Benzimidazole- and indole-substituted 1,3′-bipyrrolidine benzamides as histamine H3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.11.122

Using a focused screen of biogenic amine compounds we identified a novel series of H₃R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the ser

Full text of DOI:10.1016/j.bmcl.2009.11.122

Bioorganic & Medicinal Chemistry Letters 20 (2010) 1237–1240
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzimidazole- and indole-substituted 1,30-bipyrrolidine benzamides
as histamine H3 receptor antagonists
b
c
c
c
Derek C. Cole a, , Jonathan L. Gross , Thomas A. Comery , Suzan Aschmies , Warren D. Hirst ,
Cody Kelley c, , Ji-In Kim b, Katie Kubek c, Xiaoping Ning c,à, Brian J. Platt c, Albert J. Robichaud b,
William R. Solvibile b, Joseph R. Stock a, Gregory Tawa b, Marla J. Williams b, John W. Ellingboe a
*
a Chemical Sciences, Wyeth Research, 401 N. Middletown Rd. Pearl River, NY 10965, United States
b Chemical Sciences, Wyeth Research, Princeton, NJ 08852, United States
c Neuroscience, Wyeth Research, Princeton, NJ 08852, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Using a focused screen of biogenic amine compounds we identified a novel series of H3R antagonists. A
preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimiza-
tion of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and
efficacy in both water intake and novel object recognition models.
Received 19 October 2009
Revised 20 November 2009
Accepted 24 November 2009
Available online 4 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Histamine H3 receptor antagonist
Histamine H3 receptor inverse agonist
Histamine-3 receptors (H3R) are one of four histamine G-pro-
tein coupled receptor subtypes (H1–4R).1–3 H1R and H2R are post-
synaptic receptors involved with allergic responses and gastric
acid secretion, respectively, while the H4R is located on T-cells,
neutrophils and monocytes and is implicated in inflammation pro-
cesses.4,5 The H3R is located presynaptically on histaminergic neu-
rons in the CNS, where it acts as an autoreceptor inhibiting the
synthesis and release of histamine. H3R also acts as a heterorecep-
tor on non-histaminergic neurons inhibiting the release of other
neurotransmitters, including acetylcholine, serotonin, noradrena-
line and dopamine. Postmortem studies in humans suggest that
decreased brain histamine levels may contribute to the cognitive
decline in Alzheimer’s disease.6 Furthermore H3R agonists have
been shown to impair memory,7,8 while H3R antagonists rescue
pharmacologically or genetically induced impairments in various
animal models.9–13 Based on these findings several H3R antagonists
have advanced to clinical trials for cognitive disorders and
dementia.14
implicated in potential pharmacokinetic liabilities17 and poor brain
penetration, so more recent analogs have focused on imidazole
ring replacements, typically with a tertiary amine, (see 3–5).18–20
Wyeth’s H3R program was initiated with a screen of our focused
biogenic amine library using a competitive binding assay21 with
[3H](R)-
a
-methylhistamine and cell membranes from HEK293T
O
N
HN
O
N
O
Cl
2 (FUB 181)
HN
1 (ciproxifan)
CN
N
N
N
O
O
3 (JNJ-5207852)
4 (ABT-239)
Early H3R antagonists maintained the histamine imidazole ring,
typically connected through an alkyl chain and polar fragment,
such as an ether, to a lipophilic moiety (see ciproxifan, 115 and
FUB 181, 216 Fig. 1). The presence of the imidazole ring has been
O
N
O
N
H
N
N
N
N
* Corresponding author. Tel.: +1 845 602 4619; fax: +1 845 602 5561.
E-mail address: coledc@wyeth.com (D.C. Cole).
O
N
5 (GSK-189254)
Present address: Rutgers University, Newark, NJ 08854, United States.
6a
à
Present address: J&J Pharmaceutical Research
08560, United States.
