Potent and selective ligands for the dopamine transporter (DAT): Structure-activity relationship studies of novel 4-[2- (diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine analogues

Article abstract of DOI:10.1021/jm970595h

Molecular structural modifications of 4-[2-(diphenylmethoxy)ethyl]- 1- (3-phenylpropyl)piperidine (1a), a dopamine transporter (DAT)-specific ligand, generated several novel analogues. Biological activities of these new molecules for their binding to the

Full text of DOI:10.1021/jm970595h

699
J . Med. Chem. 1998, 41, 699-705
P oten t a n d Selective Liga n d s for th e Dop a m in e Tr a n sp or ter (DAT):
Str u ctu r e-Activity Rela tion sh ip Stu d ies of Novel
4-[2-(Dip h en ylm eth oxy)eth yl]-1-(3-p h en ylp r op yl)p ip er id in e An a logu es
Aloke K. Dutta,*,† Lori L. Coffey,‡ and Maarten E. A. Reith‡
Organix Inc., 65 Cummings Park, Woburn, Massachusetts 01801, and Department of Biomedical and Therapeutic Sciences,
University of Illinois, College of Medicine, P.O. Box 1649, Peoria, Illinois 61656
Received September 5, 1997
Molecular structural modifications of 4-[2-(diphenylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine
(1a ), a dopamine transporter (DAT)-specific ligand, generated several novel analogues.
Biological activities of these new molecules for their binding to the DAT and serotonin
transporter (SERT) were evaluated in rat striatal membranes. Some of these new analogues
were more potent and selective than GBR 12909 when their binding to the DAT relative to
SERT was compared. Thus compounds 9 and 19a were among the most potent (IC50 ) 6.6
and 6.0 nM, respectively) and selective (DAT/SERT ) 33.8 and 30.0, respectively) compounds
in this series, and they were more active than GBR 12909 (IC50 ) 14 nM, DAT/SERT ) 6.1).
Introduction of a double bond in the N-propyl side chain of these molecules did not influence
their activities to a great extent. Bioisosteric replacement of the aromatic phenyl group by a
thiophene moiety produced some of the most potent compounds in this series.
Ch a r t 1
In tr od u ction
Cocaine is a strong reinforcer and has great abuse
potential in humans.1-3 Cocaine use has reached an
epidemic proportion in the last two decades in the
United States. There is an urgent need to develop a
pharmacotherapeutic agent to treat cocaine addiction,
since currently there is no medication available to treat
this addiction. Cocaine binds to all three monoamine
transporter systems in the brain which mediate the
neuronal uptake of dopamine (dopamine transporter,
DAT), serotonin (SERT), and norepinephrine (NET).4-6
The central mechanism of cocaine addiction is attributed
to its binding to the DAT which is located presynapti-
cally in the dopaminergic neuron.7-9 Binding of cocaine
to the DAT leads to an elevated level of dopamine in
the synapse and is the underlying reason for cocaine’s
stimulatory and perhaps addictive effect.7 A significant
correlation exists between the potencies of various
cocaine-like compounds binding to the DAT and the
potencies of these same compounds producing self-
administration behavior. In a recent study, it has also
been demonstrated that knockout mice without the DAT
were not stimulated by cocaine which further reinforces
the dopaminergic hypothesis of cocaine addiction.10
Drug development targeting the DAT resulted in the
generation of some very potent and selective molecules
of diverse structural backgrounds.11-13 Comprehensive
structure-activity relationship (SAR) studies based on
the phenyl tropane class of compounds provided many
potent and selective molecules for this transpoprter.14-16
GBR compounds, which are disubstituted piperazine
derivatives, were shown to display high affinity and
selectivity for the DAT. Some well-known GBR com-
pounds, GBR 12935 and its bisfluorinated analogue
GBR 12909 (Chart 1), were shown to have high potency
for the DAT.17,18 Recent evidence suggests that GBR
12935-like compounds might have efficacy of potential
pharmacotherapeutic agents as cocaine antagonists.
Thus in locomotor-stimulating activity, GBR 12909 was
found to be less potent than cocaine in rats.19 Other
recent experiments further demonstrated that GBR
12909 could decrease cocaine-maintained responding
without having an effect on food-maintained responding
in monkeys.20,21 In human studies GBR 12909 was
found to have nonstimulant properties, and in microdi-
alysis studies in rats GBR 12909 could attenuate the
enhancement of the level of extracellular dopamine in
the striatum induced by cocaine.22,23 All of this infor-
mation strengthened the notion that a suitable deriva-
tive of a GBR-type analogue may have the potential to
antagonize cocaine action.
* To whom correspondence should be addressed.
† Organix Inc.
‡ University of Illinois.
S0022-2623(97)00595-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/05/1998

700 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Dutta et al.
