Homotryptamines as potent and selective serotonin reuptake inhibitors (SSRIs)

Article abstract of DOI:10.1016/j.bmcl.2005.01.059

A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be poten

Full text of DOI:10.1016/j.bmcl.2005.01.059

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1619–1621
Homotryptamines as potent and selective serotonin
reuptake inhibitors (SSRIs)
*
William D. Schmitz, Derek J. Denhart, Allison B. Brenner, Jonathan L. Ditta,
Ronald J. Mattson, Gail K. Mattson, Thaddeus F. Molski and John E. Macor
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492-7660, USA
Received 4 January 2005; revised 24 January 2005; accepted 25 January 2005
Abstract—A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT)
were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to
be potent SSRIs. Initial attempts at conformational restriction of the propylamine sidechain by incorporation of a quinuclidine bicy-
clic structure did not improve binding affinity at SERT.
Ó 2005 Elsevier Ltd. All rights reserved.
The importance of compounds that act as selective sero-
tonin reuptake inhibitors (SSRIs, Fig. 1) has been dem-
onstrated by their utility in treating depression, anxiety
porter protein (SERT). Reports describing SERT bind-
ing affinities of 5-hydroxytryptamine (5-HT, serotonin)
5
and related tryptamines have been published. Indole-
alkylamines with four carbon atom spacers in the form
of 4-indolylcyclohexylamines have also been investi-
1
,2
disorders, eating disorders and sexual dysfunction.
Ò
The recent approval of Lexapro (S-citalopram) for
the treatment of depression and generalized anxiety dis-
order illustrates the continuing interest in SSRIs as
6
gated. More recently, indolebutylpiperazines have been
7
reported as serotonin reuptake inhibitors. Additionally,
3-(4-piperidinyl) indoles have been described as potent
2
promising agents for the treatment of CNS disorders.
8
The SSRIs were the first rationally designed class of
compounds for the treatment of depression, and they
generally possess good tolerability and reasonable safety
and side-effect profiles. However, there is clearly room
for improvement. For example, fluoxetine, fluvoxamine
and paroxetine are all significant inhibitors of cyto-
chrome P450 (CYP) enzymes at their pharmacologically
inhibitors of serotonin reuptake. Surprisingly, little
F
H
N
N
O
O
3
,4
efficacious doses. The potential for drug–drug interac-
tions with these compounds requires careful monitoring
to avoid the risk of elevated levels of any co-adminis-
tered medications. Additionally, slow onset of action is
observed for SSRIs, typically resulting in a 2–6 weeks la-
NC
F
3
C
fluoxetine
citalopram
H
N
O
2
O
tency period before onset of antidepressant activity.
Thus, the need exists for improved SSRIs and SSRI
platforms.
O
Cl
NH
Cl
paroxetine
sertraline
F
An SSRI blocks the presynaptic reuptake of serotonin
(
5-hydroxytryptamine, 5-HT) by the serotonin trans-
O
N
NH2
O
Keywords: Homotryptamines; SSRI; Serotonin reuptake.
*
3
F C
fluvoxamine
Corresponding author. Tel.: +1 203 677 6562; fax: +1 203 677
702; e-mail: william.schmitz@bms.com
7
Figure 1.
0
960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.01.059

