Synthesis and biological evaluation of novel γ-carboline analogues of Dimebon as potent 5-HT6 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2009.04.128

Synthesis, biological evaluation and structure-activity relationships for a series of novel γ-carboline analogues of Dimebon are described. Among the studied compounds, γ-carbolines 3{8} and 3{14} have been identified as potent small molecule a

Full text of DOI:10.1016/j.bmcl.2009.04.128

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3183–3187
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel
c
-carboline analogues
of Dimebon as potent 5-HT6 receptor antagonists
b
b
b
Alexandre V. Ivachtchenko a,b, , Eugene B. Frolov , Oleg D. Mitkin , Volodymyr M. Kysil ,
*
Alexander V. Khvat b, Ilya M. Okun b,c, Sergey E. Tkachenko b,c
a Department of Organic Chemistry, Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg., Russia
b ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA
c Department of Molecular Biology and High-Throughput Screening, Chemical Diversity Research Institute, 114401 Khimki, Moscow Reg., Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis, biological evaluation and structure–activity relationships for a series of novel c-carboline ana-
TM
Received 5 March 2009
Revised 24 April 2009
Accepted 24 April 2009
Available online 3 May 2009
logues of Dimebon are described. Among the studied compounds,
c-carbolines 3{8} and 3{14} have been
identified as potent small molecule antagonists of histamine H1 (IC50 = 0.1
(IC50 = 0.37 M) receptors, respectively.
l
M) and serotonin 5-HT6
l
Published by Elsevier Ltd.
Keywords:
Dimebon
c
-Carbolines
Antagonists
Histamine H1
Serotonin 5-HT6
Analogues
During the last 60 years
c
-carbolines (2,3,4,5-tetrahydro-1H-
effectively blocked the L-type calcium channel activity with an IC50
pyrido[4,3-b]indoles) have been attracting a huge interest from sci-
entists due to a relatively broad spectrum of their biological activ-
ity.1–6 In particular, they have rightly been described as promising
antihistamine1 and local anaesthetic agents2 as well as serotonin
release inhibitors.3 They were also shown to have antidepressant4
and antiinflammatory1,5 activity. In addition, some compounds
containing the title Core fragment were found to have enhanced
neuroleptic activity.6
of 57
as promising therapeutic agent effectively suppressed NMDA recep-
tors (ED50 = 42 mg/kg),17 a weak cholinesterase inhibitor (IC50
45 M (AChE) and IC50 = 7.9
M (BuChE))18 as well as an inhibitor
of the mitochondrial permeability transition pores.19
l
M.16 Based on various in vivo studies, it can also be regarded
=
l
l
Finally, a recent clinical study of Dimebon performed by Medi-
vation has revealed a novel mechanism of action ascribed to this
compound directly related to mitochondrial signaling route.20
However, a clear understanding towards the common mechanism
of its pharmacological action has not been achieved yet.
Recently, in 2008, we have convincingly shown that Dimebon
has a much wider scope of prospective therapeutic applications.
Currently, it can be reasonably regarded as promising drug-com-
Among several different groups of
c-carboline derivatives
Dimebon I (Fig. 1) (initially named—Dimebolin, 2,8-dimethyl-
5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-
b]indole dihydrochloride) originally synthesized in 1961 by Alexey
N. Kost (Professor D. Sc.) and colleagues7 is the most famous drug-
compound within this group. It is being currently evaluated in ad-
vanced clinical trials as promising small molecule drug-candidate
for the treatment of various neurodegenerative disorders,8 including
Alzheimer9 and Huntington10 diseases as well as different types of
schizophrenia11, etc.12,13 In the cerebellum cell culture Dimebon pro-
tects neurons against the neurotoxic action of b-amyloids
pound active against several types of Adrenoceptors (a1A
, a1B,
a1D, a
2A), Dopamine (D1, D2L, D2S, D3), Histamine (H1, H2), Seroto-
nin (5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7) receptors and other
GPCR classes.21 For example, as a therapeutic agent that inhibits
histamine H1 activity Dimebon has been widely used for the treat-
ment of allergy for just more than 20 years. Therefore, due to the
remarkably broad spectrum of physiological activity as well as a
very complex mechanism of action, Dimebon can be profitably
viewed as an excellent example of drug-compound within the spe-
cific group of ‘magic shotguns’.22 Among the activities just listed
the antagonistic potency of Dimebone against serotonin 5-HT6
(EC50 = 25 l
M).14 Since 1983, Dimebon has been using in Russia as
promising antihistamine agent.15 It was also shown that Dimebon
* Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794 4931.
