The first cns-active carborane: A novel p2x7 receptor antagonist with antidepressant activity

Article abstract of DOI:10.1021/cn500054n

Relative to other polycyclic frameworks (1-3), a carborane cage (4 and Cs·5) exerts a significant biological effect as an inhibitor of the purinergic P2X₇ receptor (P2X₇R) which allows one to target depression in vivo and thus demonstrate, for the first time, that a carborane has the capacity to modify CNS activity.

Full text of DOI:10.1021/cn500054n

Letter
pubs.acs.org/chemneuro
The First CNS-Active Carborane: A Novel P2X7 Receptor Antagonist
with Antidepressant Activity
Shane M. Wilkinson,† Hendra Gunosewoyo,† Melissa L. Barron,‡,⊥ Aurelie Boucher,‡,⊥
Michelle McDonnell,⊥,§ Peter Turner,† Daniel E. Morrison,† Maxwell R. Bennett,⊥ Iain S. McGregor,∥
Louis M. Rendina,*,† and Michael Kassiou*,†,‡,⊥
†School of Chemistry, ‡Faculty of Health Science, §Discipline of Pharmacology, and ∥School of Psychology, Sydney University, NSW
2006, Australia
⊥
Brain and Mind Research Institute, 100 Mallett Street, Camperdown, NSW 2050, Australia
S
* Supporting Information
ABSTRACT: Relative to other polycyclic frameworks (1−3), a
carborane cage (4 and Cs·5) exerts a significant biological effect
as an inhibitor of the purinergic P2X7 receptor (P2X7R) which
allows one to target depression in vivo and thus demonstrate, for
the first time, that a carborane has the capacity to modify CNS
activity.
KEYWORDS: Carborane, blood-brain barrier, P2X7, polycycle, antidepressant
ince the discovery by Davies et al.1 in 1964 that 1-
toward moisture and biological degradation, and their low
Saminoadamantane (amantadine) displayed antiviral effects, toxicity. Only recently has it been conclusively demonstrated
that carboranes can cross the BBB,6 but never before has it
polycyclic hydrocarbon cage compounds, including adaman-
been reported that carboranes can elicit a CNS-modifying
effect. Herein we report the first example of a carborane-
containing compound with the ability to target the purinergic
P2X7 receptor (P2X7R) in vivo, resulting in the observation of
antidepressant activity in mice.
The P2X7R is a nonsensitizing, cation-selective ion channel
which is directly gated by ATP. However, upon repetitive or
prolonged agonist exposure, the P2X7R forms a nonselective
pore which is permeable by cations up to 900 Da.7 Formation
of this pore results in apoptosis and the production and release
of the cytokine interleukin 1β (IL-1β). High levels of IL-1β in
the brain have been implicated in depression,8 hyperalgesia9
and neurodegeneration.10 The development of a P2X7R
antagonist is thus presumed to have antidepressant, analgesic
and/or neuroprotective properties.
In recent years, we and others have comprehensively
explored the chemical space around AstraZeneca’s adamantanyl
benzamide series.11 Removing or flattening the adamantane
polycycle to a simpler cycloalkane was detrimental to P2X7R
antagonism, thereby suggesting that occupancy of a globular
hydrophobic pocket was found to be central to potent P2X7R
antagonism.12 To examine this concept further, we explored the
tane, trishomocubane, and cubane, have made unique
contributions to medicinal chemistry.2 Their rigid scaffold
provides compounds with improved metabolic stability and
allows substituents to be precisely positioned in three
dimensions. More importantly, they facilitate transport across
the blood-brain barrier (BBB) which is a major challenge in
central nervous system (CNS) drug development.