1620
W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1619–1621
attention has been given to simple homotryptamines as
potential SSRIs, despite the obvious structural similarity
(specific activity = 85 Ci/mmol) and increasing concen-
trations of test compounds for 1 h at 25 °C in a total vol-
ume of 250 lL. The amount of radioligand bound in the
presence and absence of competitor was analyzed by
plotting (À)log drug concentration versus the amount
of radioligand specifically bound. Non-specific binding
was defined with 10 lM fluoxetine. The midpoint of
the displacement curve (IC , nM), signified the potency.
5
,9
to serotonin and the above mentioned homologs.
Homotryptamines should generally lack the 5-HT recep-
1
0
tor agonism of tryptamines, but may retain SERT
5
a
affinity. In the current work described herein, we detail
the synthesis of, and in vitro SERT binding affinities for
a series of substituted homotryptamines.
5
0
Homotryptamines 2A–L were readily prepared utilizing
The results of these studies are shown in Table 1. Imme-
diately notable is the weak interaction of N,N-dimethyl
serotonin (8, bufotenin) with SERT. Equally notable is
the potent interaction of 2A, the homotryptamine ana-
log of 8. This single result suggested to us that homo-
tryptamines represented a useful, untried scaffold for
potent SSRI activity. Alkylation of the 5-hydroxy group
in 2A resulted in complete loss of activity (Table 1, com-
pounds 2A vs 2K and 2L), suggesting that C5 on the in-
dole ring of the homotryptamines was an important
SAR location on the molecule.
1
1
recently disclosed methodology from Denhart et al. In
short, substituted indoles were reacted with acrolein
using MacMillan catalysis, and the resulting aldehydes
were immediately subjected to reductive amination
using dimethylamine (Scheme 1). As an initial attempt
to investigate the effect of conformational restriction
on homotryptamines, compounds 7A and 7B were pre-
pared using Heck methodology previously reported by
1
2
Macor et al. (Scheme 2). Wittig condensation of
1
3
quinuclidine-3-carboxaldehyde (3) with ethyl triphen-
ylphosphonium acetate, followed by reduction of the
resulting ester yielded the allyl alcohol (4). Mitsunobu
coupling of the alcohol (4) with the trifluoroacetamido-
benzene derivatives (5A and 5B) afforded the key precur-
sors (6A and 6B) for intramolecular Heck cyclization.
A moderate loss in binding affinity was observed for
unsubstituted homotryptamine 2B. Substitution on the
aryl portion of the indole nucleus with electron-with-
drawing substituents provided compounds with a rela-
tively narrow range of binding affinity (IC Õs = 2–
1
2
Using standard conditions, 6A and 6B were converted
to their corresponding indole derivatives (7A and 7B,
respectively, Scheme 2).
5
0
36 nM). The most potent SSRIs were the indoles with
electron withdrawing substituents at C5 of the indole
core, and of these the 5-cyano homotryptamine 2J was
the most potent compound (IC50 = 2 nM).
The SERT binding affinities of these homotryptamine
analogs were determined using membrane homogenates
from HEK-293 cells that stably expressed human sero-
tonin transporters (HEK-hSERT cells). Membrane
a
Table 1. SERT binding affinities of homotryptamines
3
R
homogenates were incubated with 2 nM [ H]-citalopram
4
X
2
N
H
N
7
a
Compound
X
R
SERT IC50 (nM)
a, b
X
2
A
2B
5-OH
5-H
5-F
–(CH
–(CH
–(CH
–(CH
2
2
2
2
)
)
)
)
3
3
3
3
NMe
NMe
NMe
NMe
2
2
2
2
2
2
2
2
2
2
2
2
11 ± 2
58 ± 6
X
N
H
N
H
1
A-L
2 A-L
2
2
C
D
4.0 ± 0.3
7.0 ± 1.3
17 ± 3
5-Cl
Scheme 1. Reagents and conditions: (a) CH CHCHO, (2S,5S)-5-
benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one or (2S,5S)-5-benzyl-3-
methyl-2-(5-methyl-furany-2-yl)-imidazolidin-4-one, TFA, iPrOH/
2
2E
2F
5-Br
5-I
2 3
–(CH ) NMe
–(CH ) NMe
3
2
31 ± 6
29 ± 4
2G
2H
4-Cl
6-Cl
–(CH ) NMe
2
3
CH
2
Cl, À25 °C; (b) Me
2
NH, NaBH(OAc)
3
, THF, 14–37%.
–(CH ) NMe
36 ± 6
32 ± 6
2
2
2
2
3
3
3
3
2
2
2
I
7-Cl
–(CH
–(CH
–(CH
)
)
)
NMe
NMe
NMe
J
K
5-CN
5-OMe
5-OBn
2.0 ± 0.4
1100 ± 300
Br
b
c
X
NHCOCF
3
2L
–(CH ) NMe
2
3200
3
OH
CHO a, b
5
A X=F, 5B X=CN
7
A
5-F
18 ± 3
N
N
N
3
4
d
c
N
X
Br
X
7
8
B
5-CN
5-OH
2.0 ± 0.3
N
N
O
N
d
a
N
H
–(CH
2
)
2
NMe
2
1200
CF
3
a
7
A X=F, 7B X=CN
n = 3 for each reported IC50, each n represents a duplicate measure-
ment taken at five different concentrations and reported as the
average ± SEM.
6
A X=F, 6B X=CN
Scheme 2. Reagents and conditions: (a) Ph
reflux, 40%; (b) DiBAlH, CH Cl
, À78 °C, 83%; (c) diethylazodicarb-
oxylate, Ph , Et N, DMF, 80 °C,
P, THF, 0 °C, 7–15%; (d) Pd(OAc)
7–69%.
3 2
PCHCO Et, toluene,
b
c
2
2
n = 2, reported as previously described.
n = 1, reported as previously described.
Purchased from Cerilliant.
3
2
3
d
5

