Studies towards the next generation of antidepressants. Part 1: Indolylcyclohexylamines as potent serotonin reuptake inhibitors

Article abstract of DOI:10.1016/S0960-894X(01)00334-1

A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most interesting compounds proved to have subnanomolar 5-HT transporter activity, and exhibited moderate 5-HT_1A affinity.

Full text of DOI:10.1016/S0960-894X(01)00334-1

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1885–1888
Studies Towards the Next Generation of Antidepressants. Part 1:
Indolylcyclohexylamines as Potent Serotonin Reuptake Inhibitors
Kristin L. Meagher, Richard E. Mewshaw,* Deborah A. Evrard, Ping Zhou,
Deborah L. Smith, Rosemary Scerni, Taylor Spangler, Susan Abulhawa, Xiaojie Shi,
Lee E. Schechter and Terrance H. Andree
Global Chemical Sciences and Neuroscience Departments, Wyeth-Ayerst Research Laboratories, CN 8000, Princeton,
NJ08543-8000, USA
Received 23 January 2001; accepted 3 May 2001
Abstract—A series of indolylcyclohexylamines possessing potent and selective serotonin reuptake inhibition is reported. The most
interesting compounds proved to have subnanomolar 5-HTtransporter activity, and exhibited moderate 5-HT
Elsevier Science Ltd. All rights reserved.
affinity. # 2001
1A
Depression is a debilitating disease with an over-
whelming economic liability to society.1 The treatment
of depression has been revolutionized by the introduc-
tion of selective serotonin (5-HT) reuptake inhibitors
(SSRIs) that possess fewer side effects than traditional
tricyclic antidepressants.2 A serious drawback to these
SSRIs is the delay of therapeutic benefit, believed to be
caused by the inhibitory role of the 5-HT1A auto-
receptors. Upon administration of an SSRI, the 5-HT1A
receptors decrease the firing of serotonergic neurons,
resulting in no net increase of synaptic 5-HTin desired
brain regions. After repeated administration and desen-
sitization of the 5-HT1A receptors the serotonergic neu-
rons resume normal firing and therapeutic
antidepressant effects are observed.3 Co-administration
of a 5-HT1A antagonist and an SSRI has been shown by
several groups to accelerate antidepressant effects.4ꢀ8 By
merging 5-HT1A antagonism and 5-HTtransporter
reuptake inhibition into one molecular entity, a superior
antidepressant may be achievable.
another series of less recognized indole derivatives.
Since the cyclohexyl indoles (2) were known to be 5-HT
transporter ligands,11 this class was used as a starting
point to systematically introduce the 5-HT1A pharma-
cophoric requirements. We now report the synthesis and
structure–activity relationships (SAR) of a new class of
indole derivatives (i.e., 3) that potently inhibit the ser-
otonin transporter site, and begin to exhibit 5-HT1A
affinity (Fig. 1).12
Schemes 1–6 show the synthesis of the target molecules.
The indolylcyclohexyl ketone was synthesized by the
condensation of a 5-substituted indole with 1,4-cyclo-
hexanedione mono-ethylene ketal.13 Hydrolysis affor-
ded the unsaturated ketone 7. Ketal 4 was also
hydrogenated to afford 5 followed by hydrolysis to 6.14
Preparation of known 5-HTtransporter ligands was
The design of new indole derivatives based on the 5-
hydroxytryptamine (5-HT, 1) structure has been known
to produce compounds with serotonergic activity both
at the 5-HT1A receptor and 5-HTtransporter site. 9,10 In
this letter we wish to disclose our initial investigations
directed at discovering new serotonergic agents within
*Corresponding author. Tel.:+1-610-341-2910; fax: +1-610-989-
4588; e-mail: mewshar@war.wyeth.com
Figure 1. Serotonergic agents of interests.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00334-1

