Studies toward the discovery of the next generation of antidepressants. Part 2: Incorporating a 5-HT1A antagonist component into a class of serotonin reuptake inhibitors

Article abstract of DOI:10.1016/S0960-894X(01)00746-6

The design and synthesis of a novel series of indole derivatives (9) having dual 5-HT transporter reuptake and 5-HT_1A antagonist activity are described.

Full text of DOI:10.1016/S0960-894X(01)00746-6

Bioorganic & Medicinal Chemistry Letters 12 (2002) 307–310
Studies Toward the Discovery of the Next Generation of
Antidepressants. Part 2: Incorporating a 5-HT1A Antagonist
Component into a Class of Serotonin Reuptake Inhibitors
Richard E. Mewshaw,* Kristin L. Meagher, Ping Zhou, Dahui Zhou, Xiaojie Shi,
Rosemary Scerni, Deborah Smith, Lee E. Schechter and Terrance H. Andree
Global Chemical Sciences and Neuroscience Departments, Wyeth-Ayerst Research Laboratories, PO Box42528,
Philadelphia, PA 19101-2528, USA
Received 14 September 2001; accepted 31 October 2001
Abstract—The design and synthesis of a novel series of indole derivatives (9) having dual 5-HTtransporter reuptake and 5-HT
antagonist activity are described. # 2002 Elsevier Science Ltd. All rights reserved.
1A
Depression is a chronic illness that affects people of all
ages with far-reaching social and economic implica-
tions.1 Although serotonin (5-HT) selective reuptake
inhibitors (SSRIs) are currently first-line therapy for
depression, a major problem associated with SSRIs is
their delayed onset of action.2 Given antidepressant
activity is generally believed to be exerted by increased
Further support of this hypothesis was later observed
when the 5-HT1A antagonist WAY 100635 was found to
potentiate the antidepressant effects of several
SSRIs.10,11 Consequently, there has been considerable
interest by several groups to identify drug design stra-
tegies focusing on incorporating a 5-HT1A antagonist
component into a 5-HTreuptake inhibitor to bring
about a more immediate and complete antidepressant
effect (Fig. 1).12,13
3
5-HTneurotransmission, therapeutic efficacy of SSRIs
is thought to be compromised acutely due to their inhi-
bitory effect on 5-HTcell firing, which suppresses the
antidepressant effect. However, upon chronic adminis-
tration of SSRIs a desensitization of the somatodendritic
5-HT1A autoreceptors occurs, allowing serotonergic
neurons to resume their normal firing which is mani-
fested as an antidepressant effect after 2–6 weeks.4
As one of our preliminary examinations of this hypoth-
esis,14 our group focused on modifying a known class of
indoles (1) which embrace the known 5-HTuptake
inhibitor indalpine (2).15 This series of indoles was
reported as being potent 5-HTuptake inhibitors and
later derivatized without any significant loss of 5-HT
reuptake activity (e.g., 316 and 417). Due to the inherent
robust 5-HTreuptake activity of this class of indoles,
they appeared to be an excellent starting point to
attempt to incorporate 5-HT1A antagonistic activity
within a class of 5-HTreuptake inhibitors. From recent
reports in the literature,17ꢀ21 our group believed the
5-HT1A pharmacophore requirements22 could be met by
According to this hypothesis, blockade of the 5-HT1A
autoreceptors should result in an advanced therapeutic
action of the SSRI, allowing a more rapid onset of effi-
cacy.5 Interestingly, independent studies by Artigas5ꢀ7
and Blier8,9 recently reported that pindolol, the mixed
5-HT1A/b-adrenoceptor antagonist, when co-adminis-
tered with SSRIs accelerates their antidepressant effects.
*Corresponding author. Fax:+1-484-865-9399; e-mail: mewshar@war.wyeth.com
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00746-6

308
R. E. Mewshaw et al. / Bioorg. Med. Chem. Lett. 12 (2002) 307–310
Figure 1. Design strategy: incorporation of the 5-HT1A component within a 5-HTuptake inhibitor.
Scheme 1. Reagents and conditions: (a) BrCH2CH2Br/MEK; (b) ClCH2CH2OH/PPh3/DIAD/PPh3; (c) 2 N KOH/MeOH; (d) DMSO/Et3N/80 ꢁC.
tethering an appropriate aryloxyethyl moiety from the
basic nitrogen. Recently aryoxyethylamines have been
successfully utilized to produce potent 5-HT1A ligands
such as compounds 5–8.18ꢀ21 In this paper the prepara-
tion and structure–activity relationships of a series of
aryloxyethylamines (9), which represent our labora-
tories’ initial attempts to discover a potentially new
class of antidepressant agents, will be discussed.
and 34, respectively. Alkylation of 33 and 34 with 12
gave target molecules 23 and 24, respectively. The 4-
indolyl- and 5-quinolyl-oxyethyltetrahydropyridines
(i.e., 26 and 28; Scheme 3) were prepared using similar
chemistry as described in Schemes 1 and 2. The azaindole
tetrahydropyridines (i.e., 25, 27, and 29) were prepared
from commercially available 7-azaindole (35) using
analogous chemistry as depicted in Scheme 1.
Schemes 1–3 show the syntheses of target molecules 20–29.
The condensation of pyrogallol (10) and 1,2-dibromo-
ethane afforded 5-hydroxy-benzodioxan 11 in good
yield. The hydroxy benzodioxan was alkylated under
Mitsunobu conditions23 to afford the aryloxyethyl
chloride 12. Tetrahydropyridines 17–19 were prepared
by the addition of the indoles 14–16 to 4-piperidone
under basic conditions in yields ranging from 50 to
80%.24 Treatment of indole tetrahydropyridines 17–19
with 12 afforded the desired compounds 20–22. Shown
in Scheme 2 is the preparation of the piperidine ana-
logues 23 and 24. Reaction of 4-pyridinecarboxaldehyde
30 with 5-fluoroindole (15) affords 32 in good yield.25
Hydrogenation of indoles 32 and 19 over platinum
oxide under acidic conditions provided piperidines 33
Compounds were evaluated in vitro to determine activ-
ity at the 5-HTtransporter, 5-HT
receptor, and a1
1A
receptor. A binding assay protocol similar to that used
by Cheetham employing [3H]-paroxetine was used to
determine the affinity of compounds for the 5-HT
transporter (RB5-HT-T).26 Affinity for the human
transporter was determined by incubating test com-
pound and [3H]-5-HTwith human carcinoma (Jar cells),
previously treated with staurosporine to enhance trans-
porter expression, and measuring specific uptake (HC5-
HT-T).27 Human 5-HT1A binding (HC5-HT1A) was
determined with [3H]-8-OH-DPAT,28 and a1 affinity
was determined with [3H]-prazosin.29 Antagonism at the
5-HT1A receptor was determined using a [35S]-GTPgS
binding assay similar to that of Larenzo30 and a cAMP