A recently introduced polycycle in medicinal chemistry is the
carborane cluster.3 Carboranes are pseudoaromatic polyhedral
clusters consisting of boron, carbon, and hydrogen atoms which
have been utilized as a rich source of boron for boron neutron
capture therapy (BNCT).4 Carboranes can also act as useful
bioisosteres for phenyl rings and adamantane as their size and
lipophilicity are comparable but their unique structures allow
new frontiers to be explored in drug development.3,5 An
additional feature of carboranes for application in medicinal
chemistry is the ability to convert the neutral, lipophilic closo
cluster into the anionic, hydrophilic nido species in a single
synthetic step and still preserve much of the steric features of
the closo cluster. The incorporation of carboranes as a unique
bioisostere in medicinal chemistry is still in its infancy, but
there is significant interest in the exploitation of this polycycle
in recent years which can, in part, be attributed to an expanding
field of synthetic methodology, their remarkable stability
Published: April 2, 2014
© 2014 American Chemical Society
335
dx.doi.org/10.1021/cn500054n | ACS Chem. Neurosci. 2014, 5, 335−339

ACS Chemical Neuroscience
Letter
a
Scheme 1. Synthesis of Adamantane Benzamide 1 and Its Polycyclic Analogues 2−5
a
Conditions: (a) CDI, THF, rt, 1 h, then 28% NH3(aq), rt, 4 h; (b) LiAlH4, THF, reflux, 20 h; (c) 2-chloro-5-methoxybenzoic acid 9, (COCl)2, THF,
rt, 1 h, then amine, THF, Et3N, rt, 16 h; (d) (i) NaOH (1 equiv), MeOH, THF, rt, 16 h, then HCl(aq), (ii) (COCl)2, CH2Cl2, rt, 1 h, then 2-
mercaptopyridine N-oxide sodium salt, hν, DMAP, CHCl3, reflux, 1 h, (iii) NaOH, MeOH, reflux, 1 h; (e) PhMe, −10 °C to rt, 3 h, 78%; (f) hν,
Me2CO/hexanes, 8 h, 92%; (g) Zn, AcOH, rt, 5 h, 90%; (h) NaBH4, EtOH/H2O, rt, 3 h, quant.; (i) 33% HBr in CH3CO2H, sealed tube, 100 °C, 16
h; (j) t-BuOK, Et2O, rt, 16 h, 70% over 2 steps; (k) (i) TosMIC, t-BuOK, (MeOCH2)2, EtOH, 5-35 °C, (ii) LiAlH4, Et2O, reflux, 16 h, (iii) anhyd.
HCl, Et2O; (l) 2-chloro-5-methoxybenzoic acid 9, EDC·HCl, HOBt, NMM, CH2Cl2, 0 °C to rt, 16 h; (m) CsF (3 equiv), EtOH, reflux, 24 h.
Figure 1. ORTEP depictions of 2 and 4 shown with 50% displacement ellipsoids.
effect of substituting the adamantane of lead benzamide 1 with
a variety of polycyclic cages (Scheme 1). This series comprised
a cubanyl 2, trishomocubanyl 3 and the first use of carboranes
within this class, namely, closo-1,2-carboranyl 4 and nido-1,2-
carboranyl benzamide 5.
RESULTS AND DISCUSSION
■
The smallest polycycle of the series is the cubanyl benzamide 2
prepared from the commercially available methyl cubane-1,4-
diester 6 via a decarboxylation to yield cubane carboxylic acid 7
which was converted to cubanylmethylamine 8, through its
336
dx.doi.org/10.1021/cn500054n | ACS Chem. Neurosci. 2014, 5, 335−339

ACS Chemical Neuroscience
Letter
carboxamide, and subsequently coupled to 2-chloro-5-methox-
ybenzoic acid 9. Its X-ray crystal structure (Figure 1) illustrates
the highly strained 90° bond angles associated with this
polycycle.
phate (BzATP), a synthetic and more potent analogue of ATP
at P2X7R, was used (100 μM) to induce P2X7R pore formation.
Each compound was assessed over a concentration range of 1
nM to 10 μM with the pIC50 values (Table 1) determined by
spectrofluorimetry to quantify the amount of YO-PRO-1
uptake into the cells following pore formation.
The polycyclopentyl framework of D3-trishomocubanyl
benzamide 3 was prepared in 10 steps initiated by the Diels−
Alder cycloaddition reaction between cyclopentadiene 10 and
benzoquinone 11. A 2 + 2 photocyclization furnishes
Cookson’s diketone 12 which is reduced over two steps to
open the cyclobutane ring and generate the lactol 13.
Bromination followed by base-catalyzed cyclization affords the
D3-trishomocubanone 14. This ketone 14 was subjected to a
Van Leusen reaction using TosMIC with the corresponding
nitrile reduced with LiAlH4 to the precursory D3-trishomocu-
banylmethylamine 15. The amine 15 was then coupled to
benzoic acid 9 to afford the trishomocubanyl benzamide 3.