& Development, Titusville, NJ
Figure 1. Structures of H3R antagonists.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.122

1238
D. C. Cole et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1237–1240
Cl
cells over-expressing human H3 receptors (hH3R) and led to the
identification of advanced hit 6a. This compound had 102 nM bind-
ing affinity for hH3 receptors and was a potent, full antagonist,
inhibiting cAMP production in the hH3 functional assay22 with a
KB value of 11 nM. The compound also showed good overall
physiochemical properties with excellent solubility in aqueous
O
H
N
N
N
a, b, c
R
R1
buffer (>100
l
g/mL), good permeability in both PAMPA23 (4.4 ꢀ
N
10ꢁ6 cm/s) and PAMPA–BBB24 (9.4 ꢀ 10ꢁ6 cm/s) assays and passive
diffusion in a Caco-2 assay (PA>B = 84.9 ꢀ 10ꢁ6 cm/s, BA/AB = 1.3)
suggesting potentially good absorption, permeability and BBB pen-
etration properties. 6a also had low inhibition of Cyp450 enzymes
and moderate to rapid metabolism in human and rat liver micro-
somes. However, 6a has a high molecular weight (424) and c log P
(4.43), resulting in relatively low ligand efficiency (0.3) and high
LELP (c log P/LE) (14.8).25 Therefore, initial efforts were directed
at reducing the MW and c log P of the compounds to more optimal
lead-like space, and are described here.
7
NR2R3
HN
OH
HN
d, e
d
NR2R3
OMs
N
N
O
O
HNR2R3
f
The synthesis of 6a and related compounds begins with the
deprotonation of benzimidazoles followed by coupling with
methyl 4-(bromomethyl)benzoate (Scheme 1). Hydrolysis of the
ester followed by acid chloride formation generates intermediates
7, which are coupled with readily available N,N-dialkylpyrrolidin-
3-amines to afford the desired products 6. Alternatively, coupling
of the acid chlorides with 3-pyrrolidinol followed by mesylate for-
mation leads to intermediate 8, and displacement with secondary
amines gives the desired products 6. Displacement of the mesylate
prepared from (R)- or (S)-3-pyrrolidinol with inversion of the
asymmetric center is used for a stereospecific synthesis of analogs.
Initial examination of the connectivity requirement around the
central phenyl ring was accomplished using both 2- and 3-(bromo-
methyl)benzoate (Scheme 1, step a).
N
N
N
R1
R1
N
6
8
Scheme 1. Reagents and conditions: (a) NaH, methyl 2-, 3- or 4-(bromo-
methyl)benzoate, THF/DMF (5:1), rt 16 h; (b) LiOH, MeOH/water (2:1), rt, 16 h;
(c) oxalyl chloride (2 M soln. in DCM), DMF (2 drops), DCM rt, 2 h; (d) cyclic amine,
DIEA, THF, rt, 2–8 h; (e) Et3N, MsCl, DCM 0 °C to rt, 16 h; (f) amine, DMF, rt, 16 h.
NR2R3
H
N
NR2R3
N
R1
O
To vary the benzimidazole portion of the series, 3-amino substi-
tuted pyrrolidines are coupled with 4-chloromethyl benzoyl chlo-
ride affording the chloromethyl derivative 9, which is subsequently
reacted with benzimidazoles and indoles to give the desired tar-
gets 6 (Scheme 2). The 1,30-bipyrrolidines 10 are prepared from
3-aminopyrrolidines by N-Boc protection of the secondary amine,
bis-alkylation of the primary amine and deprotection (Scheme 3).
All of the compounds were evaluated for their ability to displace
X
NR2R3
N
O
N
H
a
b
N
X
R1
Cl
9
6
[3H](R)-
a-methylhistamine binding to cloned human H3 receptors
Scheme 2. Reagents and conditions: (a) DIEA, 4-chloromethyl benzoyl chloride,
THF, rt, 2–8 h; (b) NaH, THF/DMF (5:1), rt, 16 h.
Table 1
Binding affinity and functional activity of 6 analogs
stably expressed in HEK293T cells. Compounds demonstrating
suitable affinity were assayed for inhibition of cAMP production,
and shown to be full antagonists. The results are summarized in
Tables 1–3.
O
N
NR1R2
N
R3
Variations of the basic amine group (NR1R2) present in 6a led to
the identification of the pyrrolidino group (6c, Table 1) with a 10-
fold improvement in binding affinity. Interestingly, the enantio-
meric pairs (e.g., (R)- and (S)-6a) showed only a sevenfold eudismic
ratio with respect to both affinity and functional activity in favor of
the eutomer (S)-6a.