E-mail address: av@chemdiv.com (A.V. Ivachtchenko).
0960-894X/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2009.04.128

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A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3183–3187
Figure 1. Target-specific profile determined for Dimebon 3{1}.
receptors can be directly related to beneficial cognitive effects. It is
well documented that in mammalians this type of serotonin recep-
tors is thoroughly embedded in CNS and the related signaling cas-
cades are deeply implicated in processes of information
perception, learning and memory formation.23 It has also been
shown that serotonin 5-HT6 receptors regulate several neurotrans-
mitter pathways including cholinergic, noradrenergic, glutamater-
gic and dopaminergic systems.24 Thus, taking into account both the
fundamental role of this signal transduction system in regular cog-
nitive processes as well as their dysfunction caused by neurode-
generative disorders, it is therefore becoming evidently clear that
serotonin 5-HT6 receptors represent extremely attractive target
for the development of novel small molecule therapeutics for the
treatment of various neurodegenerative disorders.25
reaction with 3-vinyl pyridines becomes possible due to relatively
weak polarization of the vinyl bond.26 Thus, we have used this
strategy for the preparation of both the known compounds
3{1,2,8,13}.27 as well as novel derivatives of Dimebon 3{3-9,9-
12,14-19} (Schemes 1 and 2, Table 1).
According to the approach depicted in Scheme 1, the target
compounds 3{1-19} can be readily obtained by two different ways.
The first method (a) based on the reaction of the initial c-carboline
1 with vinyl pyridine 2 in DMSO in the presence of Na/EtONa or
NaH. The second one (method b) is the reaction between these re-
agents in the two-phase system— DMSO/KOH/(Bu4N)2SO4. The
reaction was performed successfully in accordance with the mod-
ified method described by Kost26 there dry DMSO as well as cata-
lyst—Na/NaH were jointly used to synthesize similar compounds.
During the experimental procedure we have been observing that
the alternative reaction has been proceeding much smoothly re-
sults in a fewer amount of side and oil products as well as much
better yields. It should also be remarked that under the applied
conditions the reaction with 4-vinyl pyridine 2{4} has proceeded
more readily (4–8 h, 40 °C) as compared to the reaction with 2-vi-
nyl pyridine 2{1} and it was far more tangible for 3-vinyl pyridines
2{2,3}. Therefore, a complete conversion of the initial reactants was
found to be most readily achieved only using more severe condi-
tions (12–24 h, 80 °C).
In this Letter, we describe synthesis, biological evaluation and
structure–activity relationships for a series of novel small molecule
histamine H1 and serotonin 5-HT6 receptor antagonists having
general formula II and III, which represent unique analogs of the
‘template’ molecule Dimebon I.
CH3
CH3
N
N
H3C
CH3
N
N
N
2-Methyl-5-(2-pyridin-2-ylethyl)-8-cyano- 3{20} and 2-methyl-
8-pyridin-3-yl-5-(2-pyridin-2-ylethyl)-2,3,4,5-tetrahydro-1H-pyr-
ido[4,3-b]indole 3{21} were obtained in 22% and 66% yield, respec-
R
C
H3
I
Dimebon
N
N
tively, from the corresponding 8-bromo-c-carboline 3{6} which
II
III
N
Het
Het
CH3
CH3
N
CH3
N
In turn, the overall aim of this work lies in comparative study of the
synthesized analogs against serotonin 5-HT6 and histamine H1
receptors in vitro. In the initial stages of our work we have synthe-
sized Dimebon I as well as its novel analogues which contain the
core fragments II and III.