The closo-1,2-carboranyl 4 was synthesized in 64% yield from
the amide coupling reaction between closo-1,2-carboranylme-
thylamine hydrochloride13 16·HCl and 2-chloro-5-methoxy-
benzoic acid 9. A single crystal X-ray structure of 4 was
successfully obtained (Figure 1) which confirms the presence of
the closo-1,2-carborane cage. The closo-1,2-carboranyl benza-
mide 4 was subsequently converted to the nido-7,8-carborane
analogue Cs·5 by means of a mild deboronation reaction
(Scheme 1) with CsF/EtOH in a single, high-yielding step
(95%).
Table 1. hP2X7R Inhibition Functional Assay and Lipophilic
Evaluation of the Benzamide Series 1−4 and Cs·5
a
b
c
d
benzamide
pIC50
cLogP
log D7.4
LLE
adamantanyl 1
7.98 0.15
6.36 0.12
7.49 0.19
8.07 0.19
6.43 0.10
4.12
1.46
2.98
4.30
3.42
4.31
4.29
1.44
3.68
2.94
3.18
3.78
4.99
cubanyl 2
trishomocubanyl 3
closo-carboranyl 4
nido-carboranyl Cs·5
e
−
e
−
a
pIC50 values were derived from concentration−response curves (n >
b
4) SD. Predicted using Spartan 10 (V1.1.0) using H−F calculations
with a 6-31G* basis set. Experimentally determined by HPLC
c
d
method. Ligand−lipophilicity efficiency (LLE) = pIC50 − log D.
e
Could not be predicted with software.
A trend was observed between the potency of hP2X7R
inhibition and the size of the polycyclic cage with those
molecules possessing larger polycycles, that is, 1, 3, and 4,
causing greater inhibition of hP2X7R pore formation. Indeed,
the lead adamantanyl benzamide 1 demonstrated potent
Compounds 1−4 and Cs·5 were assessed in vitro for their
ability to inhibit human P2X7R (hP2X7R) pore formation by
using a functional dye uptake assay in THP-1 cells (Figure 2).14
The P2X7R pore formation was determined by means of an
agonist-induced uptake of YO-PRO-1, a large, cationic dye
molecule (629 Da). 3′-Benzoylbenzoyl adenosine-5′-triphos-
hP2X7R antagonism (pIC50 = 7.98
0.15). Contracting the
size of the adamantane cage in 1 by the use of a D3-
trishomocubane group (3) reduced potency by approximately
one-third, while reducing the polycycle volume even further to
a cubane (2) resulted in a decrease of over one-order of
magnitude in hP2X7R inhibition. The closo-1,2-carborane cage
is equivalent in size to adamantane but is more lipophilic due to
the presence of low-polarity B−H bonds.15 Interestingly, the
closo-1,2-carboranyl benzamide 4 displayed a slight improve-
ment in hP2X7R antagonism over 1. The nido-7,8-carboranyl
benzamide Cs·5 was prepared with the aim of retaining potency
through its polycyclic cage, while simultaneously reducing the
lipophilic properties due to its anionic charge. Indeed, the
anionic charge of Cs·5 resulted in a dramatic diminution in
hP2X7R pore inhibition when compared to 4. It is worthy to
note that the Hill slope calculated for the adamantanyl 1 and
closo-1,2-carboranyl benzamide 4 is −4.3 and −2.7, respectively
(whereas the remaining benzamides equate to −1). We
speculate this is due to cooperativity, which is known to
occur for related adamantane antagonists of the P2X7R.16
Future work involving radioligand binding is intended to
elucidate the mechanistic aspects of these ligands.
Animal behavioral tests were performed in order to assess the
in vivo efficacy of benzamides 1−4 and Cs·5, evaluate their
BBB penetration, and also validate their CNS activity. The
antidepressant potential of the benzamides 1−4 and Cs·5 were
evaluated by means of a forced-swim test (FST) which induces
depressive behavior (Figure 2).17 The FST paradigm utilizes
the observation that rodents initially engage in escape-directed
behavior when placed in an inescapable scenario, but will
eventually develop a passive immobile posture which can be
measured as a model of depression.18 It has also been recently
shown that P2X7R knockout (KO) mice show resilience in the
FST (i.e., increased mobility compared to WT mice), an
observation which both validates the use of such a behavioral
Figure 2. Inhibition of human P2X7R pore formation by (a)
adamantanyl 1, (b) cubanyl 2, (c) trishomocubanyl 3, (d) closo-1,2-
carboranyl 4, and (e) nido-7,8-carboranyl Cs·5 benzamides using a
functional dye uptake assay in THP-1 cells. Pore formation was
assessed by a BzATP-induced uptake of YO-PRO-1.