N
b
Compd
NR1R2
R3
hH3 Kia (nM)
hH3 Kb (nM)
6a
NMe2
Ph
Ph
Ph
Ph
Ph
Ph
100
91
10
1200
65
440
235
390
17
11
4
6b
NMeEt
6c
6d
(S)-6a
(R)-6a
6e
Pyrrolidine
NMeEtOH
NMe2
NMe2
NMe2
In order to reduce the MW and c log P, a series of analogs were
prepared in which the 2-phenyl group in 6a is replaced with more
polar and/or smaller groups. We were gratified to see that indeed
this group could be replaced by the 2-pyridyl group (6e) with only
a slight reduction in potency, whereas replacement with the obvi-
ously smaller methyl group (6g) provides a significant (sixfold) in-
crease in affinity.
16
108
2-pyridyl
H
Me
H
6f
NMe2
3
6g
NMe2
6h
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
Pyrrolidine
23
10
27
(S)-6h
(R)-6h
(S)-6i
(R)-6i
H
H
0.5
Combining the smaller 2-substituents (i.e., H and Me) with the
preferred pyrrolidine tertiary amine leads to 6h–6i. Again in gen-
eral the (S)-isomer has slightly higher affinity and functional activ-
ity than the distomer with the eutomers exhibiting sub-nanomolar
inhibition of cAMP production. Analog 6k (Table 2) with 1,3
connectivity loses ꢂ20-fold in binding affinity, while the 1,2-con-
Me
Me
5
3
0.3
2
Displacement of [3H](R)-
a-methylhistamine binding to cloned hH3 receptors
stably expressed in HEK293T cells.
Inhibition of cAMP production in HEK293T cells stably transfected with hH3
receptors. Mean of three determinations with a standard error of 30%.
a
b

D. C. Cole et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1237–1240
1239
Table 4
NH2
Pharmacokinetic properties for (S)-6h and (S)-6n in rats
a, b
c
N
N
(S)-6h
(S)-6n
HN
N
HN
iv dose (mg/kg)
Clp (mL/min/kg)
Vss (L/kg)
2
56
3.6
2
112
7.3
Boc
10
po dose (mg/kg)
Cmax (ng/mL)
Tmax (h)
AUC (h ng/ml)
t1/2
10
1751
0.4
2736
1.3
93
10
22
1.2
63
1.9
5
Scheme 3. Reagents and conditions: (a) (Boc)2O, MeOH, rt, 16 h; (b) 1,4-dibroo-
mobutane, K2CO3, DMF, 110 °C, 16 h; (c) 2 N HCl in dioxane, rt, 3 h.
Table 2
Binding affinity of 6 analogs
F%
ip dose (mg/kg)
Cmax brain/plasma (b/p) (ng/mL)
Cmax brain (nM)
%Fu (brain)
10
92/388
245
30
O
N
6536/1086
16019
3.5
13,8
Tmax b/p (h)
AUC b/p (h ng/ml)
b/p ratio
1.0/1.0
231/1039
0.2
0.5/0.5
15007/2182
6.9
N
N
N
Compd
Connectivity
hH3 Ki (nM)
6h
6k
6l
1,4
1,3
1,2
23
400
4000
Table 5
Calculated and measured properties of selected 6 analogs
Displacement of [3H]-(R)-
a-methylhistamine binding to cloned hH3 receptors sta-
Compd
MW
c log P
p log D
PSAa
Peb
BBBc
aq sol.d
bly expressed in HEK293T cells. Mean of three determinations with a standard error
of 30%.
6a
424.5
374.5
388.5
373.5
407.9
407.9
407.9
4.2
2.6
2.9
3.6
4.4
4.4
4.4
3.4
1.4
1.6
2.3
3.0
3.0
3.0
41.3
41.4
41.4
28.5
28.5
28.5
28.5
4.4
0.3
0.3
8.3
6.5
7.3
7.8
9.4
3.7
4.0
9.4
7.0
8.6
8.1
>100
51
32
28
18
(S)-6h
(S)-6i
(S)-6m
(S)-6n
(S)-6o
(S)-6p
Table 3
13
10
Binding affinity and functional activity of 6 analogs
O
a
b
c
PSA = polar surface area.
