2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT 6 receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2005.06.067

A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT₆ activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)- 1H-indole with an IC

Full text of DOI:10.1016/j.bmcl.2005.06.067

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4230–4234
2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel
5-HT6 receptor agonists
Cecilia Mattsson,a,* Clas Sonesson,a Anna Sandahl,a Hartmut E. Greiner,b
Michael Gassen,b Jo¨rg Plaschke,b Joachim Leibrockb and Henning Bo¨ttcherb
aMedicinal Chemistry, Carlsson Research AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Goteborg, Sweden
bPreclinical Research and Development, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany
Received 4 May 2005; revised 17 June 2005; accepted 23 June 2005
Available online 1 August 2005
Abstract—A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity.
The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50 = 7.4 nM in
3H-LSD binding and an EC50 = 1.0 nM in a functional assay measuring production of cyclic AMP.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
For the investigation of the functional role of receptors
in vivo, selective agonists are widely used as pharmaco-
logical tools. However, in the 5-HT6 receptor field, only
a few publications have appeared on 5-HT6 receptor
agonists (Fig. 1).6–8 In addition, many of them have also
been found to be partial agonists in functional assays
measuring the production of cyclic AMP [i.e., LSD
(2), 2-Br-LSD].9
The human 5-hydroxytryptamine6 (5-HT6) receptor is
one of the most recently identified members of the sero-
tonergic receptor superfamily; today at least 14 different
serotonin receptor subtypes are identified in the mam-
malian CNS.1 The 5-HT6 receptor is a G-protein-cou-
pled receptor and positively linked to adenylylcyclase
activity. Within the transmembrane region, the human
5-HT6 receptor shows ꢀ30–40% homology to other
human 5-HT receptors.2
In 2000, Glennon et al. reported on the investigation of
the binding of tryptamine derivatives at human 5-HT6
receptors (compounds 3–5, Fig. 1).6 An interesting
finding from this work was that the human 5-HT6
receptors tolerate alkyl groups in the 2-position of
the indole ring and that the size of the alkyl group
has a strong influence on the pharmacological proper-
ties at the 5-HT6 receptors. For example, 2-ethyl-5-
methoxy-N,N-dimethyltryptamine (EMTD, 4) was
found to be a potent and selective 5-HT6 receptor
agonist (Ki = 16 nM), while the corresponding phenyl
analogue 5 was found to display 5-HT6 receptor antag-
onist properties.6
The mRNA of 5-HT6 receptors is predominantly local-
ized in brain regions such as nucleus accumbens, stria-
tum, olfactory tubercle, substantia nigra and
hippocampus. The localization together with high affin-
ity at the 5-HT6 receptors for several antipsychotics led
to the suggestion that these receptors might play a role
in certain types of psychoses and that they can be used
as a target in the development of new treatments for
schizophrenia.3 In addition, it has also been speculated
that the 5-HT6 receptors are involved in cognition and
learning.4,5
Substitution on the indole nitrogen with aryl-sulfonyl
groups has been reported to yield potent and selective
5-HT6 antagonists (7 and 9) or, in a few cases, partial
agonists (8) at the 5-HT6 receptor.10–12 However, mov-
ing the aryl-sulfonyl group from the indole nitrogen to
the indole 5-position generally yields potent and selec-
tive 5-HT6 receptor agonists (10, 12, and 13). Depending
on the chemical structure of the amino-alkyl side chain,
Keywords: 5-HT6, 5-Hydroxytryptamine6 agonist; 3-(1,2,3,6-Tetrahy-
dropyridin-4-yl)-1H-indole.
*
Corresponding author. Tel.: +46 31 7720605; fax: +46 31 7720601;
e-mail: cecilia.mattsson@carlssonresearch.se
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.06.067