Sch em e 1
Our ongoing SAR studies with the novel 4-[2-(diphen-
ylmethoxy)ethyl]-1-(3-phenylpropyl)piperidine analogues
resulted in the generation of potent and selective
molecules for this transporter.24-26 These compounds
are structurally similar to GBR 12935 molecules dif-
fering only with the presence of a piperidine moiety
instead of a piperazine ring located in the original GBR
structures, 1a (Chart 1). These new analogues of GBR-
type compounds turned out to be even more selective
since they did not have nonspecific piperazine acceptor
site binding activity which is present in the original
GBR molecules.27 We have demonstrated in our previ-
ous SAR studies that some of the key structural
features, which are needed for good potency and selec-
tivity in these molecules for the DAT, are the follow-
ing: (a) The unsubstituted and fluoro-substituted aro-
matic rings in the diphenylmethoxy moiety were best
tolerated. (b) Different N-benzyl substitutions, where
the different electronegative, electron-withdrawing, and
neutral groups were introduced in the aromatic ring of
the benzyl group, at the piperidine ring of the molecule
produced some of the most potent and selective mol-
ecules for the DAT, 1b (Chart 1).26 (c) Different alkyl
chain lengths connected to the 1- and 4-positions of the
piperidine ring played important roles in the activities.
One of our important findings from these SAR studies
showed that replacement of the N-propyl-3-phenyl
moiety in these molecules by a N-benzyl group resulted
in the generation of highly selective molecules for the
DAT mainly due to the reduction of affinity for the
SERT.
variations introduced into the molecule which resulted
in the development of a number of potent analogues.28,29
In some of these analogues the piperazine ring was
altered while maintaining their high affinity and po-
tency for the DAT.30,31 Also, some recent reports
described the synthesis of different series of novel
benztropine derivatives structurally resembling GBR-
type compounds and their binding affinity for the
DAT.32,33
To understand the mode of binding of our piperidine
analogues of GBR 12935 and to make a comparison with
conventional GBR compounds, further structural varia-
tions of the compound 4-[2-(diphenylmethoxy)ethyl]-1-
(3-phenylpropyl)piperidine, 1a , were undertaken by
introducing a double bond in the N-propyl side chain
and also by replacing the aromatic phenyl moiety with
bioisosteric thiophene and pyridine rings. It is of
interest to assess whether there is a differential binding
activity in these compounds as compared with their
corresponding conventional GBR analogues and also to
compare the binding results with those obtained by us
previously for other compounds in this class.
Ch em istr y
Syntheses of 7a -d and 9 were accomplished by
following our previous synthetic route as shown in
Scheme 1.25 Thus N-alkylation of ketal amine 1 with
trans-cinnamyl bromide furnished 3a , and similarly
N-acylation of 1 with trans-cinnamoyl chloride followed
by reduction with lithium aluminum hydride (LAH)
produced 3b. Deketalization of 3a ,b under acidic condi-
tions yielded piperidinones 4a ,b which on Wittig reac-
tion provided unsaturated esters 5a ,b. Reduction of the
Past and recent SAR studies in the GBR series of
molecules were carried out with different structural

Potent and Selective Ligands for the DAT
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 701
Sch em e 2
Sch em e 3
esters with LAH provided alcohols 6a ,b and hydrogena-
tion of 6b yielded saturated alcohol 8. Final compounds
7a -d and 9 were synthesized by reacting alcohols 6a ,b
and 8 with appropriate benzhydrols under azeotropic
distillation conditions.25,26,34
Syntheses of 14 and 17 are described in Schemes 2
and 3 which followed our earlier procedure. Reductive
amination of aldehyde 10 with amine 11 in the presence
of sodium cyanoborohydride produced ester 12 which
upon reduction with LAH and reaction with benzhydrol
produced the final compound 14.35 Similarly acylation
of amine 11 with the acid chloride of trans-thienylacrylic
acid provided 15 which on reduction and followed by
reaction with benzhydrol provided final target 17.
Syntheses of 19a ,b were carried out from a common
known intermediate (18) in the same way as described
before.26
GBR molecules. One of the important differences that
emerged from these SAR studies between these two
similar classes of molecules was evident from the effect
of the introduction of different N-alkyl side chains.
Thus, in the original GBR molecules, the 3-phenylpropyl
side chain produced optimum activity and selectivity.
On the contrary, in our case different benzylic substitu-
tions produced highly selective molecules for the DAT.
These divergent results may be indicative of the exist-
ence of different binding sites for these two classes of
compounds, or of different conformations induced by
these compounds in a single binding site.
Introduction of a double bond in the propyl side chain
as shown in 7a -d and 17 maintained the potency and
selectivity for the DAT in these compounds. Trisubsti-
tuted fluoro compound 7a showed good potency but
relatively less selectivity for the DAT (SERT/DAT ) 5)
(Table 1). This observation is inconsistent with our
previous results which demonstrated that, in general,
fluoro substitutions on the aromatic ring of the diphen-
ylmethoxy moiety decrease the selectivity without com-
promising the potencies of these compounds at the DAT.