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K. L. Meagher et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1885–1888
achieved by reductive amination to afford target com-
pounds 8–15 as shown in Scheme 2. The cis and trans
isomers could be easily separated by chromatography.
with 6a afforded target compounds 25a,b, 32a,b, and
33a,b.
Reacting 4-fluorophenylhydrazine with 3,4-dihy-
dropyran afforded 34, followed by conversion to bro-
mide 35 (Scheme 7). Displacement with the appropriate
amine provided compounds 38–40.
The tetrahydroisoquinoline analogue 16 was similarly
prepared by reductive amination (Scheme 3). The 5-
OMe analogue was prepared by the Mitsunobu reaction
of 5-hydroxyisoquinoline (17) and MeOH to afford 18
(Scheme 4). Compound 18 was hydrogenated over
Pt2O15 affording 19, which was reductively aminated
with 6a to give 20a,b.
Compounds were evaluated in vitro to determine affi-
nity for the 5-HTtransporter, 5-HT 1A and a1 receptors.
A protocol similar to that of Cheetham17 was used to
Preparation of the methoxy-tetrahydroisoquinolinyl
derivatives was achieved by cyclization of the appro-
priate carbamate intermediates (Schemes 5 and 6).16
Reduction with LAH, followed by reductive amination
Scheme 4. Reagents and conditions: (a) DEAD, Ph3P, MeOH, THF;
(b) H2, Pt2O, HOAc; (c) 6a, NaBH(OAc)3, HOAc, ClCH2CH2Cl.
Scheme 1. Reagents and conditions: (a) 2 N KOH in MeOH, reflux;
(b) H2, 10% Pd/C, EtOH; (c) 1 M HCl, THF.
Scheme 5. Reagents and conditions: (a) methyl chloroformate, Et3N,
THF; (b) PPA, 140 ꢁC; (c) LAH, THF, reflux; (d) 6a, NaBH(OAc)3,
HOAc, ClCH2CH2Cl.
Scheme 2. Reagents and conditions: (a) NaBH(OAc)3, HOAc,
ClCH2CH2Cl.
Scheme 6. Reagents and conditions: (a) methyl chloroformate, Et3N,
THF; (b) PPA, 140 ꢁC; (c) LAH, THF, reflux; (d) 6a, NaBH(OAc)3,
HOAc, ClCH2CH2Cl.
Scheme 3. Reagents and conditions: (a) NaBH(OAc)3, HOAc,
ClCH2CH2Cl.

K. L. Meagher et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1885–1888
1887
determine affinity for the serotonin transporter (RB5-
HT-T) and affinity for the a1 receptor was determined
by incubating rat cortical membranes with [3H]-prazo-
sin.18 Ki values were calculated from IC50 values using
the method of Cheng and Prusoff.19 Human 5-HT1A
receptor binding (HC5-HT1A) was determined by incu-
bating CHO cells transfected with human 5-HT1A
20
receptors with [3H]-8-OH-DPATand test compound.
The biological results of the simple cyclohexylamines
are shown in Table 1. These compounds exhibited
moderate to high affinity for the 5-HTtransporter and
Scheme 7. Reagents and conditions: (a) H2O, dioxane, 100 ꢁC; (b)
CBr4, PPh3, CH2Cl2; (c) Et3N, DMSO, 100 ꢁC.
Table 1. Serotonin transporter, 5HT1A and a1 affinities for compounds 8–15
Compound
R1
R2
X
A-B
cis/trans
RB5-HT-T Ki nMa
HC5-HT1A %inhib@1mM
a1 %inhib@1 mM
8a
8b
9
H
H
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
CN
CN
CN
F
CH2–CH
CH2–CH
CH¼C
cis
trans
—
cis
trans
cis
trans
—
cis
trans
—
cis
855
107
3.13
7.50
25
0%
32%
87%b
15%
37%
3%
11%
41%
0%
0%
0%
0%
0%
21%
64%c
27%
17%
28%
9%
10a
10b
11a
11b
12
13a
13b
14
CH2–CH
CH2–CH
CH2–CH
CH2–CH
CH¼C
21
16
F
8%
(CH2)2Ph
(CH2)2Ph
(CH2)2Ph
CN
CN
CN
CN
CN
CN
1.54
7.50
1.98
178
22
32%
40%
56%
10%
3%
CH2–CH
CH2–CH
CH¼C
H
(CH2)5
(CH2)5
(CH2)5
15a
15b
CH2–CH
CH2–CH
trans
152
14%
aKi values are the mean of 2–3 experiments run at six different concentrations. Each experiment was carried out in triplicate. 95% confidence limits
were generally ꢂ15% of the mean value.
bKi=374 nM.
cKi=368 nM.
Table 2. Serotonin transporter, 5HT1A, and a1 affinities for compounds 16, 20, 25, 32 and 33
Compound
R1
cis/trans
RB5-HT-T Ki (nMa)
HC5-HT1A %inhib@1 mM
a1 Ki nM
16a
16b
20a
20b
25a
25b
32a
32b
33a
33b
H
H
cis
trans
cis
trans
cis
trans
cis
trans
cis
trans
1.23
10
0.61
12
0.80
12
0.10
8
0%
10%
7%
47%
26%
48%
21%
74%b
14%
46%
337
88
920
120
5-OMe
5-OMe
7-OMe
7-OMe
6-OMe
6-OMe
8-OMe
8-OMe
11%@100
113
11%@100
228
336
1.01
7.5
66
aKi values are the mean of 2–3 experiments run at six different concentrations. Each experiment was carried out in triplicate. 95% confidence limits
were generally ꢂ15% of the mean value.
bKi=300 nM.