It was shown that in the presence of metallic sodium 5- and
8-unsubstituted 2-alkyl-c-carbolines can be easily converted into
R1
R1
method a or b
+ Het-CH=CH2
N
2{1-5}
N
H
3{1-19}
1{1-7}
Het
method a:
DMSO, Na, EtONa or NaH,
5-15 h, 90-95 oC, 10-55%
method b:
DMSO, H2O, KOH, (Bu4N)2SO4
4-24 h, 40-80 oC, 62-85%
used reagents: 1{1-7} and 2{1-5}
the corresponding 5-substituted
c-carbolines by their reaction
used reagents: 1{1,2,4,7} and 2{3}
with 2- and 4-vinyl pyridines.26 It should also be noted that the
use of aprotic solvents, for example DMSO, in this reaction leads
1{1-7}: R1 = H {1}, Me {2}, F {3}, Br {4}, CF3 {5}, CO2H {6}, MeO {7}
2{1-5}: Het = 2-Py {1}, 3-Py {2}, 6-Me-3-Py {3}, 4-Py {4}, pyrazin-2-yl {5}
to increased activation of
c-carboline anions formed in the pres-
ence of sodium or sodium hydride that, in turns, results in their
Scheme 1.

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3183–3187
3185
CH3
N
N
CH3
N
3-Py-B(OH)2, PdCl2(PPh3)2
NC
Na2CO2, EtOH, H2O
CuCN, NMP
N
3{6}
N
170 oC, 24 h, 22%
80 oC, 12 h, 66%
3{21}
3{20}
N
N
Scheme 2.
Table 1
The ability of
c-carbolines 3{1-24} to block the activity of histamine H1 and 5-HT6 receptors in cell-based assays
Compounds
Receptors
IC50 M)
(
l
No.
Het
R1
R2
Histamine H1
5-HT6
Phase-1
Phase-2
3{1}
3{2}
3{3}
3{4}
3{5}
3{6}
3{7}
3{8}
6-Me-Py-3
2-Py
2-Py
2-Py
2-Py
2-Py
2-Py
3-Py
3-Py
3-Py
3-Py
6-Me-Py-3
4-Py
4-Py
4-Py
4-Py
4-Py
4-Py
Me
H
Me
MeO
F
Br
CF3
H
Me
F
CF3
F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
0.16
1.82
0.50
4.67
0.94
0.12
0.56
0.10
0.50
0.65
>10
0.11
0.12
0.16
0.39
0.12
0.22
>10
1.58
0.93
10.0
nd*
0.61
nd
1.59
0.41
3.16
0.93
Nd
0.73
0.50
3.98
nd
0.47
nd
0.89
15.75
0.86
8.36
2.98
1.04
1.59
5.99
0.44
>10
5.80
10.69
8.91
0.37
4.34
3.24
6.40
>10
3{9}
3{10}
3{11}
3{12}
3{13}
3{14}
3{15}
3{16}
3{17}
3{18}
3{19}
3{20}
3{21}
3{22}
3{23}
3{24}
H
Me
MeO
F
CF3
CO2H
Me
CN
3-Py
Me
Me
Me
Me
Me
Me
Me
nd
7.94
nd
nd
nd
Pyrazin-2-yl
2-Py
2-Py
2-Py
3-Py
0.32
1.29
7.16
>10
2.79
7.57
2.06
7.47
43.20
Inactive
Inactive
Inactive
Me
N-Me-piperidin-4-yl
N-Me-piperidin-4-yl
N-Me-piperidin-4-yl
nd
nd
4-Py
* nd—‘Not detected’.
CH3
N
have previously been prepared (Scheme 2). Thus, the reaction of
compound 3{6} with CuCN in N-methylpyrrolidone (NMP) at
170 °C for 24 h led to the first compound 3{20}, while the reaction
between 3{6} and 3-pyridylboronic acid in aq. EtOH at 80 °C for
12 h yielded the second one in the presence of Pd-based catalyst.
N-Methyl 4-[8-methyl-5-(2-pyridine-ethyl)-1,3,4,5-tetrahydro-
2H-pyrido[4,3-b]indol-2-yl]piperidines 3{22-24} were obtained
H
CH3
N
N
NaBH(OAc)3
DCM
H3C
N
H3C
+
40 oC, 12 h, 85%
N
N
H
H
O
5
by the reaction between N-methylpiperidin-4-one 5 and c-carbo-
4
6
2{1,2,4}
line 4 followed by N-arylation of the obtained intermediate 6 with
various vinyl pyridines 2{1,2,4} (Scheme 3). Thus, the initial com-
ponents 4 and 5 have reacted in DCM at 40 °C also in the presence
of sodium triacetoxyborohydride. Twenty hours later reductive
amination has led to the formation of the intermediate product 6
(yield 85%). The latter was then easily converted into the target
compounds 3{22-24} by the reaction with vinyl pyridines 2{1,2,4}
in aq DMSO in the presence of NaOH/(Bu4N)2SO4. The reaction
had been progressively proceeding at 40 °C for 12 h, and the final
products were formed in high yields (65–80%).