On the other hand, disubstituted compound 7b was
unexpectedly somewhat less potent and selective indi-
cating the contribution of unfavorable electronegative
F atom interactions. Compounds 7c,d turned out to
have similar potency and selectivity. Thus the presence
of a fluorine atom in the aromatic ring of the N-
phenylpropylene part of 7d did not make any difference
in its activity. On the other hand, compound 9, the
saturated version of compound 7d , was almost twice as
potent and more selective than 7d (IC50 ) 6.6 vs 10.8
Bioch em istr y
Biological studies of the newly synthesized compounds
were carried out with membranes prepared from rat
brain striatum as described earlier.25,26 Binding analy-
ses were performed to determine their activity at the
DAT and SERT in brain. The DAT in the rat striatal
tissue was labeled with a tritiated potent analogue of
cocaine, [3H]WIN 35,428, and the SERT was labeled
with [3H]citalopram.
Resu lts a n d Discu ssion
Our previous SAR studies on GBR-type molecules
resulted in the identification of active molecular deter-
minants, some of which are different from the original

702 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Dutta et al.
Ta ble 1. Affinity and Selectivity of Drugs at the Dopamine and Serotonin Transporters in Rat Striatum
IC50 (nM)
compd
R
R′
R′′
X
Y
DAT,[3H]WIN 35,428a
SERT, [3H]citaloprama
SERT/DAT
GBR 12 909
14.0 ( 0.6
15.1 ( 2.0
41.4 ( 8.0
10.1 ( 1.6
10.8 ( 3.2
6.6 ( 1.4
29.9 ( 0.3
9.8 ( 2.4
6.0 ( 0.5
11.7 ( 1.0
86.6 ( 10.2
75.8 ( 22.1
271.2 ( 18.4
231.8 ( 4.5
205.2 ( 13.3
223.4 ( 32.2
194.1 ( 20.0
290.8 ( 63
6.2
5.00
6.5
22.9
19
33.8
6.5
29.6
30.00
7.3
7a
7b
7c
7d
9
14
17
19a
19b
Ph-pF
Ph-pF
Ph
Ph
Ph
F
F
F
CHdCH
CHdCH
CHdCH
CHdCH
(CH2)2
(CH2)2
CHdCH
(CH2)2
CH
CH
CH
CH
CH
N
H
H
F
F
H
H
H
H
H
H
H
F
Ph
Ph
Thb
CH
CH
Thb
Thb
H
H
180.4 ( 21.6
85.7 ( 2.6
(CH2)2
a
The DAT was labeled with [3H]WIN 35,428, and the SERT was labeled with [3H]citalopram. Results are average ( SEM of three
b
independent experiments assayed in triplicate. Thiophene.
19nM and SERT/DAT ) 33.8 vs 19), which might indicate the DAT. Selectivity of these molecules for the DAT
the important contribution of conformational flexibilities
in 9. It was previously reported by others that in the
GBR 12935 series the double-bond unsaturation in the
N-propyl side chain yielded slightly more potent com-
pounds than their saturated counterparts when their
affinities to the DAT were compared.13,29 In our case,
we saw a reverse trend with the saturated version being
more potent. Thus, compounds 9 and GBR 12909 were
more potent than the unsaturated versions 7d ,b, re-
spectively. More elaborate future SAR studies will help
to reach a more firm conclusion regarding this trend.
Bioisosteric replacement of the phenyl ring in these
compounds by thiophene and pyridine rings retained
their biological activity.36 Thus, compounds 19a ,b
where one of the phenyl groups in the diphenylmethoxy
moiety was replaced with a thiophene group, retained
the potency and selectivity. 19a and 9 were equally
active and were the most potent and selective com-
pounds in this series. In compounds 14 and 17, the
aromatic ring of the N-alkyl side chain was replaced by
pyridine and thiophene rings, respectively, and 17 was
the most potent and selective of the two. Our previous
SAR studies on derivatives containing N-benzyl substi-
tutions demonstrated that bioisosteric replacement at
a certain position maintained the activity but at a
different position diminished it26 and thus show a
pattern different from our current results. The data
taken together suggest the importance of the length of
the N-alkyl chain between the piperidine ring and the
aromatic moiety. The present results are consonant
with recently published SAR studies on GBR 12935
derivatives where it was demonstrated that a thiophene
moiety was a more potent bioisosteric replacer than a
pyridyl moiety.29
were measured by comparing their binding relative to
SERT. Future binding characterization of these com-
pounds with the NET will enable us to assess their
selectivity with respect to NET as well. Some of these
compounds described here are among the most potent
GBR-type compounds known. In general, introduction
of a double bond in the N-propyl side chain did not have
a major effect on the biological activity. Nevertheless,
the greater conformational flexibility in the saturated
N-propyl chain versions as in 9 and 19a ,b resulted in a
more favorable interaction with the DAT. Our current
results also reestablished our previous finding concern-
ing the role of N-benzyl substitutions in the maximal
selectivity for the DAT since these current compounds
with N-propyl substitutions are not as selective. On the
other hand, some of these current compounds are more
potent than GBR 12909 and also are more potent than
the previously reported most active piperidine class of
GBR-type compounds for their binding to the DAT.25,26
Replacement with a thiophene ring produced the most
active compound indicating more tolerance for the
thiophene ring by the DAT compared to the pyridine
moiety. It is important to note that 19a ,b as reported
here are a racemic mixture. It will be interesting to
find out in future studies whether one of the optical
antipodes is mostly responsible for the potency and
selectivity for the DAT.
