Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles

Article abstract of DOI:10.1016/j.bmcl.2009.11.037

Syntheses, biological evaluation, and structure-activity relationships for a series of novel 5-styryl and 5-phenethyl analogs of dimebolin are disclosed. The novel derivatives and dimebolin share a broad spectrum of activities against therapeutically relevant targets. Among all synthesized derivatives, 2,8-dimethyl-5-[(Z)-2-phenylvinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in dole and its 5-phenethyl analog are the most potent blockers of 5-HT₇, 5-HT₆, 5-HT_2C, Adrenergic α₂ and H₁ receptors. The general affinity rank order towards the studied receptors was Z-3(2) > 4(2) ≥ 4(3) ? dimebolin, all of them having highest affinities to 5-HT₇ receptors.

Full text of DOI:10.1016/j.bmcl.2009.11.037

Bioorganic & Medicinal Chemistry Letters 20 (2010) 78–82
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles
b
a
b
Alexandre V. Ivachtchenko a,b, , Eugen B. Frolov , Oleg D. Mitkin , Sergei E. Tkachenko ,
*
Ilya M. Okun b, Alex V. Khvat b
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
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses, biological evaluation, and structure–activity relationships for a series of novel 5-styryl and
5-phenethyl analogs of dimebolin are disclosed. The novel derivatives and dimebolin share a broad spec-
trum of activities against therapeutically relevant targets. Among all synthesized derivatives, 2,8-
dimethyl-5-[(Z)-2-phenylvinyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and its 5-phenethyl analog
Received 19 August 2009
Revised 5 November 2009
Accepted 10 November 2009
Available online 14 November 2009
are the most potent blockers of 5-HT7, 5-HT6, 5-HT2C, Adrenergic a2 and H1 receptors. The general affinity
rank order towards the studied receptors was Z-3(2) > 4(2) P 4(3) ꢀ dimebolin, all of them having high-
Keywords:
Pyridoindoles
Dimebolin
Dimebon
est affinities to 5-HT7 receptors.
Ó 2009 Elsevier Ltd. All rights reserved.
Receptor
Serotonergic
5-HT7
5-HT6
5-HT2C
Adrenergic
Alpha 2
Histamineergic
H1
Calcium mobilization
Dimebolin dihydrochloride, 2,8-dimethyl-5-[2-(2-methylpyri-
dine-5-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (A), is
an excellent example of a drug that best illustrates a ‘magic shot-
gun’ concept.1 This old antihistamine drug2 was shown to exhibit
neuroprotective activity3 and is being successfully tested in clinical
trials as a treatment for Alzheimer’s4 and Huntington’s5 diseases. It
was established6 that besides the histaminergic receptors (H1 and
H2), dimebolin displays a rather broad spectrum of pharmacologi-
presents obvious value for improving efficacy of Alzheimer’s
disease treatment. Recently, we have shown syntheses and SAR
analysis of dimebolin analogs, 2,8-disubstituted-5-(2-heterocyclyl-
ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles.6 These analogs
exhibited broad spectra of biological activities with considerable
sensitivity to substitutions in 2-, 5-, and 8-positions. In this work,
we describe synthesis and preliminary testing results of previously
unknown 5-(2-styryl)-, 3, and 5-(2-phenethyl)-, 4, derivatives of
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles.
cal activities targeting adrenergic receptors (a1A, a1B, a1D, a2A),
dopaminergic receptors (D1, D2L, D2S, D3), serotonergic receptors
(5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7) as well as some other recep-
tors, ion channels and enzymes.
Due to the broad spectrum of Dimebon action on many thera-
peutically important targets, the precise mechanism of its anti-Alz-
heimer’s activity is still elusive. Therefore, synthesis of dimebolin
analogs and assessment of their effects on the therapeutic targets
We found that at 80 °C, aryl acetylenes 2(1–6) easily react with
2,3,4,5-tetrahydro-1H-c-carbolines 1(1–5) in a biphasic system
DMSO–60% KOH in water solution in the presence of tetrabutylam-
monium sulfate as a phase-transfer catalyst. This reaction leads to
formation of previously unknown mixtures of (Z)- and (E)-isomers
of 2-methyl-5-styryl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles
3(1–15) (Scheme 1). The mixtures contain 90–95% of (Z)-isomer
and 5–10% of (E)-isomer, some of which were chromatographically
separated.
* Corresponding author. Tel.: +1 858 794 4860; fax: +1 858 794 4931.