337
dx.doi.org/10.1021/cn500054n | ACS Chem. Neurosci. 2014, 5, 335−339

ACS Chemical Neuroscience
Letter
model for this target and also provides a maximal response
benchmark for P2X7R antagonism.19
may be inhibiting BBB penetration, which consequently
eliminated their efficacy in the FST. Interestingly, substituting
adamantane for closo-1,2-carborane in the benzamides does not
increase the lipophilicity of the drug as previously reported in
literature.15 The log D7.4 of 4 is almost equal to that of 1.
However, if 4 is converted to Cs·5, a significant drop in
lipophilicity by 3 orders of magnitude is observed, and one can
thus readily convert a BBB-impenetrable molecule into a CNS-
active drug in a single synthetic step.
Prior to the FST, a drug tolerability test was performed on
the mice with doses up to 20 mg/kg showing no adverse effects
to body temperature, locomotor activity, or body weight (see
the Supporting Information). The mice were then injected with
20 mg/kg of 1−4 and Cs·5 or vehicle and subjected to a 6 min
FST. Compared to wild-type (WT) mice, P2X7R KO mice
remained 32
14% more mobile in the FST, thus
demonstrating their antidepressant-like phenotype. Remark-
ably, the trend observed in the functional cell assay was
reversed in the in vivo behavioral assay; that is, compounds 1, 3,
and 4 exerted no significant antidepressant behavior. In
contrast, despite 2 and Cs·5 having the lowest pIC50 values
in the series, these compounds were shown to impart significant
antidepressant activity (16% and 13% more mobile than WT,
respectively). It should be noted that the FST experiments were
all performed with mass concentrations of 20 mg/kg and so the
relative administered concentration for benzamide Cs·5 (43
μmol/kg) was lower than that of the other benzamides 1−4
(59−66 μmol/kg) assessed in this study due to its significantly
higher MW; that is, Cs·5 inferred significant antidepressant
activity of the series despite it being assessed at the lowest dose
concentration. Furthermore, despite a very limited collection of
studies that demonstrate the capacity of carboranes to cross the
BBB,6b this is the first study which has demonstrated the ability
of a carborane to modify CNS activity.
The ligand−lipophilicity efficiency (LLE)22 evaluation of the
benzamide series (Table 1, column 5) establishes the nido-7,8-
carborane Cs·5 as a good lead candidate (LLE ≥ 5). Despite its
equivalent in vitro and in vivo results, the higher lipophilicity of
cubanyl 2 suggests it will be less bioavailable and may be more
susceptible to metabolism. Regardless of its adverse lip-
ophilicity, the high potency of the closo-1,2-carboranyl 4
makes it the second best candidate by LLE analysis. However,
based on its inactivity in vivo, further structure−activity studies
of the aryl moiety would need to be undertaken before this
compound could be considered for any further development.
CONCLUSION
■
In conclusion, this study makes a significant contribution to the
emerging area of utilizing carboranes as pharmacophores in
drug development. The equivalent size and lipophilicity of the
closo-carborane and the adamantane cages led to identical
biological results in this work. However, closo-1,2-carborane has
a distinct advantage over adamantane due to its robust
exogenous scaffold providing excellent metabolic stability and
the ability to be converted readily to its corresponding anionic
nido-carborane cluster. The significant in vivo antidepressant
activity of Cs·5 is consistent with CNS P2X7R inhibition. This
study represents the first account of a carborane molecule
possessing CNS-modifying activity, thereby pioneering the
application of carboranes in future CNS drug development
strategies.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and data for both chemical and
biological studies. This material is available free of charge via
the Internet at http://pubs.acs.org.
Figure 3. Average immobility time (s) in which mice remained
stationary over the final 3 min of a 6 min FST. Wild-type mice were
injected (20 mg/kg) with either 1, 2, 3, 4, Cs·5, or vehicle (WT) 20
min prior to a 6 min FST. P2X7R knockout mice (KO) were injected
with vehicle. Error bars denote SEM; *P < 0.05, **P < 0.01, Mann−
Whitney U-test against WT.
AUTHOR INFORMATION
Corresponding Authors
■
*(M.K.) Telephone: +61 2 9351 0849. Fax: +61 2 9351 9146.
E-mail: michael.kassiou@sydney.edu.au.
*(L.M.R.) Telephone: +61 2 9351 4781. Fax: +61 2 9351 3329.