Exp er im en ta l Deta il
Analytical silica gel-coated TLC plates (Si 250F) were
purchased from Baker, Inc. and were visualized with UV light
or by treatment with phosphomolybdic acid (PMA). Flash
chromatography was carried out on Baker silica gel (40 µM).
1H NMR spectra were routinely obtained at 100 MHz on a
Bruker WP-100-SY spectrometer. The NMR solvent used was
CDCl3 as indicated. TMS was used as an internal standard.
Elemental analyses were performed by Atlantic Microlab, Inc.
and were within (0.4% of the theoretical value.
Con clu sion
[3H]CFT (83.5 Ci/mmol) and [3H]citalopram (85.7 Ci/mmol)
were obtained from DuPont-New England Nuclear (Boston,
In this report, we have described the synthesis and
biological studies of potent and specific molecules for

Potent and Selective Ligands for the DAT
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5 703
MA). Cocaine hydrochloride was purchased from Mallinckrodt
Chemical Corp. (St. Louis, MO). CFT naphthalenesulfonate
was purchased from Research Biochemicals, Inc. (Natick, MA).
of THF was added triethyl phosphonoacetate (1.1 g, 4.8 mmol)
dissolved in 20 mL of THF. The solution was stirred at room
temperature for 10 min followed by refluxing for 15 min. After
cooling, a solution of compound 4a (0.87 g, 4.0 mmol), in 20
mL of THF, was added dropwise. The reaction mixture was
heated to reflux for 1.5 h, and THF was removed in vacuo.
The product was partitioned between ether and water. The
organic layer was dried over Na2SO4, and the crude material
was flash-chromatographed (silica gel). The pure compound
5a was eluted with EtOAc/hexane (2:3), 0.9 g (78% yield), as
an oil. 1H NMR (CDCl3): δ 1.27 (3H, t, J ) 4.5 Hz, (CH3)-
CH2-), 2.25-2.62 (6H, m), 3.07 (2H, t, J ) 3 Hz, -N-(CH2)-
CH2-), 3.28 (2H, d, J ) 4.5 Hz, -N-(CH2)-CHd), 4.16 (2H, q, J
) 4.5 Hz, CH3-(CH2)-), 5.65 (1H, s, (CH)-COOEt), 6.12-6.62
P r oced u r e A: Syn th esis of 1-(3-P h en yl-2-p r op en yl)-4-
p ip er id on e Eth ylen e Keta l (3a ). 4-Piperidone ethylene
ketal (3 g, 20.8 mmol) and cinnamyl bromide (5.2 g, 26 mmol)
were dissolved in 35 mL of DMF. Potassium carbonate (8 g)
was then added, and the mixture was heated overnight in an
oil bath at 70 °C under nitrogen. The reaction mixture was
brought to room temperature, and water (100 mL) was added.
The product was extracted into an ether layer (250 mL) and
dried over Na2SO4. The crude product was collected and
purified by flash column chromatography (silica gel). Elution
with EtOAc/hexane (1:1) provided pure compound 3a , 4 g (74%
yield), as a colorless liquid. 1H NMR (CDCl3): δ .80 (4H, t, J
) 3 Hz, -(CH2)-CH2-N-), 2.60 (4H, t, J ) 3 Hz, -CH2-(CH2)-N-
), 3.18 (2H, d, J ) 4.5 Hz, -(CH2)-CHdCH-), 3.95 (4H, s, -O-
(CH2)2-O-), 6.12-6.60 (2H, m, -(CHdCH)-CH2-), 7.15-7.40 (5H,
m, -Ph). Anal. (C16H21NO2‚0.15H2O) C, H, N.
P r oced u r e B: Syn th esis of 1-(4′-F lu or ocin n a m oyl)-4-
p ip er id on e Eth ylen e Keta l (2). trans-4-Fluorocinnamic
acid (4 g, 2.4 mmol) was suspended in 150 mL of dry methylene
chloride, and into it was added a couple of drops of DMF.