E-mail addresses: av@chemdiv.com, iokun@chemdiv.com, ilyaokun@sbcglobal.
net (A.V. Ivachtchenko).
Unlike vinylpyridines,6,7 styrene does not react with 2,8-
dimethyl-2,3,4,5-tetrahydro-1H-c-carboline 1(1), which can be
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.11.037

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 20 (2010) 78–82
79
Scheme 1. Synthesis of compounds 3(1–15) and 4(2–13).
Table 1
explained by weaker electrophilicity of the styrene double bond as
compared to vinylpyridines. Therefore, desired 5-phenethyl-
The ability of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles 3, 4 to block the activity of
serotonin 5-HT6 receptors in cell-based assays
2,3,4,5-tetrahydro-1H-
c-carbolines 4(2–13) were obtained by
hydrogenation of 5-styrene-2,3,4,5-tetrahydro-1H-
c-carbolines
Compounds
R1
R2
Ar (HetAr)
IC50
Compd 3
(l
M)
3(2–13) in ethanol over PtO2 with a 74–91% yield (Scheme 1).
The structures of compounds 3 and 4 were confirmed using LC–
MS and 1H NMR spectroscopy. Molecular mass of ions determined
by LC–MS, as well as proton chemical shifts in 1H NMR spectra, cor-
respond to the expected molecules. In the 1H NMR spectra of (Z)-iso-
mers 3(1–11), doublet proton signals of double bonds are present at
6.6–6.8 ppm with a coupling constant of 8.8 Hz. In the 1H NMR spec-
tra of (E)-isomers 3(1,2,7), the doublet signals can be seen at 6.8–
6.9 ppm with substantially higher coupling constant of 14.8 Hz.
Such a difference in the constants is generally characteristic for
cis- and trans-isomers. The structures of compounds 13(14,15) were
established based on Nuclear Overhouser Effect (NOE) NMR exper-
iments. Two double-proton multiplets (AA’BB’-system) can be seen
at 4.2–4.3 and 2.8–3.0 ppm in the 4(2–11) salts spectra due to the
presence of the aryl–ethyl group in position ‘5’.
5-HT6 receptor antagonists have recently emerged as one of the
highly promising approaches to treatment of CNS diseases.8,9 In
mammals, these receptors are exclusively localized in CNS and
mainly in brain areas responsible for learning and memory.10 It
has also been shown that 5-HT6 receptors are modulators of other
neurotransmitter systems11 including cholinergic, noradrenergic,
glutaminergic, and dopaminergic systems, which play fundamen-
tal roles in cognitive processes and formation of normal and ‘path-
ologic’ memory. Taking into consideration that besides the
histamine receptors, dimebolin exhibits a rather high affinity to
5-HT6 receptors, we first studied 5-styryl- and 5-phenethyl-(com-
pounds 3 and 4, respectively) derivatives of the 2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indoles for the ability to antagonize serotonin 5-
HT6 receptors (Table 1). The experiments were performed in a
cell-based assay, where effects of the compounds were assessed
by their ability to inhibit functional cellular responses to serotonin.
Stimulation of the HEK-293 cells, expressing human recombinant
5-HT6 receptor, with serotonin leads to increased intracellular
levels of cAMP, as measured using cAMP-LANCE technology12 (Per-
kin–Elmer).
Compd 4
1.16
Dimebolin
(Z)-3(1)
(E)-3(1)
(Z)-3(2), 4(2)
(E)-3(2)
(Z)-3(3), 4(3)
(Z)-3(4), 4(4)
(Z)-3(5), 4(5)
(Z)-3(6), 4(6)
(Z)-3(7), 4(7)
(E)-3(7)
(Z)-3(8), 4(8)
(Z)-3(9), 4(9)
(Z)-3(10), 4(10)
(Z)-3(11), 4(11)
4(12)
Me
H
H
Me
Me
Me
Me
Me
Me
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
2-Me–Py-5
Ph
Ph
Ph
5.73
2.58
0.087
1.68
0.91
0.18
2.81
0.55
1.00
1.75
1.44
2.95
5.58
1.50
0.158
Ph
4-Me–C6H4
4-F–C6H4
4-CF3–C6H4
4-MeO–C6H4
Ph
0.276
0.977
4.07
0.666
0.692
F
F
F
F
Ph
4-Me–C6H4
4-F–C6H4
4-CF3–C6H4
4-MeO–C6H4
Ph
Ph
Ph
Ph
2.27
1.13
20.7
2.35
0.974
1.05
F
CF3
MeO
Me
F
4(13)
(Z)-3(14)
(Z)-3(15)
1.98
3.72
Each concentration curve was measured in duplicates (see Supplementary data for
details).
potency. In corresponding E-isomers, substitution of hydrogen (E)-
3(1) with either methyl-((E)-3(2)) or fluoro-((E)-3(7)) group did
not produce substantial changes in their 5-HT6 receptor antagonis-
tic potencies.