E-mail: lou.rendina@sydney.edu.au.
The failure of benzamides 1, 3, and 4 to demonstrate
antidepressant activity in mice despite their potent hP2X7R
inhibition values suggests a likely inability of these compounds
to cross the BBB and/or poor interspecies crossover.
Calculated physicochemical properties (Table 1, column 3) of
the benzamide series advocate lipophilic penalties may indeed
prevent crossing of the BBB.
To validate the BBB penetration with lipophilicity, the log
D7.4 values of the benzamides were determined experimentally
by using a HPLC method (Table 1, column 4).20 The three
benzamides 1, 3, and 4, which showed no antidepressant
behavior in the FST, were shown to have log D7.4 values much
greater than the range reported for successful CNS drugs
(cLogP < 3).21 These values indicate that a high lipophilicity
Author Contributions
S.M.W. synthesized benzamides 1−5 and prepared drafts of this
article. H.G. assisted in the synthesis of 2 and 3. M.L.B.
performed the functional cell assays. A.B. and M.M. carried out
the animal behavior testing which was directed by I.S.M. P.T.
determined the X-ray crystal structure of 2 and 4. D.E.M.
prepared the carborane precursor 16·HCl and performed
statistical analysis on the biological results. L.M.R. supplied
carborane precursors and directed synthetic work involving
carboranes. M.K. directed synthetic and in vitro work. M.R.B.,
M.K., and L.M.R. jointly conceived this project. The manuscript
was prepared by M.K. and L.M.R. based on drafts written by
S.M.W.
338
dx.doi.org/10.1021/cn500054n | ACS Chem. Neurosci. 2014, 5, 335−339

ACS Chemical Neuroscience
Letter
(15) Lesnikowski, Z. J. (2007) Boron units as pharmacophores - new
applications and opportunities of boron cluster chemistry. Collect.
Czech. Chem. Commun. 72, 1646−1658.
(16) Michel, A. D., Chambers, L. J., Clay, W. C., Condreay, J. P.,
Walter, D. S., and Chessell, I. P. (2007) Direct labelling of the human
P2X7 receptor and identification of positive and negative cooperativity
of binding. Br. J. Pharmacol. 151 (1), 84−95.
Funding
The work presented herein was supported in part by
NH&MRC and the European Union’s Seventh Framework
Programme [FP7/2007-2013] INMiND (Grant Agreement
No. HEALTH-F2-2011-278850).
Notes
(17) Porsolt, R. D., Brossard, G., Hautbois, C., and Roux, S. (2001)
Rodent Models of Depression: Forced Swimming and Tail Suspension
Behavioral Despair Tests in Rats and Mice. In Current Protocols in
Neuroscience, Vol. 14, pp 1−8, John Wiley & Sons, Inc., New York.
(18) Cryan, J. F., and Holmes, A. (2005) The ascent of mouse:
advances in modelling human depression and anxiety. Nat. Rev. Drug
Discovery 4 (9), 775−790.
(19) Boucher, A. A., Arnold, J. C., Hunt, G. E., Spiro, A., Spencer, J.,
Brown, C., McGregor, I. S., Bennett, M. R., and Kassiou, M. (2011)
Resilience and reduced c-Fos expression in P2X7 receptor knockout
mice exposed to repeated forced swim test. Neuroscience 189, 170−
177.
(20) Haky, J. E., and Young, A. M. (1984) Evaluation of a Simple
HPLC Correlation Method for the Estimation of the Octanol-Water
Partition Coefficients of Organic Compounds. J. Liq. Chromatogr. 7
(4), 675−689.
(21) Pajouhesh, H., and Lenz, G. (2005) Medicinal chemical
properties of successful central nervous system drugs. Neuro-
therapeutics 2 (4), 541−553.
The authors declare no competing financial interest.
REFERENCES
■
(1) Davies, W. L., Grunert, R. R., Haff, R. F., McGahen, J. W.,
Neumayer, E. M., Paulshock, M., Watts, J. C., Wood, T. R., Hermann,
E. C., and Hoffmann, C. E. (1964) Antiviral Activity of 1-
Adamantanamine (Amantadine). Science 144 (3620), 862−863.
(2) Joubert, J., Geldenhuys, W. J., Van der Schyf, C. J., Oliver, D. W.,
Kruger, H. G., Govender, T., and Malan, S. F. (2012) Polycyclic Cage
Structures as Lipophilic Scaffolds for Neuroactive Drugs. Chem-
MedChem 7 (3), 375−384.