N
Pe = effective permeability measured by PAMPA method (ꢀ10ꢁ6 cm/s).23
N
BBB = blood–brain barrier permeability measured by PAMPA–BBB method
(ꢀ10ꢁ6 cm/s).24
N
X
d
Aqueous solubility lg/mL at pH 3.1.
Compd
X
hH3 Ki (nM)
hH3 Kb (nM)
(S)-6m
(S)-6n
(S)-6o
(S)-6p
H
15
2.4
0.3
2.1
0.9
However, the brain and plasma exposure measured after
a
7-Cl
6-Cl
5-Cl
2.5
150
130
30 mg/kg ip injection in rats shows a significant improvement with
AUCs of 15007 and 2182 h ng/mL for brain and plasma, respec-
tively, and a brain to plasma ratio of 6.9. The fraction of (S)-6n un-
bound in brain is 3.5%, giving a free drug concentration of 229 ng/
mL or 562 nM at Tmax, approximately 25-fold greater than the rH3
affinity (rH3 Ki = 21.7 nM). Compound (S)-6n demonstrates >1000-
fold selectivity for hH3R over hH1R and hH2R receptors and >100-
fold selectivity over various serotonin (5-HT2a,2c,6,7), dopamine
Displacement of [3H]-(R)-
a-methylhistamine binding to cloned hH3 receptors sta-
bly expressed in HEK293T cells. Mean of three determinations with a standard error
of 30%.
nected analog 6l is nearly 200-fold less potent, showing a strict
requirement for the 1,4 substitution pattern among these ligands.
The pharmacokinetic profile of (S)-6h in rats indicates high
clearance, moderate volume of distribution and half-life and excel-
lent bioavailability (Table 4). Brain and plasma exposure measured
after a 10 mg/kg ip injection show AUCs of 231 and 1039 h ng/mL
respectively, indicating a brain to plasma ratio of 0.22. The low
brain exposure is somewhat surprising given the low MW, c log P
and polar surface area (PSA) of (S)-6h (see Table 5).26,27
Replacing the benzimidazole with an indole ((S)-6m) and
chloro-substituted indoles ((S)-6n–p) results in compounds which
are calculated to have a slightly higher log P and lower PSA. While
the solubility of these analogs is slightly reduced the permeability
in both PAMPA and PAMPA–BBB is improved significantly, suggest-
ing potentially improved brain to plasma ratios. The unsubstituted
indole analog (S)-6m demonstrates comparable activity to the cor-
responding benzimidazole ((S)-6h) however the 7-chloro deriva-
tive (S)-6n has sixfold increased affinity and functional activity at
the hH3R (Table 3).
(D2) and alpha adrenergic (a1,2a) receptors in binding assays.
The selective H3R agonist (R)-a-methylhistamine has been
shown to induce a dose dependent increase in water consumption
in rats mediated by H3R within the CNS.28,29 This increased water
intake effect was blocked by (S)-6n dosed intraperitoneally (ip)
at both 10 and 30 mg/kg (Fig. 2).
Furthermore, H3R antagonists have been shown to reverse de-
lay-dependent deficits in rodent novel object recognition by
enhancing memory encoding and/or retention.30,31 In the novel ob-
ject recognition model, rats previously exposed to identical objects
can discriminate between a novel object and a familiar, previously
experienced object, during a subsequent trial. Figure 3 shows a sta-
tistically significant differential exploration of the novel and famil-
iar object for rats dosed with (S)-6n (minimally efficacious
dose = 0.3 mg/kg) prior to the learning trial. The preferential explo-
ration of the novel object demonstrates enhanced object recogni-
tion memory in rats dosed with (S)-6n relative to those dosed
with vehicle and represents efficacy as a cognitive enhancer.
In summary, we have identified a potent and selective series
of H3R antagonists. Optimization led to analogs with increased
Unfortunately, the rat pharmacokinetic profile of (S)-6n shows
rapid clearance, low exposure and oral bioavailability (Table 4).