DMSO, H2O,
KOH, (Bu4N)2SO4
6
3{22-24}
4-24 h, 40-80 o
65-80%
C
Scheme 3.
All the synthesized c-carbolines 3{1-24} have then been tested
on their ability to block Ca-dependent signaling cascades induced
by histamine H1 receptors in SK-N-SH cells. The inner concentration
of unbound Ca2+ was measured using Ca-sensitive dye—Fura-2.28
After activation of the histamine H1 receptors a dramatic increase
in [Ca2+] along the kinetic curve exhibiting changes in Ca2+ concen-
tration in the cell cytoplasm was observed (phase-I) followed by a
All the synthesized compounds were sufficiently characterized
by 1H NMR, LCMS and HR-MS spectral data. Satisfactory analytical
data consistent with the shown molecular structures were ob-
tained for all compounds (see Supplementary data).

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A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3183–3187
gradual decrease (phase-II). During phase-I, the release of Ca2+ ions
from intracellular stores29 was registered, whereas phase-II was
accompanied by two oppositely directed processes: extruding
Ca2+ from the cytoplasm and their penetration into neurons from
the cytoplasm through the store-dependent calcium channels.30
The ability of c-carboline derivatives to accelerate the decrease
in intracellular Ca2+ rate after stimulation of the histamine H1
receptors by histamine (Table 1, Phase-2) varied in the range of
0.41 lM to >10 lM and depended crucially on the nature of sub-
stituents used. In most cases their activity is 1.5–25 times lower
To estimate the effects of the synthesized c-carbolines towards
as compared to the suppression of histamine H1 receptors during
calcium flows maintained by histamine H1 receptors correspond-
ing experiments were performed in two different ways: (a) the
tested compounds were added to a mixture to be analyzed previ-
ous to histamine treatment, then the intensity of phase-I has been
cautiously estimated; (b) compounds were added to a mixture
immediately after histamine treatment, then the velocity of cyto-
solic calcium ion concentration falling in phase-II was determined.
The obtained data that reflects the observed activity of compounds
which have been tested during experimental procedures, exhibited
in IC50 values, is thoroughly summarized in Table 1.
Phase-I. One exception is 5-(2-pyridine-2-ylethyl)-c-carbolines
3{2,5}; their inhibitory potency against histamine H1 receptors is,
in turn, 1.5–2 times lower than required for the acceleration of
Ca release from the cytoplasm.
To investigate the antagonistic potential of the synthesized
Dimebon analogues 3{1-24} towards 5-HT6 receptors we have stud-
ied their inhibitory potency in HER293 cells stimulated by seroto-
nin. Under normal conditions, these cells continuously produce
recombinant human serotonin 5-HT6 receptors. Serotonin-depen-
dent stimulation of these receptors led to enhanced production of
intracellular cyclic AMP which, in turns, was used as a control indi-
cator. Its level has been continuously monitored using LANCE
technology.31
As clearly shown in Table 1, modifications in the structures of
the obtained
c-carbolines 3{1-24} lead to significant differences
in their ability to block the histamine-induced calcium flows in
phase-I. In particular, the most active compounds 3{1,6,10,12-
14,16,17} have IC50 values of 100–200 nm, whereas compounds
3{2,4,11,18,20-24} have been found to have much weaker activity
As shown in Table 1, the antagonistic activity of
c-carbolines
3{1-24} highly depends on the nature of side substituents. The
IC50 value was found to be very spread along the range of
ranged around 1.29
10,15,19} were found to exhibit moderate activity.