Oxalyl chloride was then added, and the solution was stirred
at room temperature for 8 h. Solvent was removed in vacuo,
and the residue was dried in the pump. The residue was
redissolved in methylene chloride containing triethylamine (20
g) and cooled in an ice bath. Into the cold solution was added
dropwise a solution of ketal 1 (3.09 g, 2.16 mmol) dissolved in
methylene chloride. The solution was brought back to room
temperature and stirred for an additional 2 h. The solution
was diluted with water, and the product was extracted into
the EtOAc layer. The crude product was chromatographed
over a silica gel column, and the pure product was eluted with
a EtOAc/hexane (1:1) mixture, 5.72 g (83% yield), as an oil.
1H NMR (CDCl3): δ 1.78 (4H, t, J ) 3.0 Hz, -(CH2)-CH2-N-),
3.65-3.90 (4H, m, -(CH2)-CH2-N-), 4.00 (4H, s, -(CH2)-O-), 6.82
(1H, d, -CHd(CH)-, J ) 15 Hz, trans coupling), 7.0-7.72 (5H,
m, -(CH)dCH- + -Ph). Anal. (C16H18NFO3) C, H, N.
P r oced u r e C: Syn th esis of 1-[3-(4′-F lu or op h en yl)-2-
p r op en yl]-4-p ip er id on e Eth ylen e Keta l (3b). Lithium
aluminum hydride (LAH) (3 g, 79 mmol) was suspended in
100 mL of dry THF, and the solution was cooled in an ice bath.
The amide 2 (4 g, 13.7 mmol), dissolved in 25 mL of THF, was
added dropwise into the cold solution. The solution was
refluxed for 2 h, and after cooling (ice bath) unreacted LAH
was quenched by careful addition of an excess amount of 10%
NaOH solution. The solution was filtered, and THF was
removed in vacuo. The product was partitioned between water
and the ethyl acetate layer. Organic layer was dried over Na2-
SO4, and the product 3b was collected, 3 g (79% yield), as a
viscous liquid. 1H NMR (CDCl3): δ 1.80 (4H, t, J ) 3 Hz,
-(CH2)-CH2-N-), 2.30-2.65 (4H, m), 3.15 (2H, d, J ) 4.5 Hz,
-(CH2)-CHdCH-), 3.95 (4H, s, -O-(CH2)2-O-), 6.05-6.56 (2H,
m, -(CHdCH)-), 6.85-7.45 (4H, m, Ph-F). Anal. (C16H20NFO2)
C, H, N.
P r oced u r e D: Syn th esis of 1-(3-P h en yl-2-p r op en yl)-
4-p ip er id on e (4a ). 1-(3-Phenyl-2-propenyl)-4-piperidone eth-
ylene ketal, 3a (3.8 g, 17.6 mmol), was dissolved in 100 mL of
benzene/water (3:1) containing 15% HCl. The solution was
refluxed for 24 h, and benzene was removed in vacuo. The
acid was neutralized by adding an excess amount of solid
NaHCO3, and the crude product was extracted into the ethyl
acetate (250 mL) layer. The organic layer was dried over Na2-
SO4. The crude product was purified by flash column chro-
matography over a silica gel column, and the pure product 4a
was eluted with EtOAc/hexane (1:1), 1.5 g (48% yield), as an
oil. 1H NMR (CDCl3): δ 2.50 (4H, t, J ) 3 Hz, -(CH2)-CH2-
N-), 2.84 (4H, t, J ) 3 Hz, -CH2-(CH2)-N-), 3.25 (2H, d, J ) 4.5
Hz, -(CH2)-N-), 6.12-6.65 (2H, m, -(CHdCH)-), 7.18-7.45 (5H,
m, -Ph). Anal. (C14H17NO‚0.15H2O) C, H, N.
(2H, m, -(CHdCH)-), 7.2-7.45 (5H, m, -Ph). Anal. (C18H23
-
NO2) C, H, N.
P r oced u r e F : Syn t h esis of 4-[2-(Dip h en ylm et h oxy)-
eth yl]-1-(3-p h en yl-2-p r op en yl)p ip er id in e (7c). Benzhy-
drol (0.9 g, 4.7 mmol), 1-(3-phenyl-2-propenyl)-4-(2-hydroxy-
ethyl)piperidine, 6a (0.33 g, 1.34 mmol), and p-toluenesulfonic
acid (0.33 g, 1.73 mmol) were mixed together in 65 mL of
benzene, and the solution was heated to reflux under azeo-
tropic distillation conditions overnight, under nitrogen. Ben-
zene was removed in vacuo, and the residue was partitioned
between ether (100 mL) and saturated NaHCO3. The ether
layer was separated and dried over Na2SO4. The crude
mixture was chromatographed over a silica gel column, and
7c was eluted with a EtOAc/hexane (1:1) mixture, 0.1 g (20%
yield), as a viscous oil. 1H NMR (CDCl3): δ 1.25-2.05 (9H,
m), 2.90-3.00 (2H, m), 3.12 (2H, d, J ) 4.5 Hz, -(CH2)-
CHdCH-), 3.48 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 5.3 (1H, s,
-O-(CH)-Ph2), 6.12-6.60 (2H, m, -(CHdCH)-Ph), 7.15-7.45
(15H, m, 3Ph). Free base was converted into its oxalate salt,
mp 161-162.1 °C. Anal. (C29H33NO‚(COOH)2‚H2O) C, H, N.
