Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with 5-HT transporter and 5-HT1A affinity

Article abstract of DOI:10.1016/j.bmcl.2004.08.030

Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds 11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT_1A affinity. Moreover, several of these compounds possess func

Full text of DOI:10.1016/j.bmcl.2004.08.030

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5281–5284
Novel aryloxy-8-azabicyclo[3.2.1]oct-3-enes with
5-HT transporter and 5-HT1A affinity
Adam M. Gilbert,a,* Thomas Coleman,a Jason Kodah,a Richard E. Mewshaw,b
Rosemary Scerni,c Lee E. Schechter,c Deborah L. Smithc and Terrance H. Andreec
aChemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965-1215, USA
bChemical and Screening Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA
cDepartment of Neuroscience, Wyeth Research, CN-8000, Princeton, NJ 08543-8000, USA
Received 1 July 2004; revised 12 August 2004; accepted 14 August 2004
Available online 17 September 2004
Abstract—Joining aryl 8-azabicyclo[3.2.1]oct-3-enes with aryloxyethanes and aryloxypropanes produces novel series of compounds
11 and 12 with potent 5-HT-T affinity and moderately potent 5-HT1A affinity. Moreover, several of these compounds possess func-
tional 5-HT1A antagonism. Optimal compounds are, 4-indolyloxyethane 21, 4-indolyloxypropanes 25, and 27, which possess potent
5-HT-T affinity (5-HT-T Ki: 21: 1.2nM, 25: 0.54nM, 27: 0.38nM) and good 5-HT1A affinity/antagonism (5-HT1A Ki, [35S]GTPcS:
Emax (%): 21: 111.1nM, 0%; 25: 173.2nM, 0%; 27: 107nM, 0%).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
5-HT1A component
5-HT1A component
N
Ar1
O
n = 0,1
Although used for many years as effective antidepres-
sants, first generation selective serotonin reuptake inhib-
itors (SSRIs) possess shortcomings that might be
remedied with agents that have additional desired prop-
erties. The major drawback with the current line of
SSRIs is that they have a delayed onset before the
beneficial therapeutic effect is observed. One approach
to create a fast-acting SSRI is to combine, in a single
molecule, an agent with SSRI activity + 5-HT1A antago-
nist activity since activation of 5-HT1A autoreceptors by
serotonin (5-HT) is believed to decrease the firing of
serotonergic neurons.1 Thus an agent with both activi-
ties (SSRI and 5-HT1A antagonism) would be a signifi-
cant improvement on currently approved therapies. As
proof of concept, co-administration of 5-HT1A antago-
nists/partial antagonists and SSRIs has been clinically
shown to induce faster antidepressant action than
administration of SSRIs alone.2,3
H
N
R
R = H, OH
n
O
Ar
N
n
R
1
2
Ar2
5-HT reuptake component
Figure 1. Design strategy.
5-HT reuptake component
of antidepressant agents based on Ôthe overlapping type
approachÕ. This strategy uses a common nitrogen to
amalgamate the 5-HT1A and 5-HT uptake site pharmaco-
phore (Fig. 1). In Part 2 we discovered that compounds
that fell into the generic structure 1 had both 5-HT1A
antagonism and 5-HT uptake site activity.6 In this arti-
cle we will expand upon template 1 by replacing the
piperidinyl moiety with the tropane framework, as well
as tethering either the 2-aryloxyethyl or 3-aryloxy-2-prop-
anol side chains (i.e., 2).
Recently our laboratories4–7 and others8–13 have dis-
closed efforts toward discovering a potentially new class
2. Chemistry
Keywords: Serotonin transporter; Serotonin 1A receptor.
*
Target molecules were synthesized according to the proce-
dures outlined in Schemes 1–3. Aryloxyethyl chlorides
Corresponding author. Tel.: +1 845 602 4865; fax: +1 845 602
5561; e-mail: gilbera@wyeth.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.08.030