Substitution of hydrogen in position R2 of (Z)-3(2) and (Z)-3(7)
with the methyl group leads to a 23-fold ((Z)-3(14)) and 4-fold
((Z)-3(15)) reduction in the compound potencies.
Substitution of the aryl fragment of the 2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indoles profoundly affects their 5-HT6 receptor antag-
onistic activity. Thus, in the series of 2,8-dimethyl-5-((Z)-styryl)-
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, (Z)-3(2–6), the IC50
values increase from 0.087 lM for (Z)-3(2) to 2.81 lM for (Z)-
3(5) (32-fold maximal difference) with the potency rank order of
the aryl substituents Ph (Z)-3(2) > 4-F–C6H4 (Z)-3(4) > 4-MeO–
C6H4 (Z)-3(6) P 4-Me–C6H4 (Z)-3(3) > 4-CF3–C6H4 (Z)-3(5).
Interestingly, in the series of 2-methyl-8-fluoro-5-((Z)-styryl)-
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, (Z)-3(7–11), the aryl
substitutions exhibit substantially lesser influence on the com-
pound potencies (only sixfold difference between the IC50 values
for the compounds with highest, (Z)-3(7), and lowest, (Z)-3(10),
potency). The potency rank order is: Ph P 4-Me–C6H4 = 4-MeO–
C6H4 > 4-F–C6H4 > 4-CF3–C6H4. For this 8-fluoro series, (Z)-3(7–
As evident from the data in Table 1, the potency of the 2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indoles 3 and 4 profoundly depends
on both the nature and stereochemistry of the substituents, with
IC50 values varying from 0.087 lM ((Z)-3(2)) to 20.7 lM (4(10)).
The most striking differences in 5-HT6 receptor potency can be
seen upon substitutions of compounds with the Z configuration.
Transition from 8-unsubstituted styryl-derivatives (Z)-3(1), to cor-
responding 8-methyl (Z)-3(2), and 8-fluoro (Z)-3(7), derivatives
led, respectively, to 66-fold and 6-fold increase in the antagonistic

80
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 20 (2010) 78–82
11) in general is similar to that of the 8-methyl series (Z)-3(2–6),
with the Ph-substituted compounds having highest and 4-CF3–
C6H4-substituted ones having lowest potencies.
fluxes induced by histamine. Upon activation of the H1 receptors
with histamine, the [Ca2+]i changes exhibit biphasic kinetics, fast
[Ca2+]i increase in Phase 1 and much slower reduction of [Ca2+
in Phase 2 (Fig. 1).
]
i
Similar rank order trends in the aryl substituents’ effect on the
compound potencies as antagonists of 5-HT6 receptors were found
in the series of 8-methyl-substituted 4(2–6) and 8-fluoro-substi-
tuted 4(7–11) 5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
doles. Substitution of Me-Pyr in dimebolin with Me–C6H4 in 4(3)
or with F–C6H4 in (Z)-3(4) leads to 4–6-fold increase in the po-
tency. Generally, the compounds with a phenyl moiety showed
lowest IC50 and compounds with a 4-CF3–C6H4 moiety—highest
IC50 values. In all cases, the compounds with 4-Me–C6H4 and 4-
MeO–C6H4 moieties were practically equipotent.
Phase 1 is caused by release of calcium ions from intracellular
stores.14 Phase 2 is a superposition of at least two counter-fluxes;15
Ca2+ removal by Ca2+ pumps, and their entry from extracellular
media. The Ca2+ fluxes in Phase 2 could also be controlled by the
same receptor activation.16,17 The synthesized compounds were
tested in two experimental settings as exemplified in Figure 1 for
(Z)-3(2). To assess their effect on the histamine-induced peak
[Ca2+]i values in Phase 1, the compounds were added to the cells
15–20 s before histamine (Fig. 1A). To assess the compound effect
on a rate of [Ca2+]i dissipation from the cytoplasm in Phase 2, the
compounds were added 20–30 s after histamine (Fig. 1B).