Syn th esis of 1-[3-(3′-P yr id yl)p r op yl]-4-[(eth oxyca r bon -
yl)m eth yl]p ip er id in e (12). Amine hydrochloride 11 (0.25
g, 1.6 mmol), which was obtained as a predominantly methyl
ester, and 3-pyridinepropionaldehyde, 10 (0.2 g, 1.4 mmol),
were dissolved in 25 mL of dry MeOH with 0.3 g of triethyl-
amine. Into the solution was added 4 Å molecular sieves (2.5
g), and the reaction mixture was stirred at room temperature
for 1.5 h. Sodium cyanoborohydride (0.13 g, 2.1 mmol) was
added into the solution, and the reaction was continued for
an additional 12 h. The reaction mixture was filtered through
Celite, and the filtrate was collected. Crude material was
chromatographed over a silica gel column. Pure compound
was eluted with a 30% MeOH/EtOAc mixture, 0.22 g (48%
yield), as a colorless liquid. 1H NMR showed the presence of
the methyl ester. 1H NMR (CDCl3): δ 1.35-2.10 (9H, m),
2.20-2.44 (4H, m), 2.64 (2H, t, J ) 4.5 Hz, -CH2-(CH2)-pyridyl),
2.84-2.96 (2H, m), 3.66 (3H, s, COO(CH3)-), 7.14-8.45 (4H,
m, pyridyl). Anal. (C16H24N2O2‚0.4H2O) C, H, N.
Syn th esis of N-[3-(4′-F lu or op h en yl)-2-p r op en yl]-4-p i-
p er id on e (4b). Ketal 3b (2.2 g, 7.9 mmol) was converted into
4b, 1.1 g (61% yield), as a colorless oil (procedure D). 1H NMR
(CDCl3): δ 2.4-2.58 (4H, m, 2-N-CH2-(CH2)-), 2.68-2.88 (4H,
m, 2-N-(CH2)-CH2-), 3.25 (2H, d, J ) 4.5 Hz, -(CH2)-CHdCH-),
6.05-6.62 (2H, m, -(CHdCH)-Ph), 6.85-7.45 (4H, m, -PhF).
Anal. (C14H16NFO‚0.1H2O) C, H, N.
Syn th esis of 1-[3-(4′-Flu or op h en yl)-2-p r op en yl]-4-[(eth -
oxyca r bon yl)m eth ylen e]p ip er id in e (5b). Keto compound
4b (1 g, 4.2 mmol) was converted into 5b, 1.1 g (85% yield), as
a colorless oil (procedure E). 1H NMR (CDCl3): δ 1.27 (3H, t,
J ) 4.5 Hz, (CH3)-CH2-), 2.25-2.68 (6H, m), 2.95-3.18 (4H,
m, -N-(CH2)-CH2- + -(CH2)-CHdCH-), 4.16 (2H, q, J ) 4.5 Hz,
CH3-(CH2)-), 5.65 (1H, s, d(CH)-COOEt), 6.04-6.58 (2H, m,
-(CHdCH)-), 6.90-7.40 (4H, m, -PhF). Anal. (C18H22NFO2‚
0.1H2O) C, H, N.
Syn th esis of 1-(3-P h en yl-2-p r op en yl)-4-(2-h yd r oxyeth -
yl)p ip er id in e (6a ). Compound 5a (0.76 g, 2.6 mmol) was
converted into alcohol 6a , 0.6 g (95% yield), as a colorless
viscous liquid (procedure C). 1H NMR (CDCl3): δ 1.19-2.53
(9H, m), 2.91-3.18 (4H, m, -N-(CH2)-CH2- + -(CH2)-CHdCH-),
P r oced u r e E: Syn th esis of 1-(3-P h en yl-2-p r op en yl)-4-
[(eth oxyca r bon yl)m eth ylen e]p ip er id in e (5a ). Into a sus-
pension of NaH (60% oil dispersion, 0.24 g, 5 mmol) in 25 mL

704 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 5
Dutta et al.
3.69 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 6.29-6.61 (2H, m, Ph-
(CHdCH)-CH2-), 7.23-7.41 (5H, m, -Ph). MS (CI): m/e 246.2
(M + H)+.