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A. M. Gilbert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5281–5284
roethyl chloroformate,15 protection of the secondary
amine with (Boc)2O to form 8,16 addition of an aryl lith-
ium, followed by dehydration/deprotection with TFA
(Scheme 2). Aryloxyalkyl chlorides 4 and aryloxyepox-
ide 6 were combined with aryl 8-azabicyclo[3.2.1]oct-3-
enes 10 by heating in MeCN in the presence of K2CO3
to produce target compounds 11 and 12 (Scheme 3).
a (n=1) or
b (n=2)
Ar1
Ar1
Cl
OH
O
n
3
4
Ar1 = 4-Indanyl, 5-Quinolinyl, 8-
Quinolinyl, 4-Indolyl, 4-(1-Methyl)indolyl,
8-Benzodioxanyl
1HNMR, IR, and ESMS spectroscopy confirmed the
structures of all newly prepared compounds. The enantio-
mers of 11 and diastereomers of 12 were not separated
and were tested as racemic/diastereomeric mixtures,
respectively.
HN
HN
c
OH
O
O
5
6
Scheme 1. Reagents and conditions: (a) 2-chloroethanol, Ph3P,
DEAD, THF, 0–23°C, (b) 3-chloropropanol, Ph3P, DEAD, THF,
0–23°C, (c) NaH, (2R)-(À)-glycidyl tosylate, THF, 23°C.
3. Pharmacology
All new aryloxy-8-azabicyclo[3.2.1]oct-3-enes 11 and 12
were tested in vitro to determine affinity for the 5-HT1A
receptor, and 5-HT transporter (5-HT-T). Human 5-
HO
Ar2
O
O
a
b
HT1A (HC-5-HT1A) receptor binding was deter-
O
O
mined via the displacement of [3H]-8-OH-DPAT from
human 5-HT1A/transfected CHO cells according to the
method of Dunlop et al.17 Assessment of compound
agonism/antagonism on the HC-5-HT1A receptor was
determined using a [35S]GTPcS assay.18 A protocol
similar to that of Cheetham et al. was used to determine
rat 5-HT transporter affinity (RB5-HT-T).19
N
N
MeN
O
O
7
8
9
Ar2
c
HN
10
Biological data for all newly prepared aryloxyethyl 8-
azabicyclo[3.2.1]oct-3-enes 11 is presented in Table 1.
Thus 2-naphthyl 8-azabicyclo[3.2.1]oct-3-ene 1 was ini-
tially combined with a 4-indanyl-ethyl group to produce
13 (11: Ar1 = 4-indanyl, Ar2 = 2-naphthyl), a compound
with very potent 5-HT-T affinity but no 5-HT1A affinity.
The Ar1 = 5-quinolinyl (14) and Ar1 = 8-quinolinyl (15)
analogs possess sub-nM affinity for the 5-HT-T with
increasing 5-HT1A affinity compared to 13. Changing
the Ar2 = 2-naphthyl moiety of 15 to an Ar2 = 2-indolyl
moiety produces an important increase in 5-HT1A affin-
ity the resulting compound 16 possesses potent 5-HT-T
affinity and moderately potent 5-HT1A antagonism (16:
5-HT-T: 11nM; 5-HT1A: 320nM, Emax: 0%). Com-
pound 17 has a similar potency profile as 16 however
this compound possesses partial 5-HT1A antagonism
(17: 5-HT-T: 0.2nM, 5-HT1A: 295nM; Emax: 25%).
Since 17 has very potent affinity for 5-HT-T, it was
decided to keep the Ar1 = 4-indolyl substituent and
make further variations at Ar2.
Ar2 = 2-Naphthyl, 2-Indolyl
3,4-Dichlorophenyl, 3-Benzo[b]thiophenyl
3-Indolyl
Scheme 2. Reagents and conditions: (a) (1) 1-chloroethyl chlorofor-
mate, DCE, 80°C; (2) MeOH, 50°C; (3) (Boc)2O, i-PrOH, H2O,
NaOH, 23°C; (b) ArLi, THF, À78 to 23°C; (c) TFA, CH2Cl2, 23°C.
Ar2
Ar1
HN
Cl
Ar1
N
O
O
n
n
4
11
a
or
HN
10
N
O
O
O
OH
Ar2
6
12
Two isosteric modifications of the Ar2 = 2-naphthyl
moiety give compounds with reduced 5-HT1A affin-
ity––18 (Ar2 = 3,4-dichlorophenyl; 39% @ 1000nM)
and 19 (Ar2 = 3-benzothiophenyl; 11% @ 1000nM).
The corresponding N(Me) analog of 17 shows reduced
5-HT1A and 5-HT-T affinity (20: Ar1 = 4-(1-methyl)ind-
Scheme 3. Reagents and conditions: (a) K2CO3, MeCN, 80°C.
and aryloxypropyl chlorides were prepared via a
Mitsunobu reaction between phenols 3 and 2-chloroeth-
anol or 3-chloropropanol.14 4-Oxiranylmethoxy-(1H)-
indole 6 was prepared from 4-hydroxyindole 5 via
deprotonation with NaHfollowed by reaction with
(2R)-(À)-glycidyl tosylate.
olyl; 5-HT-T: 4.4nM; 5-HT1A: 33% @ 1000nM; Emax
:
100%). However a jump in 5-HT1A potency was seen
with 21 where the Ar2 = 2-naphthyl moiety of 17 was
changed to an Ar2 = 3-indolyl group. Moreover, this
compound possesses potent 5-HT-T affinity and is
a functional antagonist at the 5-HT1A receptor (21:
5-HT-T: 1.2nM, 5-HT1A: 111.1nM, Emax: 0%). Addi-
Aryl 8-azabicyclo[3.2.1]oct-3-ene derivatives 10, were
prepared by demethylation of tropinone 7 with 1-chlo-