It should be noted that within each group of compounds, 5-(2-
pyridine-2-ylethyl)- 3{2-9}, 5-(2-pyridine-3-ylethyl)- 3{1,8-12} as
well as 5-(2-pyridine-4-ylethyl)-
served activities are dramatically different by one or two orders
of magnitude. The top activity was assigned for 8-unsubstituted
derivatives 3{8,13} as well as for 8-bromo- 3{6}, 8-fluoro-
3{12,16}, 8-methyl- 2{1,14} as well as 8-trifluoromethyl- 3{17}
l
M and IC50 > 10.0
l
M. Compounds 3{3,5,7,9,
0.37
22-24}. Within the group of 5-(2-pyridine-2-yl)-
9} the most active compound was 2,8-dimethyl-
(IC50 = 0.86 M); its activity was remarkably close to that observed
in a similar assay performed for Dimebon (IC50 = 0.89 M). A
slightly lower inhibitory potency, as compared to 8-methyl-
carboline 3{3}, was detected for 8-bromo- 3{6}, 8-trifluoromethyl-
3{7} and 8-fluoro- 3{5} -carbolines (IC50 = 1.04 M, 1.59 M and
2.98 M, respectively). Among the compounds described a rela-
l
M (compound 3{14}) to absolutely inactive compounds 3{
-carbolines 3{2-
-carboline 3{3}
c
c
l
c-carbolines 3{13-18} the ob-
l
c-
c
l
l
l
c
-carbolines (see Table 1). The corresponding values of IC50 are dis-
persed exponentially from 0.1 M (for compound 3{8}) up to
0.225 M (for compound 3{17}). The minimum activity was ob-
served for 8-pyridine-3-yl- 3{9} (IC50 = 7.16 M), 8-trifluoro-
methyl- 3{11} (IC50 > 10 M) and 8-carboxy- 3{18} (IC50 > 10 M)
-carbolines. It was found that within each group of the tested
compounds the activity correlates with the nature of the substitu-
ent in position 8(C) of -carboline, but differently. Thus, within the
group of 5-(2-pyridine-2-ylethyl)- -carbolines 3{2-9} the highest
inhibitory activity was observed for 8-bromo- -carboline 3{6}
(IC50 = 0.12 M). Within the 5-(1-pyridine-3-ylethyl)- 3{1,8-12}
and 5-(1-pyridine-4-ylethyl)- 3{13-18} -carboline series the
highest activity was determined for 8-methyl- 3{1,14}, 8-fluoro-
3{12,16} and 8-unsubstituted -carbolines 3{8,13}; the corre-
sponding IC50 values were in the range of 0.10–0.16 M. In turn,
8-unsubstituted -carbolines 3{2,3,5} in the line of 5-(2-pyridine-
4-ylethyl)- -carbolines 3{2-9} were found to be significantly less
active (IC50 = 1.82 M, IC50 = 0.5 M and 0.94 M, respectively)
tively poor activity was observed for 8-unsubstituted analogues,
including compound 3{2}, 8-methoxy- 3{4}, 8-cyano- 3{8} and
l
l
8-pyridine-3-yl- 3{9}
7.467 M and >10 M, respectively).
An analogous relationship between the antagonistic activity
and nature of substituent in position 8(C) was observed for -carb-
olines 3{8-12} and 3{13-18}. Among these compounds 2,8-di-
methyl-substituted -carbolines 3{9,14} were the most active
agents (IC50 = 0.44 M and 0.37 M, respectively). It should also
c-carbolines (IC50 = >10 lM, 8.365 lM,
l
l
l
l
l
c
c
c
c
c
l
l
c
be noted that the replacement of 5-pyridinyl-ethyl substituents
by 5-pyrazinyl-ethyl analogues led to a significant decrease in their
antagonistic potential. Thus, 2,8-dimethyl-5-(2-pyrazine-2-yl-
methyl)-c-carboline 3{19} (IC50 = 2.06 lM) is 2.5–6 times less
active as compared to 2,8-dimethyl-5-(2-pyridine-ylmethyl)-c-
l
c
c
l
carbolines 3{1,3,9,14}.
c
In this work we have also estimated a target-specific profile of
the synthesized compounds towards various receptors. The corre-
sponding activity was determined by measuring the amount of
c
l
l
l
than analogues 3{1,8,12-14,16} described just above.
radiolabeled ligands displaced by the testing
c-carbolines which
An interesting correlation across these three series has been ob-
was used in a concentration of 10 M. A comparative study across
l
served in the case of 8-fluoromethyl-
particularly amongst two groups of
(2-pyridine-2-ylethyl)- or 5-(2-pyridine-4-ylethyl)-fragment com-
pounds 3{7,17} have high values of activity (IC50 = 0.56 M and
IC50 = 0.22 M, respectively), whereas within the 5-(2-pyridine-3-
ylethyl)- -carboline series compound 3{11} has relatively poor
activity (IC50 > 10 M).