(3) Issa, F., Kassiou, M., and Rendina, L. M. (2011) Boron in Drug
Discovery: Carboranes as Unique Pharmacophores in Biologically
Active Compounds. Chem. Rev. 111 (9), 5701−5722.
(4) Issa, F., Ioppolo, J. A., and Rendina, L. M. (2013) 3.30 - Boron
and Gadolinium Neutron Capture Therapy. In Comprehensive
Inorganic Chemistry II (Reedijk, J., and Poeppelmeier, K., Eds.), 2nd
ed., pp 877−900, Elsevier, Amsterdam.
(22) Leeson, P. D., and Springthorpe, B. (2007) The influence of
drug-like concepts on decision-making in medicinal chemistry. Nat.
Rev. Drug Discovery 6 (11), 881−890.
(5) Hawthorne, M. F., and Pushechnikov, A. (2012) Polyhedral
borane derivatives: Unique and versatile structural motifs. Pure Appl.
Chem. 84, 2279−2288.
(6) (a) Crossley, E. L., Issa, F., Scarf, A. M., Kassiou, M., and
Rendina, L. M. (2011) Synthesis and cellular uptake of boron-rich
pyrazolopyrimidines: exploitation of the translocator protein for the
efficient delivery of boron into human glioma cells. Chem. Commun.
47, 12179−12181. (b) Hawkins, P. M., Jelliss, P. A., Nonaka, N., Shi,
X., and Banks, W. A. (2009) Permeability of the Blood-Brain Barrier to
a Rhenacarborane. J. Pharmacol. Exp. Ther. 329 (2), 608−614.
(7) Surprenant, A., Rassendren, F., Kawashima, E., North, R. A., and
Buell, G. (1996) The cytolytic P2Z receptor for extracellular ATP
identified as a P2X receptor (P2X7). Science 272 (5262), 735−738.
(8) Basso, A. M., Bratcher, N. A., Harris, R. R., Jarvis, M. F., Decker,
M. W., and Rueter, L. E. (2009) Behavioral profile of P2X7 receptor
knockout mice in animal models of depression and anxiety: Relevance
for neuropsychiatric disorders. Behav. Brain Res. 198 (1), 83−90.
(9) Samad, T. A., Moore, K. A., Sapirstein, A., Billet, S., Allchorne, A.,
Poole, S., Bonventre, J. V., and Woolf, C. J. (2001) Interleukin-
1[beta]-mediated induction of Cox-2 in the CNS contributes to
inflammatory pain hypersensitivity. Nature 410 (6827), 471−475.
(10) Zunszain, P. A., Anacker, C., Cattaneo, A., Choudhury, S.,
Musaelyan, K., Myint, A. M., Thuret, S., Price, J., and Pariante, C. M.
(2012) Interleukin-1[beta]: A New Regulator of the Kynurenine
Pathway Affecting Human Hippocampal Neurogenesis. Neuropsycho-
pharmacology 37 (4), 939−949.
(11) Baxter, A., Bent, J., Bowers, K., Braddock, M., Brough, S.,
Fagura, M., Lawson, M., McInally, T., Mortimore, M., Robertson, M.,
Weaver, R., and Webborn, P. (2003) Hit-to-Lead studies: The
discovery of potent adamantane amide P2X7 receptor antagonists.
Bioorg. Med. Chem. Lett. 13 (22), 4047−4050.
(12) Dombroski, M. A., and Duplantier, A. J. (2004) Preparation of
3-(3,5-dioxo-4,5-dihydro-3H-(1,2,4)triazin-2-yl)benzamides as P2X7
inhibitors for the treatment of inflammatory diseases. Patent
WO2004058270A1.
(13) Wilson, J. G., Anisuzzaman, A. K. M., Alam, F., and Soloway, A.
H. (1992) Development of carborane synthons: synthesis and
chemistry of (aminoalkyl)carboranes. Inorg. Chem. 31 (10), 1955−
1958.
(14) Donnelly-Roberts, D. L., Namovic, M. T., Han, P., and Jarvis, M.
F. (2009) Mammalian P2X7 receptor pharmacology: comparison of
recombinant mouse, rat and human P2X7 receptors. Br. J. Pharmacol.
157 (7), 1203−1214.
339
dx.doi.org/10.1021/cn500054n | ACS Chem. Neurosci. 2014, 5, 335−339