C. Mattsson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4230–4234
4231
Figure 1. Structures of 5-HT6 receptor ligands.
antagonists can also be achieved (11 and 14).7,8 For in-
stance, in the 5-arylsulfonamido-3-(pyrrolidin-2-ylmeth-
yl)-1H-indole class, the stereochemistry was found to
influence the functional activity. The (R)-enantiomers
(10) were found to be potent agonists, while the (S)-
enantiomers (11) displayed antagonist activity.7
2. Chemistry
The 3-substituted tetrahydropyridine-indoles (15–21 and
24–29), piperidine-indole (23) and the 8-azabicy-
clo[3.2.1]oct-2-en-3-yl-indole (22) derivatives were made
from the corresponding 2,5-disubstituted indoles
according to Scheme 1.14 Some of these indoles are com-
mercially available and others were made by an im-
proved Madelung synthesis.15,16
As part of a medicinal chemistry programme directed
towards the design and synthesis of new potent and
selective 5-HT6 receptor agonists for the evaluation of
the function of 5-HT6 receptors in vivo, we performed
a high throughput screening on the Merck KGaA
chemical library in order to identify new chemical
leads. Compound 6 was discovered to be a potent
and selective 5-HT6 receptor ligand (IC50 = 2 nM),
and when 6 was tested in the cAMP assay, it was
found to be a 5-HT6 receptor antagonist.13 For the
tryptamine series, it is known that the size of the 2-al-
kyl/aryl group influence the agonist/antagonist proper-
ty at the 5-HT6 receptors.6 Therefore, we speculated
that a similar approach could switch compound 6 into
agonist properties by replacing the 2-phenyl group with
smaller alkyl groups.
3. Results and discussion
The affinity of the compounds for human 5-HT6 recep-
tors, stably expressed in HEK cells, was evaluated.2 The
intrinsic activity (IA) of the compounds at the 5-HT6
receptor was determined by measuring their effect on
cAMP production in BHK cells and compared to the ef-
fect elicited by 5-HT.17 In addition, the potency for the
agonists was measured and presented as the EC50 level.
The results are presented in Tables 1–4. EMTD (4) is
included for comparative purposes.
In the first screening campaign, we examined the effect
of small alkyl groups in the 2-position on the 5-meth-
oxy-indole scaffold. According to Table 1, the unsubsti-
tuted 5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-
Herein, we report on the structure–activity relationship
(SAR) for analogues to compound 6 with the aim to find
novel 5-HT6 receptor agonists.

4232
C. Mattsson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4230–4234
Scheme 1. Reagents and conditions: (a) (t-BuO2C)2O, THF, heat; (b) 2 equiv s-BuLi, R2CON(OMe)Me, THF, À40 °C to room temperature;
(c) CF3CO2H, CH2Cl2; (d) H3PO4, AcOH, 80 °C; (e) NaB(OAc)3H, CH2O, AcOH, THF or R3-X, K2CO3, CH3CN; (f) Pd/C, NH4HCO2, EtOH.
indole (RU 24969, known as 5-HT1A/1B agonist, 17) was
found to display moderate affinity to the 5-HT6 recep-
tors (IC50 = 79 nM).18 In the intrinsic activity assay, this
Table 2. 5-HT6 binding affinity and functional cAMP data for
different derivate of 5-chloro substituted indoles
Table 1. 5-HT6 binding affinity and functional cAMP data for
different derivatives of 5-methoxy substituted indoles
Compound R1
R2
IC50
(nM)
EC50
(nM)
IAb
(%)
a
b
22
AMe 40
AMe 40
10,000
16
75
53
R1
R2
IC50
(nM)
EC50
(nM)
IAb
(%)
a
b
Compound
3020
1819
19
46
AEt
AEt
AEt
AMe
AH
85 ( 15)c
710
ND
7.9
113
ND
100
100
55
AMe 7.4 ( 1.6)c 1.0 ( 0.40)d 92d
23
300
90
AEt
APr
30
40
ND
ND
ND
ND
ND
ND
15
20
1618
1718
80
5.8
21
AiPr 100
79
200
a Displacement of [3H]-LSD binding to cloned h5-HT6 receptors stably
expressed in HEK cells.2 Single determination.
b Stimulation of cAMP production in BHK cells.17 Single determina-
tion. ND, not determined.
a Displacement of [3H]-LSD binding to cloned h5-HT6 receptors stably
expressed in HEK cells.2 Single determination.
b Stimulation of cAMP production in BHK cells.17 Single determina-
tion. ND, not determined.
c Mean of four determination ( SEM).
c Mean of two determination ( SEM).
d Mean of three determination ( SEM).