The activity of 2,8-dimethyl-5-(2-pyrazine-2-ylethyl)-
line 3{19} (IC50 = 0.32 M) is strikingly similar to that observed
for 5-(2-pyridine-ethyl)-containing analogues 3{3} (IC50 = 0.5 M),
3{9} (IC50 = 0.5 M) and 3{14} (IC50 = 0.16 M). And finally, among
the series of 2-(1-methylpiperidine-4-yl)- -carbolines 3{22-24}
the most active compound was 5-(2-pyridine-3-ylethyl)- -carbo-
line 3{23} (IC50 = 2.79 M), whereas 5-(2-pyridine-2-ylethyl)-
carboline 3{22} was revealed to be relatively inactive.
c
-carbolines 3{7,11,17}. Thus,
the data obtained has revealed a distinctive relationship between
‘fingerprint’ spectra and pharmacological activity of the com-
pounds which have been tested in cell-based assays. This observa-
tion can be neatly illustrated by the example of the Dimebon
c
-carbolines which contain 5-
l
l
(Fig. 1) and c-carboline dihydrochloride 3{3} profiles (Fig. 2).
c
In summary, here we have described synthesis and activity of
TM
l
novel small-molecule analogues of Dimebon . In particular, it
c
-carbo-
was found that inhibitory activity of the synthesized c-carbolines
l
towards histamine H1 and serotonin 5-HT6 receptors is highly
dependent on the substitutions on the core scaffold, radically at
the 2-, 5- and 8-position. Thus, the compounds contained H, F,
Br, CH3 and CF3 substituents in position 8(C) as well as 2-pyri-
dine-3(4)-ylethyl fragments in position 5(N) have shown potent
antagonistic activity against histamine H1 receptors, whereas only
8-methyl-substituted derivatives were found to have promising
l
l
l
c
c
l
c-

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3183–3187
3187
Figure 2. Target-specific profile determined for c-carboline dihydrochloride 3{3}. This compound was used in a concentration of 10 lM.
9. Doody, R. S.; Gavrilova, S. I.; Sano, M.; Thomas, R. G.; Aisen, P. S.; Bachurin, S. O.;
Seely, L.; Hung, D. Lancet 2008, 372, 207.
10. Wu, J.; Li, Q.; Bezprozvanny, I. Mol. Neurodegener. 2008, 3, 15.
11. Bachurin, S. O.; Grigoriev, V. V.; Morozova, M. A.; Beniashvili, A. G. WO Patent
No. 087425, 2007; Chem. Abstr. 2007, 147, 203976.
12. Galenko-Yaroshevskii, P. A.; Cherednik, I. L.; Bartashevich, V. V.; Sheikh-Zade,
Yu. R.; Khankoeva, A. I. Bull. Exp. Biol. Med. 1997, 124, 691.
13. Hung, D. WO Patent No. 036410, 2008; Chem. Abstr. 2008, 148, 394417.
14. Bachurin, S.; Bukatina, T.; Lermontova, N.; Tkachenko, S.; Afanasiev, A.;
Grigoriev, V.; Grigorieva, I.; Ivanov, Y.; Sablin, S.; Zefirov, N. Ann. N.Y. Acad.
Sci. 2001, 939, 425.
pharmacological potential towards serotonin 5-HT6 receptors. It is
also quite interesting that the introduction of other substituents in
position 8(C) has led to a significant loss in activity. In turn, the
nature of heterocyclic fragment anchored in position 5(N) of the
c-carboline scaffold has no significant impact on the activity of
the tested compounds against 5-HT6 receptors.
Acknowledgments
15. Matveeva, I. A. Farmakologiya Toksikologiya 1983, 46, 27.
16. Lermontova, N. N.; Redkozubov, A. E.; Shevtsova, E. F.; Serkova, T. P.; Kireeva, E.
G.; Bachurin, S. O. Bull. Exp. Biol. Med. 2001, 132, 1079.
17. Grigorev, V. V.; Dranyi, O. A.; Bachurin, S. O. Bull. Exp. Biol. Med. 2003, 136,
474.
The authors would like to sincerely thank Dr. Yan A. Ivanenkov
(ChemDiv. Inc) for discussion and invaluable help in preparation of
the manuscript.