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K. L. Meagher et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1885–1888
Our initial attempts to incorporate 5-HTtransporter
and 5-HT1A activity into a single molecule resulted in
the identification of a novel class of indolylalkylamines.
The indolylcyclohexylamines disclosed here generally
possessed potent 5-HTtransporter affinity and low to
moderate 5-HT1A affinity. The incorporation of the
methoxy-substituted tetrahydroisoquinoline moiety led
to a slight increase in 5-HT1A affinity. The most potent
tetrahydroisoquinoline derivative with dual activities
Table 3. 5-HTtransporter, 5HT 1A, and a1 affinities for 38–40
Compound
R1
RB5-HT-T
Ki (nMa)
HC5-HT1A
Ki (nM)
a1
Ki (nM)
38
39
40
H
5-OMe
6-OMe
4.85
1.94
1.39
48%@1000
242.9
288
35
31.4
58
was 32b (5-HTtransporter,
Ki=8 nM: 5-HT1A
Ki=300 nM). In the course of our research we dis-
covered a novel, potent and selective SSRI (32a).
Research is continuing in our laboratories toward the
discovery of a dual activity agent having a more
aKi values are the mean of 2–3 experiments run at six different con-
centrations. Each experiment was carried out in triplicate. 95% con-
fidence limits were generally ꢂ15% of the mean value.
balanced 5-HTreuptake and 5-HT
activity profile.
1A
SAR studies focused on the replacement of the tetra-
hydroisoquinoline moiety with more optimized 5-HT1A
pharmacophoric groups will be reported in due course.
exhibited selectivity over the a1 receptor. Moderate 5-
HT1A activity was observed only in the unsaturated
analogue 9 (Ki=374 nM). Substitution at the indole 5
position with a cyano or fluoro led to an improvement
on 5-HTtransporter affinity ( 8a,b vs 10a,b and 11a,b).
Comparing the benzyl analogues to the corresponding
phenethylamine analogues (i.e., 9 vs 12: 10b vs 13b), an
increase in 5-HTtransporter affinity was observed,
while the affinity of the cis analogues remained the same
(10a vs 13a). Unsaturation in the cyclohexyl ring
increased 5-HTtransporter and 5-HT 1A affinity for both
the benzyl and phenethylamines (i.e., 9 and 12).
Removal of the phenyl ring, as shown with the piper-
idinyl derivatives (i.e., 14, 15a, and 15b), resulted in a
detrimental effect with respect to 5-HTtransporter and
5-HT1A affinities.
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