C. Mattsson et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4230–4234
4233
Table 3. Substitution at the basic nitrogen in the 5-chloro-2-methyl-3-
(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety
and potent agonist at the 5-HT6 receptors in the cAMP
assay with an EC50 = 1.0 nM.
Replacing the piperidene ring in 18 with a tropinen ring
(22) or a dimethyl-aminoethyl side chain (30) reduced
the affinity, potency and intrinsic activity at 5-HT6
receptors.20
The influence of different N-alkyl groups on the 5-HT6
receptor affinity in the 5-chloro-2-methyl-3-(1,2,3,6-tet-
rahydropyridin-4-yl)-1H-indole series was also investi-
gated. The data in Table 3 indicate that further
improvement in 5-HT6 receptor affinity is not possible
to achieve for this agonist series by increasing the size
of the N-alkyl group. A bulky group, such as a benzyl,
was found to be detrimental to the 5-HT6 receptor affin-
ity. The data are also in good agreement with data from
published 5-HT6 receptor antagonists, both in the tetra-
hydropyridine and the tryptamine series.10,21 The affini-
ty for these 5-HT6 antagonists was found to be sensitive
to increasing the size of the alkyl group on the basic
nitrogen.
Compound R1
R2
IC50
(nM)
EC50
(nM)
IAb
(%)
a
b
1819
2414
25
AH
AMe 7.4 ( 1.6)c 1.0 ( 0.40)d 92d
AMe
AEt
APr
AMe 10
AMe 30
AMe 60
2.9
152
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
26
27
AnBu AMe 50
28
29
ABn
AEt
AMe 600
AEt 70
a Displacement of [3H]-LSD binding to cloned h5-HT6 receptors stably
expressed in HEK cells.2Single determination.
b Stimulation of cAMP production in BHK cells.17 Single determina-
tion. ND, not determined.
c Mean of four determination ( SEM).
d Mean of three determination ( SEM).
The 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-
yl)-1H-indole (18) was examined further for selectivity
against several serotonergic and dopaminergic receptors
and compared with EMTD (4) (Table 4). The selectivity
of compound 18 for 5-HT6 was greater than 20-fold
over 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-
HT4, 5-HT7, D2, D3, D4 receptors and the 5-HT trans-
porter protein but showed significant affinity for the
5-HT3 receptors. By reintroducing the 5-methoxy group
(16), selectivity against 5-HT3 can be achieved as shown
in the tryptamine series.6
compound turned out to be a partial agonist with low
potency (EC50 = 200 nM). However, the introduction
of a methyl (16) or ethyl (15) group in the 2-position
did not alter affinity but rendered compounds with full
agonist properties with high potency (EC50 = 5.8 and
7.9 nM, respectively).18 Interestingly, these compounds
were found to be more potent agonists than EMTD
(4, EC50 = 710 nM).6 The reduction of the piperidene
double bond yielded a compound (23) with three- to
four fold lower affinity for the 5-HT6 receptors, indicat-
ing the importance of a p–p stabilized conformation of
the piperidene ring for an optimal interaction with the
5-HT6 receptors.
In summary, a new class of potent and selective 5-HT6
receptor agonists has been discovered and they may be-
come useful tools in the investigation of the functional
role of 5-HT6 receptors. By replacing the more flexible
amino ethyl side chain in the tryptamine series with
a rigidified piperidene ring, potent 5-HT6 receptor
agonists were achieved. The most promising candidate
was found to be 5-chloro-2-methyl-3-(1,2,3,6-tetrahy-
dropyridin-4-yl)-1H-indole (18) having an IC50 of
7.4 nM for the 5-HT6 receptors and in the functional as-
say, measuring production of cyclic AMP, 18 was found
to display full agonist properties with an EC50 value of
1.0 nM.
A second screening campaign was performed with the
5-chloro-indole scaffold and different 2-alkyl groups.
In contrast to the 5-methoxy-indole analogues, the 5-
chloro-indole moiety seems to be more sensitive to the
size of the 2-alkyl group (Table 2). The affinity trend,
when increasing the size and bulkiness of the 2-alkyl
group, shows that the optimal size is a methyl group
(18).19 Interestingly, this compound proved to be a full
Table 4. Binding affinity for other 5-HT receptors
a
IC50 (nM)
Compound
r5-HT1A
r5-HT1B
5-HT1D
h5-HT2A
h5-HT2C
5-HT3
5-HT4
h5-HT6
h5-HT7
46
1819,e
1618
>1000
660 ( 65)b
430
>1000
180 ( 15)b
310
1400
110 ( 3.3)c
>1000
620
240 ( 5.7)c
>1000
5500
450 ( 23)c
>1000
>1000
34 ( 11)b
>1000
44
620 ( 240)b
9800
85 15b
7.4 ( 1.6)d
80
1500
3000 ( 700)b
9800
a Binding methods according to Bartoszyk et al.22 5-HT1D (calf), 5-HT3 (NG 108 cells), 5-HT4 (guinea pig).22 Single determination.
b Mean of two determination ( SEM).
c Mean of three determination( SEM).
d Mean of four determination ( SEM).
e hD2, hD3 and hD4 IC50 > 1000 nM, 5-HT transporter protein IC50 4500 nM.

4234
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12. Russell, M. G. N.; Baker, R. J.; Barden, L.; Beer, M. S.;
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