A convenient procedure for the synthesis of nonsymmetrical bivalent selective serotonin reuptake inhibitors using polymer-supported reagents

Article abstract of DOI:10.1016/S0960-894X(00)00576-X

A convenient synthesis of nonsymmetrical bivalent inhibitors of the serotonin transporter is described. The synthesis utilizes polymer-supported reagents that allow for rapid access to novel bivalent ligands without the need for isolation or purification of synthetic intermediates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00576-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2741±2743
A Convenient Procedure for the Synthesis of Nonsymmetrical
Bivalent Selective Serotonin Reuptake Inhibitors Using
Polymer-Supported Reagents
Amir P. Tamiz,a Paola Conti,a Mei Zhang,b Kenneth M. Johnsonb
and Alan P. Kozikowskia,*
aDrug Discovery Program, Department of Neurology, Georgetown University Medical Center,
3970 Reservoir Road, NW, Washington, DC 20007-2197, USA
bDepartment of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031, USA
Received 5 July 2000; accepted 28 September 2000
AbstractÐA convenient synthesis of nonsymmetrical bivalent inhibitors of the serotonin transporter is described. The synthesis
utilizes polymer-supported reagents that allow for rapid access to novel bivalent ligands without the need for isolation or puri®ca-
tion of synthetic intermediates. # 2000 Elsevier Science Ltd. All rights reserved.
Selective serotonin reuptake inhibitors (SSRIs) such as
¯uoxetine (Prozac)1a and paroxetine (Paxil),1b among
others, have been developed for the treatment of depres-
sion and related psychological disorders (Fig. 1).2a h We
recently discovered an interesting aspect of the serotonin
transporter (SERT) structure±activity relationships
(SARs), namely that signi®cant selectivity and potency
can be achieved through use of a bivalent ligand
approach.3,4 The length of the linking chain could be
used as a means to eliminate activity at the dopamine
(DAT) and the norepinephrine transporters (NET). Our
SAR studies thus far support the possible existence of
dual binding sites at the SERT, where an enhancement
of potency of greater than 8000-fold is achieved by
bridging two neighboring recognition sites via a linking
chain of ®ve methylene units.3 As such proximal bind-
ing sites at the SERT may di€er in their topology, we
sought a rapid means to synthesize a series of non-
symmetrical bivalent ligands to further explore the pos-
Figure 1.
sibility to optimize the ligand potency and selectivity at
the SERT. We envisioned a synthesis that utilizes poly-
mer-supported reagents whereby a series of non-
symmetrical bivalent ligands can be rapidly and
conveniently prepared in 5±100 mg quantities for com-
plete in vitro and in vivo biological evaluation.
Chemistry
Scheme 1 delineates the chemistry used to prepare the
compounds in this series. Brie¯y, acid hydrolysis of ( )-
methyl 4b-(4-chlorophenyl)-1-methylpiperidine-3a-car-
boxylate (( )-2)5 followed by the treatment of the acid
intermediate with (COCl)2 in CH2Cl2 gave the acid
chloride 3 which was used without further puri®cation in
*Corresponding author. Tel.: +1-202-687-0686; fax: +1-202-687-0617;
e-mail: kozikowa@giccs.georgetown.edu
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00576-X