5.34 (1H, s, -(CH)-O-), 7.15-8.50 (14H, m, 2Ph- + pyridyl).
Free base was converted into its oxalate salt, mp 126-130.3
°C. Anal. (C28H34N2O‚2(COOH)2‚1.3H2O‚0.1(COOH)2) C, H,
N.
Syn th esis of 1-[3-(4′-F lu or op h en yl)-2-p r op en yl]-4-(2-
h yd r oxyeth yl)p ip er id in e (6b). Compound 5b (1.27 g, 4.19
mmol) was converted into alcohol 6b, 1.06 g (96% yield), as a
colorless viscous liquid (procedure C). 1H NMR (CDCl3): δ
1.10-2.66 (9H, m), 2.83-3.17 (4H, m, -N-(CH2)-CH2- + -(CH2)-
CHdCH-), 3.69 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 6.10-6.56
(2H, m, Ph-(CHdCH)-CH2-), 6.85-7.40 (4H, m, -PhF). MS
(CI): m/e 264.2 (M + H)+.
Syn th esis of 1-[3-(4′-Flu or oph en yl)pr opyl]-4-(2-h ydr oxy-
eth yl)p ip er id in e (8). Compound 6b (0.5 g, 1.9 mmol) was
dissolved in 50 mL of ethanol, and 10% Pd/C was then added
into the solution. The solution was then hydrogenated in a
Parr hydrogenation apparatus for 8 h. The solution was
filtered through Celite, and the filtrate was collected. Ethanol
was removed in vacuo, and the product 8 was collected and
dried in the pump, 0.45 g (90% yield). 1H NMR (CDCl3): δ
1.08-2.45 (13H, m), 2.61 (2H, t, J ) 4.5 Hz, -(CH2)-Ph), 2.85-
2.96 (2H, m), 3.67 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 6.85-
7.28 (4H, m, -PhF). MS (CI): m/e 266.3 (M + H)+.
Syn th esis of 4-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-
1-(3-p h en yl-2-p r op en yl)p ip er id in e (7b). Compound 6a
(0.27 g, 1.1 mmol) was reacted with 4,4′-difluorobenzhydrol
(0.72 g, 3.3 mmol) to produce 7b, 0.1 g (20% yield). 1H NMR
(CDCl3): δ 1.15-2.05 (9H, m), 2.90-3.02 (2H, m), 3.14 (2H,
d, J ) 4.5 Hz, -(CH2)-CHdCH-), 3.45 (2H, t, J ) 3.0 Hz, -CH2-
(CH2)-O-), 5.28 (1H, s, -O-(CH)-Ph2), 6.15-6.62 (2H, m,
-(CHdCH)-Ph), 6.92-7.40 (13H, m, 2Ph-F + Ph). Free base
was converted into its oxalate salt, mp 162.7-163.5 °C. Anal.
(C29H31NFO‚(COOH)2‚H2O) C, H, N.
Syn th esis of 4-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-
1-[3-(4′-flu or op h en yl)-2-p r op en yl]p ip er id in e (7a ). Com-
pound 6b (0.3 g, 1.14 mmol) was reacted with 4,4′-difluorobenz-
hydrol (0.82 g, 3.76 mmol) to produce 7a , 0.3 g (57% yield). 1H
NMR (CDCl3): δ 1.20-2.68 (11H, m), 2.88-3.05 (2H, m), 3.10
(2H, d, J ) 4.5 Hz, -(CH2)-CHdCH-), 3.44 (2H, t, J ) 3.0 Hz,
-CH2-(CH2)-O-), 5.28 (1H, s, -O-(CH)-FPh2), 6.05-6.55 (2H, m,
-(CHdCH)-Ph), 6.92-7.40 (12H, m, 3Ph-F). Free base was
converted into its oxalate salt, mp 172.5-173.5 °C. Anal.
(C29H30NF3O‚(COOH)2) C, H, N.
Syn th esis of 1-[3-(2′-Th ien yl)a cr yloyl]-4-[(eth oxyca r -
bon yl)m eth yl]p ip er id in e (15). Acid chloride of thienyl
acrylic acid (0.43 g, 2.49 mmol) was reacted with amine 11
(0.4 g, 2.5 mmol) to produce ethyl ester 15a , 0.23 g, and methyl
ester 15, 0.17 g (76% yield combined), as a colorless oil.
Compound 15 was further characterized. 1H NMR (CDCl3):
δ 1.00-2.35 (11H, m), 3.68 (3H, s, (CH3)OOC-), 6.70 (1H, d,
-CHd(CH)-, J ) 15 Hz, trans coupling), 7.00-7.35 (3H, m,
thienyl), 7.80 (1H, d, -CO-(CH)dCH-, J ) 15 Hz, trans
coupling). Anal. (C15H19NSO3) C, H, N.