1240
D. C. Cole et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1237–1240
2. Lovenberg, T. W.; Roland, B. L.; Wilson, S. J.; Jiang, X.; Pyati, J.; Huvar, A.;
6
4
2
0
Jackson, M. R.; Erlander, M. G. Mol. Pharmacol. 1999, 55, 1101.
3. Hough, L. B. Mol. Pharmacol. 2001, 59, 415.
4. Hill, S. J.; Ganellin, C. R.; Timmerman, H.; Schwartz, J. C.; Shankley, N. P.; Young,
J. M.; Schunack, W.; Levi, R.; Haas, H. L. Pharmacol. Rev. 1997, 49, 253.
5. Hofstra, C. L.; Desai, P. J.; Thurmond, R. L.; Fung-Leung, W. P. J. Pharmacol. Exp.
Ther. 2003, 305, 1212.
*
6. Panula, P.; Rinne, J.; Kuokkanen, K.; Eriksson, K. S.; Sallmen, T.; Kalimo, H.;
Relja, M. Neuroscience 1998, 82, 993.
*
7. Blandina, P.; Giorgetti, M.; Bartolini, L.; Cecchi, M.; Timmerman, H.; Leurs, R.;
Pepeu, G.; Giovannini, M. G. Br. J. Pharmacol. 1996, 119, 1656.
8. Prast, H.; Argyriou, A.; Philippu, A. Brain Res. 1996, 734, 316.
9. Miyazaki, S.; Onodera, K.; Imaizumi, M.; Timmerman, H. Life Sci. 1997, 61, 355.
10. Meguro, K.; Yanai, K.; Sakai, N.; Sakurai, E.; Maeyama, K.; Sasaki, H.; Watanabe,
T. Pharmacol. Biochem. Behav. 1995, 50, 321.
11. Fox, G. B.; Pan, J. B.; Esbenshade, T. A.; Bennani, Y. L.; Black, L. A.; Faghih, R.;
Hancock, A. A.; Decker, M. W. Behav. Brain Res. 2002, 131, 151.
12. Komater, V. A.; Browman, K. E.; Curzon, P.; Hancock, A. A.; Decker, M. W.; Fox,
G. B. Psychopharmacology (Berl.) 2003, 167, 363.
#
#
13. Komater, V. A.; Buckley, M. J.; Browman, K. E.; Pan, J. B.; Hancock, A. A.; Decker,
M. W.; Fox, G. B. Behav. Brain Res. 2005, 159, 295.
14. Celanire, S.; Wijtmans, M.; Talaga, P.; Leurs, R.; de Esch, I. J. Drug Discovery
Today 2005, 10, 1613.
0
0
3
10
30
15. Esbenshade, T. A.; Krueger, K. M.; Miller, T. R.; Kang, C. H.; Denny, L. I.; Witte, D.
G.; Yao, B. B.; Fox, G. B.; Faghih, R.; Bennani, Y. L.; Williams, M.; Hancock, A. A. J.
Pharmacol. Exp. Ther. 2003, 305, 887.
(S)-6n (mg/kg, i.p.)
16. Stark, H.; Huls, A.; Ligneau, X.; Purand, K.; Pertz, H.; Arrang, J. M.; Schwartz, J.
C.; Schunack, W. Arch. Pharm. (Weinheim) 1998, 331, 211.
Ramh (2.5 mg/kg, i.p.)
17. Yang, R.; Hey, J. A.; Aslanian, R.; Rizzo, C. A. Pharmacology 2002, 66, 128.
18. Apodaca, R.; Dvorak, C. A.; Xiao, W.; Barbier, A. J.; Boggs, J. D.; Wilson, S. J.;
Lovenberg, T. W.; Carruthers, N. I. J. Med. Chem. 2003, 46, 3938.
19. Cowart, M.; Pratt, J. K.; Stewart, A. O.; Bennani, Y. L.; Esbenshade, T. A.;
Hancock, A. A. Bioorg. Med. Chem. Lett. 2004, 14, 689.
Figure 2. Effect of (S)-6n on (R)-a-methylhistamine (Ramh)-induced water con-
sumption in rats. *p <0.05 versus veh; #p <0.05 versus Ramh alone.