18. Lermontova, N. N.; Lukoyanov, N. V.; Serkova, T. P.; Lukoyanova, E. A.;
Bachurin, S. O. Bull. Exp. Biol. Med. 2000, 129, 544.
19. Bachurin, S. O.; Shevtsova, E. P.; Kireeva, E. G.; Oxenkrug, G. F.; Sablin, S. O. Ann.
N. Y. Acad. Sci. 2003, 993, 334.
Supplementary data
20. Hung, D. Dimebon, 11th Int. Conf. Alzheimer’s Dis. Relat. Disord. (ICAD), July
26–31, Chicago, 2008, Abst. S4-04-05.
21. Tkachenko, S. E.; Ivachtchenko, A. V.; Khvat, A.; Lavrovsky, Y.; Okun, I. 1st
International Conference on Drug Design and Discovery, February 2–6, Dubai,
2008, Abst. IL 187.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.04.128.
References and notes
22. Roth, B. L.; Sheffler, D. J.; Kroeze, W. K. Nat. Rev. Drug Discovery 2004, 3, 353.
23. Ge´rard, C.; Martres, M.-P.; Lefe‘vre, K.; Miquel, M.-C.; Verge, D.; Lanfumey, L.;
Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Res. 1997, 746, 207.
24. Dawson, L. A.; Nguyen, H. Q.; Li, P. Neuropsychopharmacology 2001, 25, 662.
25. Holenz, J.; Pauwels, P. J.; Diaz, J. L.; Merce, R.; Codony, X.; Buschmann, H. Drug
Discovery Today 2006, 11, 283.
26. Kost, A. N.; Yurovskaya, M. A.; Mel‘nikova, T. V.; Potanina, O. I. Khim. Geterotsikl.
Soedin. 1973, 2, 207.
27. Shadurskii, K. S.; Il’yuchenok, T. Yu.; Trifimov, F. A.; Kost, A. N. Farmakologiya
Toksikologiya 1969, 32, 482.
28. Neher, E. Neuropharmacology 1995, 34, 1423.
29. Burgess, G. M.; Godfrey, P. P.; McKinney, J. S.; Berridge, M. J.; Irvine, R. F.;
Putney, J. W., Jr. Nature 1984, 309, 63.
30. Kato, N.; Tanaka, T.; Yamamoto, K.; Isomura, Y. J. Physiol. 1999, 519, 467.
31. Hurt, S.; Harney, H.; Xie, H.; Le, H.; Stanaker, R.; Illy, C.; Manchanda, R. SBS’ 11th
Annual Conference and Exhibition. Drug Discovery: From Targets to Candidates.
September 11–15, Geneva, Switzerland, 2005, P03021.
1. Berger, L.; Corraz, A. J. U.S. Patent No. 3522262, 1970; Chem. Abstr. 1971, 073,
120600z.
2. Kharkevich, D. A. Farmakologiya Toksikologiya 1967, 20, 6.
3. Verhovskiy, Y. G.; Kokina, L. P. Farmakologiya Toksikologiya 1968, 3, 209.
4. Phillip, J. R.; Paul, O. J. U.S. Patent No. 3419568, 1968; Chem. Abstr., 1969, 070,
068175m.
5. Yamamoto, H.; Narfvura, Y.; Nakao, M.; Atsumi, T.; Kobayashi, T. U.S. Patent No.
3535326, 1967; Chem. Abstr. 1968, 074, 125428e.
6. Harbert, C. A.; Plattner, J. J.; Welch, W. M.; Weissman, A.; Koe, B. K. J. Med. Chem.
1980, 23, 635.
7. Shadurski, K. S.; Danusevich, I. K.; Kost, A. N.; Vinogradova, E. V. U.S. Patent No.
1138164, 1985; Chem. Abstr. 1985, 102, 198010.
8. (a) Zefirov, N. S.; Afanas’ev, A. Z.; Afanas’eva, S. V.; Bachurin, S. O.; Tkachenko, S.
E.; Grigor’ev, V.; V.; Yurovskaya, M. A. U.S. Patent No. 7071206, 2006.; (b) Abou-
Gharbia, M.; Patel, U. R.; Webb, M. B.; Moyer, J. A.; Andree, T. H.; Muth, E. A.
J. Med. Chem. 1987, 30, 1818.