Considering the role of an 8-substituent in 5-phenethyl-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indoles, we showed that the potency
of the 8-methyl substituted compound 4(2) (IC50 = 0.158
4–7-fold reduced upon its substitution with either 8-F (4(7)), or
8-CF3 (4(12)), or 8-MeO (4(13)).
l
M) is
The data are summarized in Table 2. It can be seen that the
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles 3 and 4 are highly po-
tent blockers of histamine-induced stimulation of the Phase 1 in
Ca2+ mobilization from intracellular stores with IC50 values varying
The stereo orientation in the 5-styrene position plays a signifi-
cant role in determining 5-HT6 receptor antagonistic potency. For
example, comparison of the most potent 5-HT6 receptor antagonist
2,8-dimethyl-5-((Z)-styryl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]in-
dole, (Z)-3(2), with its isomer, (E)-3(2), shows almost 20-fold de-
crease in the potency, and reduction of the styrene double bond
in 4(2) leads to further twofold reduction in the potency. However,
change in the orientation of substituents around the styrene bond
upon transition from the low potency compound (Z)-3(1) to its iso-
mer (E)-3(1) is not accompanied by substantial changes in the
potency.
Originally, dimebolin, (2,8-dimethyl-5-[2-(6-methylpyridin-3-
yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole dihydrochlo-
ride), was developed as an antihistamine drug,2,3 therefore, it
was prudent to test several of the synthesized analogs of 2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indoles 3 and 4 for their ability to
interact with histamine H1 receptors. Kinetics of the calcium intra-
cellular concentrations, [Ca2+]i, induced by histamine addition to
the SK-N-SH cells endogenously expressing H1 receptors, were
measured using calcium-sensitive ratiometric fluorescent dye
Fura-213 on a spectrofluorometer RF-5301PC. Effectiveness of the
compounds was assessed by their ability to affect the calcium
from 0.03
pounds to increase Ca2+ removal rate in Phase 2 were 2–5.5 times
lower than potency in blocking Phase 1, and varied from 0.13
(4(7)) to 2.13 M ((E)-3(1)) depending on the substituents.
lM (4(4)) to 0.345 lM ((E)-3(1)). Potencies of the com-
l
M
l
Substitution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole in the
8-position with methyl, (Z)-3(2), did not produce substantial
increase in potency against H1 receptor compared with non-substi-
tuted (Z)-3(1), in contrast to the effect of this substitution on 5-HT6
receptors potency. However, changes in styrene configuration from
(Z)-3(1) to (E)-3(1) led to a 10-fold reduction in the potency of the
compound to block H1 receptors. The nature of the aryl substituent
also does not seem to have significant effect on H1 receptor affinity
in the series of 4(2–6) and 4(7–11).
Specificity profiles were determined for the most potent com-
pounds,
2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles
(Z)-3(2),
4(2),and 4(3), using a panel of 31 therapeutic targets, including
GPCRs, ion channels, and transporters, by their ability to displace
radio-labeled ligands of these targets (Fig. 2 (data shown only for
(Z)-3(2))).
The specificity profiles showed that the new 2,3,4,5-tetrahydro-
1H-pyrido[4,3-b]indoles 3 and 4 display a rather broad spectra of
Figure 1. Effect of (Z)-3(2) on histamine-induced [Ca2+]i temporal profile in SK-N-SH cells. (A) (Z)-3(2) was added 15 s before histamine. (B) (Z)-3(2) was added 30 s after
histamine. Typical data is shown.

A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 20 (2010) 78–82
81
Table 2
The ability of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles 3, 4 to block the activity of histamine H1 receptors in cell-based assays
Compds
R1
R2
Ar (HetAr)
IC50 (lM)
Compd 3
Compd 4
Phase 1
Phase 2
Phase 1
0.158
Phase 2
1.58
Dimebolin
(Z)-3(1)
(E)-3(1)
(Z)-3(2), 4(2)
4(3)
4(4)
4(5)
4(6)
4(7)
4(8)
4(10)
4(11)
4(12)
Me
H
H
Me
Me
Me
Me
Me
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2-Me–Py-5
Ph
Ph
0.033
0.345
0.07
0.181
2.13
0.154
Ph
0.04
0.146
0.131
4-Me–C6H4
4-F–C6H4
4-CF3–C6H4
4-MeO–C6H4
Ph
4-F–C6H4
4-CF3–C6H4
4-MeO–C6H4
Ph
0.112
0.030
0.098
0.066
0.04
0.031
0.035
0.032
0.068
0.104
F
F
F
CF3
MeO
4(13)
Ph
Each concentration curve was measured in duplicates (see Supplementary data for details).