R. E. Mewshaw et al. / Bioorg. Med. Chem. Lett. 12 (2002) 307–310
309
assay reported by Dunlop.31 Emax refers to the maximum
agonist effect observed. Since 5-HT1A antagonism is of
interest in this study, the IC50 values were calculated.
the double bond of 22 (i.e., 24) led to a 4-fold higher
5-HT1A affinity at the expense of a 31-fold loss of 5-HT
transporter affinity. Replacing the piperidinyl moiety
with a piperidinylmethyl group (i.e., 21 vs 23) resulted in
a 2-fold loss in 5-HT1A affinity while having a beneficial
effect on 5-HTuptake affinity. Indole derivative 26
was found to have much higher 5-HT1A and 5-HT
transporter affinity than both its benzodioxan (20) and
Shown in Table 1 are the biological results of target
molecules 20–29. Comparing tetrahydropyridinyl-
indoles 20–22, revealed the 5-fluoro substituent had a
detrimental effect for the 5-HTreuptake site. Reducing
Scheme 2. Reagents and conditions: (a) MeOH/50% NaOH/5-F-indole; (b) Et3SiH/TFA/CH2Cl2; (c) Pt2O/AcOH/H2; (d) DMSO/Et3N/80 ꢁC.
Scheme 3. Reagents and conditions: (a) 2 N KOH in MeOH; (b) ClCH2CH2OH/PPh3/DIAD/THF; (c) DMSO/Et3N/80 ꢁC.
Table 1. Aryoxylethylamine indole derivatives (20–29)32
Compd
Ar
X
Y–Z
R
n
HC5-HT-T Ki
(nM)
RB5-HT-T Ki
(nM)
HC5-HT1A Ki
(nM)
GTPgS Emax
(IC50, nM)
cAMP Emax
(IC50, nM)
RBa1 Ki
(nM)
20
21
22
23
24
25
26
27
28
29
A
A
A
A
A
A
B
B
C
C
C
C
C
C
C
N
C
N
C
N
C¼C
C¼C
H
5-F
6-F
5-F
6-F
H
H
H
H
H
0
0
0
1
0
0
0
0
0
0
45.0
46.9
19.8
nd
127.8
276
41.2
175
93.6
387
0.17
1.17
0.15
0.01
4.7
18.0
0.03
1.46
0.23
6.89
78.3
83.3
83.6
168.2
19.6
43.9
21.6
10.9
92.6
71.6
21.0 (222)
11.0 (684)
53.0 (nd)
nd
29.5 (666)
30.0 (nd)
7.5 (115)
7.0 (38.9)
14 (524)
0.0 (181)
0.0 (115)
0.0 (1036)
nd
4.7
30
4.1
nd
2.8
C¼C
CH2CH2
CH2CH2
C¼C
nd
0.0 (920)
0.0 (969)
0.0 (33)
0.0 (12)
0.0 (686)
0.0 (90)
33
C¼C
0.19
0.90
3.6
C¼C
C¼C
C¼C
78.0
nd, no data.

310
R. E. Mewshaw et al. / Bioorg. Med. Chem. Lett. 12 (2002) 307–310
quinoline analogues (28). When comparing the aza-
indoles to their indole analogues higher affinity for the
5-HT1A receptor and lower affinity for the 5-HTtrans-
porter was observed (25 vs 20; 27 vs 26; 29 vs 28). To
our delight, all the compounds in this study were
found to be 5-HT1A antagonists. In general, a major
limitation of the compounds discussed in this investiga-
tion was their high affinity for the a1 receptor. Due to this
shortcoming this particular class of molecules was not
further pursued.
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In conclusion, we have demonstrated that a known class
of 5-HTreuptake inhibitors can be modified to incor-
porate both 5-HT1A affinity and antagonist activity.
Though this class of molecules was not selective due to
their a1 receptor affinity, this study clearly demonstrates
the potential of creating a new class of antidepressants
embracing both 5-HTreuptake and 5-HT
antagonist
1A
activity. Investigations are currently underway in our
laboratories to improve upon these findings by creating
molecules which are both more selective and potent at
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