A. M. Gilbert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5281–5284
5283
Table 1. Serotonin transporter affinity, 5-HT1A affinity and [35S]GTPcS: Emax values for aryloxytropenes 11
Ar2
Ar1
N
O
11
Compound
Ar1
Ar2
RB5-HT-T Ki (nM)a
HC5-HT1A Ki (nM)a
[
35S]GTPcS: Emax (%)b
13
14
15
16
17
18
19
20
21
22
4-Indanyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Indolyl
5.0
0.4
0% @ 1000nM
15% @ 1000nM
44% @ 1000nM
320
Not tested
29
95
5-Quinolinyl
8-Quinolinyl
5-Quinolinyl
4-Indolyl
0.5
11.0
0.2
0
25
2-Naphthyl
295
4-Indolyl
4-Indolyl
3,4-Dichlorophenyl
3-Benzo[b]thiophenyl
2-Naphthyl
0.5
39% @ 1000nM
11% @ 1000nM
33% @ 1000nM
111.1
5
Not tested
15.0
4.4
4-(1-Methyl)indolyl
4-Indolyl
8-Benzodioxanyl
100
0
3-Indolyl
3-Indolyl
1.2
4.0
85.5
65
a Ki values are the mean of two experiments run at six different concentrations. 95% confidence limits were generally 10% of the mean value.
b Emax values are reported from one experimental run at six different concentrations.
Table 2. Serotonin transporter affinity, 5-HT1A affinity and [35S]GTPcS: Emax values for aryloxytropenes 12
Ar2
R
HN
O
N
12
Compound
R
Ar2
RB5-HT-T Ki (nM)a
49% @ 1000nM
46% @ 1000nM
HC5-HT1A Ki (nM)a
[
35S]GTPcS: Emax (%)b
23
24
25
26
27
H3-Indolyl
H2-Naphthyl
0.65
0.14
14
81
OH2-Naphthyl
H3,4-Dichlorophenyl
OH3,4-Dichlorophenyl
0.54
0.65
0.38
173.2
44% @ 1000nM
107
0
Not tested
0
a Ki values are the mean of two experiments run at six different concentrations. 95% confidence limits were generally 10% of the mean value.
b Emax values are reported from one experimental run at six different concentrations.
tional 5-HT1A potency is seen with 22, but this
compound functions as a partial agonist (22: 5-HT-T:
4.0nM; 5-HT1A: 85.5nM; Emax: 65%).
(26: 5-HT-T: 0.65nM, 5-HT1A: 44% @ 1000nM). Incor-
poration of the pindolol (S)-OHgroup gives 27, a com-
pound with excellent 5-HT-T affinity and good 5-HT1A
affinity/antagonism (27: 5-HT-T: 0.38nM, 5-HT1A
107nM, Emax: 0%).
:
Extension of the 4-indolyloxyethyl chain to a 4-indolyl-
oxypropyl linker produces the compounds in Table 2.
Compound 23, the 3-carbon analog of 21, compara-
tively has similar 5-HT-T affinity and weaker 5-HT1A
4. Summary
affinity (23: 5-HT-T: 0.65nM; 5-HT1A
: 49% @
1000nM, Emax: 14%). The corresponding Ar2 = 2-naph-
thyl analogs (24) has a similar biological profile as 23
and shows 5-HT1A agonism (Emax: 81%). However,
introduction of an (S)-OHgroup produces 25, which
has substantially more affinity for the 5-HT1A receptor
compared to 24, and is a full 5-HT1A antagonist (25:
5-HT-T: 0.54nM, 5-HT1A: 173.2nM; Emax: 0%). This re-
sult is consistent with the fact that 25 contains the struc-
ture of pindolol, a known 5-HT1A antagonist in the
dorsal raphe.20 A similar strategy has been used to in-
duce 5-HT1A antagonism in aryloxypropyl piperidine
analogs.11 Like the propyloxy analogs 23 and 24, 26 pos-
sesses excellent 5-HT-T affinity but weak 5-HT1A affinity
We have disclosed a series of novel aryloxy-8-azabicy-
clo[3.2.1]octanes that have potent affinity for the
5-HT-T and good to moderate 5-HT1A affinity. In addi-
tion, structure–activity relationships have been deline-
ated such that these compounds can have 5-HT1A
antagonist functional activity via the optimization of
the Ar1 and Ar2 groups in 11 and 12. Most interestingly,
indole analog 21 (Table 1) and pindolol analogs 25 and
27 (Table 2) possesses potent 5-HT-T affinity and mod-
erately potent 5-HT1A affinity. Moreover, these com-
pounds function as full 5-HT1A antagonists. Further
studies concerning agents that target the 5-HT1A and
5-HT-T receptors will be reported in due course.

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