W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1619–1621
1621
Compounds 2A–J, 7A,B were also evaluated for binding
affinity at norepinephrine and dopamine transporters.
They were all found to be selective for the serotonin
transporter over both the norepinephrine and dopamine
5. (a) Horn, A. S. J. Neurochem. 1973, 21, 883–888; (b)
Adkins, E. M.; Barker, E. L.; Blakely, R. D. Mol.
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1
4
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7
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Because of the inherent flexible nature of the aminopro-
pyl sidechain in our homotryptamine derivatives, con-
formational constraint was seen as a logical next step
in understanding our new SSRI pharmacophore. While
the incorporation of conformational restriction in sero-
tonin agonists for selective binding at 5-HT receptor
8
9. (a) Meagher, K. L.; Mewshaw, R. E.; Evrard, D. A.;
Zhou, P.; Smith, D. L.; Scerni, R.; Spangler, T.; Abulh-
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1
5
subtypes has been previously described, fewer reports
have detailed the effects of such studies on SERT li-
1
6
gands. As an initial investigation into the effect of side-
chain conformational restriction on the binding affinity
of homotryptamines 2C and 2J, the corresponding
quinuclidines 7A and 7B were synthesized as described
above. The activities of the pairs (2C vs 7A and 2J vs
1
0. (a) Pinder, R. M.; Green, D. M.; Brewster, K.; Thompson,
P. B. J. J. Pharm. Pharmacol. 1973, 25, 847–848; (b) 5-HT6
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7
B) were not significantly different within each pair,
suggesting that the quinuclidine conformation did not
significantly alter the molecular recognition of the
homotryptamines for SERT. We are continuing in our
efforts to examine other conformational constraints of
the aminopropyl sidechain in 2C and 2J and will report
those results in due course.
1
1
1
1. Denhart, D. J.; Mattson, R. J.; Ditta, J. L.; Macor, J. E.
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In conclusion, simple N,N-dimethylhomotryptamines
exhibited potent binding affinity at SERT. Those
derivatives containing an electron withdrawing group
at the C5 position of the indole nucleus were the most
potent SSRIs. Introduction of a quinuclidine moiety as
a conformational restriction within the propylamine
side chain did not appreciably affect SERT binding
affinity.
9
77.
14. Percent inhibition at both norepinephrine and dopamine
transporters was found to be <50% at a concentration of
1 lM for all active (<1000 nM) SERT compounds listed in
Table 1. The most potent compounds exhibited the best
selectivity; for example, 2J showed 14% inhibition at the
norepinephrine transporter and 4% at the dopamine
transporter at 1 lM.
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