Figure 2. Target-specific profile determined for 2,8-dimethyl-5-((Z)-styryl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, (Z)-3(2). Displacement of corresponding radio-labeled
ligand was measured at the compound concentration of 1
values SD are presented.
lM. Shown is a typical experiment performed in duplicates, where the radio labeled ligand displacement
potential pharmacological activities including adrenergic (a1A
,
a1B
,
affinity to 5-HT7 andlowestone todopamine D2S receptors withsome
variabilityinpotencyrankordersforotherreceptors. Theaffinityrank
a1D, a2A), dopaminergic (D1, D2L, D2S, D3), histaminergic (H1 and
H2), serotonergic (5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, 5-HT7) as well
as some other receptors and ion channel targets. The specificity
profiles of these newly synthesized derivatives of 2,3,4,5-tetrahy-
dro-1H-pyrido[4,3-b]indoles are very similar to the dimebolin pro-
file that we have previously published.6
Binding analysisofthe tested compoundsmeasured byconcentra-
tion-dependent displacement of radio-labeled ligands (Table 3)
showed that like dimebolin, Z-3(2), 4(2), and 4(3) exhibit highest
orders are for dimebolin: 5-HT7 > 5-HT6 P adrenergic
5-HT2C = adrenergic 2A > dopamine D2S; Z-3(2): 5-HT7 = adrenergic
2A P 5-HT2C = 5-HT6 P 5-HT2A = adrenergic 1A > dopamine D2S
4(2): 5-HT7 > 5-HT2C = 5-HT6 = 5-HT2A = adrenergic 2A > adrenergic
1A > dopamine D2S; and 4(3): 5-HT7 > adrenergic 2A = 5-HT2A = 5-
HT2C = 5-HT6 > adrenergic a1A
a1A = 5-HT2A =
a
a
a
;
a
a
a
.
The novel compounds demonstrate much higher affinity to all
of the receptors studied, Z-3(2) having approximately two orders

82
A. V. Ivachtchenko et al. / Bioorg. Med. Chem. Lett. 20 (2010) 78–82
Table 3
Supplementary data
Affinity, pKi, of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, Z-3(2), 4(2), and 4(3), to
selected GPCR receptors as measured by competition with radio-labeled ligands
(n = 2)
Supplementary data (description of compound syntheses and
biological assay methods) associated with this article can be found,
in the online version, at doi:10.1016/j.bmcl.2009.11.037.
Target
pKi
(Z)-3(2)
Dimebolin
4(2)
4(3)
References and notes
Adrenergic a1A
Adrenergic a2A
Dopamine D2S
Serotonin 5-HT2A
Serotonin 5-HT2C
Serotonin 5-HT6
Serotonin 5-HT7
7.22
6.96
6.20
7.21
7.12
7.47
8.10
8.85
9.62
7.46
9.00
9.32
9.21
9.68
7.72
8.70
7.07
8.70
8.92
8.70
9.60
8.15
9.09
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of magnitude higher affinity to adrenergic
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a2A, 5-HT2C, 5-HT2A, and
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The affinities of the three novel derivatives and Dimebon to-
wards different receptors correlate very well. The Pearson correla-
tion coefficients (r) between Z-3(2) and the other three compounds
were better than 0.98 and regression coefficients were
2.357 0.1987 for 4(2), 33.33 1.595 for 4(3), and 16.60 1.123
for dimebolin.
In summary, we have described syntheses and biological evalu-
ations of novel small-molecule 5-styryl and 5-phenethyl-substi-
tuted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, which possess
activities to a broad spectrum of therapeutic targets characteristic
for dimebolin but with substantially higher affinities. In general,
steric orientation of 5-styryl substitution plays an important role
in the affinity of the molecules to 5-HT6 and H1 receptors. The most
promising molecule, 2,8-dimethyl-5-[(Z)-2-phenylvinyl]-2,3,4,5-
tetrahydro-1H-pyrido[4,3-b]indole, has the highest affinity among
other derivatives in a majority of the receptors.
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