2742
A. P. Tamiz et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2741±2743
Scheme 1. Reagents and conditions: (a) HCl (10%); (b) (COCl)2, CH2Cl2; (c) diamine spacer, TEA, CH2Cl2; (d) RC(O)Cl, TEA, CH3CN; (e) TFA
(5% in CH2Cl2); (f) 6, TEA, CH3CN; (g) TG amino resin.
the next step. In a parallel synthesis fashion, commer-
cially available p-xylene diamine trityl resin 5 (Nova-
biochem) was reacted with the appropriate acid chloride
in CH3CN. The solvent was removed by ®ltration, and
the resins were washed with CH3CN. The tethered
monosubstituted diamine was then released from the tri-
tyl resin support by treatment with TFA (5% in CH2Cl2).
The solvent was removed in vacuo and the residue trea-
ted with TEA (4 molar equiv based on 5) and acid chlo-
ride 3 (2 molar equiv based on 5) in CH3CN. NovaSyn1
TG amino resin LL (Novabiochem, 2 molar equiv based
on 5) was added after agitation for 6 h to remove all of
the unreacted acid chloride, and the mixture was ®ltered
after an additional 6 h of mixing at 50ꢀC. Evaporation of
the mother liquor gave the ®nal compound. All of the
compounds in this series were isolated as the free bases
(Na2CO3 wash) and puri®ed by chromatographic methods
for biological evaluation purposes.6
endings (synaptosomes).5 The uptake data are listed in
Table 1.
In general, all compounds showed reasonably good
anity and selectivity for the SERT. In particular,
compounds 4a and 4b exhibit remarkable potency and
selectivity for the SERT as noted previously.3 In fact, 4a
is one of the more potent SSRIs reported to date.
However, none of the nonsymmetrical inhibitors (7a±7j)
prepared in this series are as potent as the parent com-
pounds 4a and 4b. This observation suggests that the
two binding sites on the SERT complex may have simi-
lar anity for the dimer head groups. Also, these data
support the notion that the bivalent ligands bind to the
SERT recognition sites in a manner that requires spe-
ci®c binding interactions, rather than some nonspeci®c
interaction with a simple hydrophobic region located
either in the surrounding membrane or in the SERT
protein itself.
All ®nal compounds were tested for their ability to
inhibit high anity uptake of dopamine (DA), sero-
tonin (5-HT), and norepinephrine (NE) into rat nerve
In conclusion, a general synthesis of a series of non-
symmetrical bivalent ligands is reported. The chemistry
Table 1. Ki values for selected bivalent inhibitors at dopamine, norepinephrine, and serotonin transporters
[3H]DAa
[3H]NEa
[3H]5-HTa
Selectivity ratio (Kis)
DA/5-HT NE/5-HT
624 24
Compound
R
Uptake Ki (nM)
Uptake Ki (nM)
Uptake Ki (nM)
Fluoxetineb
Ð
Ð
Ð
Ph
>2500
2268Æ167
1960Æ200
dNT
>4000
3710Æ210
NT
>5000
>4000
NT
>7000
>2000
>2000
176Æ3.5
74Æ1.1
399Æ6.7
NT
1040Æ160
1540Æ50
NT
508Æ147
651Æ100
NT
>1000
>1000
>2000
7.3Æ0.7
0.32Æ0.03
1.2Æ0.1
30Æ5.0
33Æ3.8
84Æ16
4a
4bc
7a
7b
7c
7d
7e
7f
>7000
1633
Ð
231
332
Ð
3-Cl±Ph
4-Cl±Ph
2,4-Cl2±Ph
3-CF3±Ph
4-CF3±Ph
4-MeO±Ph
4-Me±Ph
CH2CH2Ph
CHˆCH(4-Cl±Ph)
>121
44
Ð
>143
>12
Ð
>36
>30
>29
32
18
Ð
15
1.9
Ð
>5
139Æ64
35Æ0.22
334Æ100
92Æ15
7g
7h
7i
195Æ37
67Æ12
>15
>29
7j
69Æ0.23
aData are meanÆstandard error of at least three experiments as described in ref 5b.
bSee ref 5b.
cSee ref 3.
dNT, not tested.

A. P. Tamiz et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2741±2743
2743
allows convenient and rapid access to a novel series of
bivalent ligands without the need for the isolation or
puri®cation of the synthetic intermediates. Starting
from trityl resin 5, the synthesis can be completed in less
than 48 h using as little as 15 mL of solvent per 100 mg
of the resin. The present work thus broadens the scope
of SAR to be used to better understand the structural
motifs required to achieve high potency and selectivity
at the SERT for the purposes of drug discovery, and is
readily applicable to the synthesis of other bivalent
ligands.
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K. M.; Kozikowski, A. P. J. Am. Chem. Soc. 2000, 122, 5393.
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Acknowledgements
We are indebted to the NIH, National Institute on Drug
Abuse (DA11548 and 10458) for their support of this work.
5. (a) Kozikowski, A. P.; Araldi, G. L.; Boja, J.; Meil, W. M.;
Johnson, K. M.; Flippen-Anderson, J. L.; George, C.; Saiah,
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References and Notes
6. Reagents and solvents were obtained from commercial
suppliers and used as received. All the polymer-based reagents
were purchased from Novabiochem Corp. All reactions were
performed under an inert atmosphere of nitrogen. Final com-
pounds described were puri®ed by chromatography on silica
gel, and were characterized by NMR and mass spectroscopy
(sequential gas chromatography mass spectrometry measured
in the EI mode at an ionization potential of 70 eV). Com-
pounds 4a and 4b gave satisfactory C, H, N analyses.
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