20. Heightman, T. D. WO2004035544, 2004.
Novel
40
21. HEK293T cells expressing the human cloned histamine H3 receptor were
harvested in phosphate-buffered saline (PBS) and pelleted by centrifugation at
1000g for 5 min at 4 °C and membranes were prepared by homogenizing the
cell pellets in ice-cold 50 mM Tris–HCl buffer, pH 7.4 and 0.5 mM EDTA for
approximately 30 s using a Polytron homogenizer. The homogenates were
centrifuged at 40,000g for 30 min at 4 °C, and the resulting pellet was re-
homogenized and centrifuged as described above. The membranes were finally
Familiar
30
*
**
*
resuspended in 50 mM Tris–HCl buffer, pH 7.4 at
approximately 1 mg protein/mL, and were stored at -70 °C until use.
a concentration of
Receptor binding studies were carried out on these membranes in 50 mM
20
10
0
Tris–HCl buffer, pH 7.4, at room temperature. Assays consisted of 100
displacing compound (final concentration of 0.05 nM–500 nM) or buffer, 20
of [3H]R- -methylhistamine at a final concentration of 5 nM and the reaction
was initiated by the addition of 100 mL of human H3 receptor membranes
(30 g of protein/well). Nonspecific binding was determined in the presence of
lL of
lL
a
l
10 mM clobenpropit. The experiments were terminated by rapid filtration
through a GF/B filter plate (presoaked in 0.1% (v/v) polyethyleneimine), and
then the filters were washed with ice-cold buffer (50 mM Tris–HCl). Filters
were dried and then 25 lL of Microscint 20 was added to each well.
Radioactivity was determined by liquid scintillation spectrometry using a
Packard TopCount.
0
0.1
0.3
1
3
(S)-6n (mg/kg i.p.)
22. Functional in vitro activity of the compounds was determined in cAMP
accumulation assays. Culture media was removed from the cells and they were
washed twice with PBS (Ca2+/Mg2+-free) containing 500
l
M IBMX. Cells were
detached, by gentle tapping, and resuspended in the same buffer. 2000 cells/
well were incubated with histamine, 10 forskolin and test
compounds (0.03 nM–10 M) in a total volume of 30 L in 96-well plates for
Figure 3. Novel object recognition in rats after ip dosing of the H3R antagonist (S)-
6n. *p <0.03; **p <0.005.
1
lM
lM
l
l
30 min at 30 °C. Cyclic AMP levels were then measured using the HitHunter
cAMP kit (DiscoveRx, Fremont, CA) according to the manufacturer’s
affinity and potency, and further modulation of the physical prop-
erties of the series led to (S)-6n, which has excellent brain to plas-
ma exposure and demonstrated efficacy in both the water intake
and novel object recognition rat models.
instructions. Chemiluminescent signals were detected using
TopCount. Data were analyzed using Prizm.
a Packard
23. Kerns, E. H.; Di, L. Drug Discovery Today 2003, 8, 316.
24. Di, L.; Kerns, E. H.; Fan, K.; McConnell, O. J.; Carter, G. T. Eur. J. Med. Chem. 2003,
38, 223.
25. Keseru, G. M.; Makara, G. M. Nat. Rev. Drug Disc. 2009, 8, 203.
26. Clark, D. E. Drug Discovery Today 2003, 927.
Acknowledgments
27. Lobell, M.; Molnar, L.; Keseru, G. M. J. Pharm. Sci. 2003, 92, 360.
28. Clapham, J.; Kilpatrick, G. J. Eur. J. Pharmacol. 1993, 232, 99.
29. Kraly, F. S.; Tribuzio, R. A.; Kim, Y. M.; Keefe, M. E.; Finkell, J. Physiol. Behav.
1995, 58, 1091.
We thank Christine Huselton, Jonathan Schantz, William Adams
and Adedayo Adedoyin for providing PK data.
30. Blandina, P.; Giorgetti, M.; Cecchi, M.; Leurs, R.; Timmerman, H.; Giovannini, M.
G. Inflamm. Res. 1996, 45, S54.
References and notes
31. Pascoli, V.; Boer-Saccomani, C.; Hermant, J. F. Psychopharmacology (Berl) 2009,
202, 141.
1. Arrang, J. M.; Garbarg, M.; Schwartz, J. C. Nature 1983, 302, 832.