only at the 5-HT1D receptor.
Replacement of the piperidine moiety in 2 with an azetidine
system provided compound 3a with an encouraging overall activ-
ity profile (5-HT1/SerT pKi >7.2). Disappointingly, further investiga-
tion of the nature of this sidechain resulted in less potent
analogues 3b–c.
Linking the quinoline ring to the 4-position of a piperidine
moiety via an oxygen atom or a methyloxy group proved detri-
Figure 2. Compound 1 docked (a) into the 5-HT1A receptor model and (b) into a model of the 5-HT transporter. Some key interactions are shown as dashed lines in (a).

H. T. Serafinowska et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5581–5585
5585
marked restoration of potency at the 5-HT1A/1B receptors and the
Acknowledgement
5-HT reuptake site however affinity for the 5-HT1D receptor re-
mained almost unchanged when compared to 1a. Compound
1c incorporating a one carbon sidechain22 (Fig. 1) was virtually
inactive.
We are indebted to our colleagues from the DMPK Department
at Psychiatry CEDD Harlow for providing in vivo data.
References and notes
We had reasoned that replacement of the flexible linker with
a piperazine ring directly attached to the quinoline would com-
pletely restrict movement of the ligand with respect to its inter-
action with the TM3 aspartate. This indeed proved to be the case
and docking of compound 1 into the 5-HT1A receptor model re-
vealed a binding mode which was somewhat different from that
described previously for compound 2.18 It was found to sit in a
more horizontal position with respect to the TM bundle axis.
In addition to the salt bridge formed between the piperazine
nitrogen and asp_3:3223, the quinoline ring sat in the ‘classic
1. (a) Asberg, M.; Erickson, B.; Matenson, B.; Traskman-Bendz, L.; Wagner, A. J.
Clin. Psychiatry 1986, 47, S23; (b) De Montigny, C.; Chaput, Y.; Blier, P. Int. Acad.
Biomed. Drug Res. 1993, 5, 8.
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E.; Rosenzweig-Lipson, S. J. Am. Soc. Exp. Neurotherapeutics 2005, 2, 590.
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agonist pocket’ forming a
p–p stacking with Phe_6:51 and to a
8. Artigas, F.; Celada, P.; Laruelle, M.; Adell, A. TIPS 2001, 22, 224.
9. Blier, P.; Bergeron, R. J. Clin. Psychiatry 1998, 59, 16.
lesser extent Phe_6:52. The quinoline nitrogen itself was 2.9 Å
from the hydroxyl of Thr_5:43 thus forming a weak hydrogen
bond. At 1.8 Å an arginine at the N-terminal region of the second
extracellular loop (Arg_4:65) formed a strong hydrogen bond to
10. Roberts, C.; Price, G. W.; Jones, B. J. Eur. J. Pharmacol. 1997, 326, 23.
11. (a) Dawson, L. A.; Ngueyen, H. Q. Neuropharmacology 2000, 39, 1044; (b)
Newman, M. E.; Shalom, G.; Ran, A.; Gur, E.; Van de Kar, L. D. Eur. J. Pharmacol.
2004, 486, 25; (c) Shalom, G.; Gur, E.; Van de Kar, L. D.; Newman, M. E. Naunyn-
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G. W. Neurosci. Lett. 2001, 300, 45.
the piperazine’s anilinic nitrogen. This arginine also had a
p-cat-
ion interaction with the face of the quinoline ring. Finally, the
1,4-benzoxazinone ring formed H-bonds with Ser_2:54 (2.8 Å)
and Ser_7:46 (1.8 Å) and a
p–p interaction with Tyr_7:43. Inter-
14. Scott, C.; Soffin, E. M.; Hill, M.; Atkinson, C. J.; Langmead, P. B.; Wren, P. B.;
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estingly, all these residues are conserved across the three
receptors.
Docking of compound 1 into the 5-HT transporter model
showed that the primary salt bridge interaction was with Asp_98
in TM1. This has been previously implicated from SDM experi-
ments24 with other monoaminergic transporters. The molecules
generally need to be fairly linear but otherwise the interactions
are largely hydrophobic and non-specific which would explain
the relative lower increase in potency observed between 1 and 2
(see Fig. 2b).
Encouragingly, pharmacokinetic profiling in the rat revealed
that compound 1 showed low in vivo clearance of 7 ml/min/kg,
good brain exposure with Cmax of 360 ng/mL, a B/B ratio of 1.0
and an estimated oral bioavailability of 72% (following oral admin-
istration at 3 mg/kg to the male rat).
15. Atkinson, P. J.; Bromidge, S. M.; Duxon, M. S.; Gaster, L. M.; Hadley, M. S.;
Hammond, B.; Johnson, C. N.; Middllemiss, D. N.; North, S. E.; Price, G. W.;
Rami, H. K.; Riley, G. J.; Scott, C. M.; Shaw, T. E.; Starr, K. R.; Stemp, G.; Thewlis,
K. M.; Thomas, D. R.; Thompson, M.; Vong, A. K. K.; Watson, J. M. Bioorg. Med.
Chem. Lett. 2005, 15, 737.
16. Starr, R. K.; Price, G. W.; Watson, J. M.; Atkinson, P. J.; Arban, R.; Melotto, S.;
Dawson, L. A.; Hagan, J. J.; Upton, N.; Duxon, M. S. Neuropsychopharmacology
2007, 32, 2163.
17. Bertani, B.; Borriello, M.; Bozzoli, A.; Bromidge, S. M.; Granci, E.; Leslie, C.;
Serafinowska, H.; Stasi, L.; Vong, A.; Zucchelli, V. WO Patent Int. Appl. 2004/
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18. Lovell, P. J.; Blaney, F. E.; Goodacre, C. J.; Scott, C. M.; Smith, P. W.; Starr, K. R.;
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In conclusion, extensive modifications of the 1-ethoxypiperi-
dine linker in compound 2 have led to the discovery of novel, po-
tent serotonin reuptake inhibitors displaying high affinities for
the 5-HT1A/1B/1D receptors. Compound 1 has a considerably im-
proved pharmacokinetic profile in comparison with 218 and it is
a suitable candidate for a further in vivo evaluation with the aim
of identifying more effective antidepressant agents.
21. Quillot, F. D.; Thibonet, J.; Marsacq, D.; Abarbri, M.; Duchene, A. Tetrahedron
Lett. 2000, 41, 9981.
22. Compounds 1b and 1c were prepared via alkylation of 6-(4-chlorobutyl)-2H-
1,4-benzoxazin-3(4H)-one and reductive amination of 3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-6-carbaldehyde (see Ref. 17).
23. The residue numbering scheme is from Ballesteros, J. A.; Weinstein, H. Methods
Neurosci. 1995, 25, 366.
24. Kitayama, S.; Shimada, S.; Xu, H.; Markham, L.; Donovan, D. M.; Uhl, G. R. Proc.
Natl. Acad. Sci. U.S.A. 1992, 89, 7782.