Syn th esis of 1-[3-(2′-Th ien yl)-2-pr opylen e]-4-(2-h ydr oxy-
eth yl)p ip er id in e (16). Compound 15 (0.15 g, 0.74 mmol) was
converted into 16, 0.14 g (77% yield), as a viscous liquid
(procedure C). 1H NMR (CDCl3): δ 1.10-1.48 (9H, m), 2.94-
3.15 (4H, m), 3.71 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 5.95-
7.20 (5H, m, -(CHdCH)- + thienyl). MS (CI): m/e 252.1 (M +
H)+.
Syn th esis of 4-[2-(Dih en ylm eth oxy)eth yl]-1-[3-(2′-th i-
en yl)-2-p r op ylen e]p ip er id in e (17). Compound 16 (0.16 g,
0.63 mmol) was converted into the final product 17, 0.13 g (50%
yield), as a viscous liquid. 1H NMR (CDCl3): δ 1.18-1.95 (9H,
m), 2.90-3.15 (4H, m, -(CH2)-CHdCH- + -CH2-(CH2)-N-), 3.50
(2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 5.34 (1H, s, -(CH)-O-), 5.96-
6.70 (2H, m, -(CHdCH)-), 6.95-7.40 (13H, m, 2Ph- + thienyl).
Free base was converted into its oxalate salt, mp 151.7-153.6
°C. Anal. (C29H33O5NS‚0.4H2O) C, H, N.
Syn th esis of 4-[2-[(2-Th ien yl)p h en ylm eth oxy]eth yl]-1-
(3-p h en ylp r op yl)p ip er id in e (19a ). Phenyl(2-thienyl)meth-
anol (0.5 g, 2.6 mmol) was dissolved in 25 mL of dry benzene,
and into it was added thionyl chloride (0.37 g). The solution
was refluxed for 1 h, and benzene along with excess thionyl
chloride was removed in vacuo. The residue was dried in the
pump. Crude chloride was dissolved in toluene, and into it
was added 1-benzyl-4-(2-hydroxyethyl)piperidine, 18 (0.18 g,
0.72 mmol). The solution was refluxed under nitrogen for 1.5
h, and thin-layer chromatography showed the formation of a
new product. Solvent was removed in vacuo, and the crude
compound was taken in saturated NaHCO3 solution. Crude
product was extracted into the ethyl acetate layer and dried
over Na2SO4. Crude product was chromatographed over a
silica gel column, and the pure product was eluted with a 1:1
EtOAc/hexane mixture to give 19a , 0.12 g (40% yield), as a
viscous liquid. 1H NMR (CDCl3): δ 1.10-2.05 (11H, m), 2.25-
2.45 (2H, m), 2.64 (2H, t, J ) 4.5 Hz, -CH2-(CH2)-Ph), 2.85-
2.98 (2H, m), 3.49 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-), 5.55 (1H,
s, -(CH)-O-), 6.78-7.45 (13H, m, 2Ph + thienyl). Free base
was converted into its oxalate salt, mp 197.1-197.9 °C. Anal.
(C27H33ONS‚(COOH)2‚0.3H2O) C, H, N.
Syn t h esis of 4-[2-(Dip h en ylm et h oxy)et h yl]-1-[3-(4′-
flu or op h en yl)-2-p r op en yl]p ip er id in e (7d ). Compound 6b
(0.2 g, 1.14 mmol) was reacted with benzhydrol (0.5 g, 2.66
mmol) to produce 7d , 0.23 g (38% yield). 1H NMR (CDCl3): δ
1.15-2.70 (11H, m), 3.08-3.35 (4H, m, -N-(CH2)-CH2- +
-(CH2)-CHdCH-), 3.50 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 5.31
(1H, s, -O-(CH)-Ph2), 6.05-6.62 (2H, m, -(CHdCH)-PhF), 6.94-
7.50 (14H, m, 2Ph + Ph-F). Free base was converted into its
oxalate salt, mp 141.5-143.1 °C. Anal. (C29H32NFO‚(COO-
H)2‚0.5H2O) C, H, N.
Syn t h esis of 4-[2-(Dip h en ylm et h oxy)et h yl]-1-[3-(4′-
flu or op h en yl)p r op yl]p ip er id in e (9). Compound 8 (0.36 g,
1.35 mmol) was reacted with benzhydrol (0.9 g, 4.37 mmol) to
produce 9, 0.28 g (48% yield). 1H NMR (CDCl3): δ 1.15-2.40
(13H, m), 2.61 (2H, t, J ) 4.5 Hz, -(CH2)-Ph), 2.80-2.95 (2H,
m), 3.49 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-), 5.30 (1H, s, -O-
(CH)-Ph2), 6.85-7.35 (14H, m, 2Ph + Ph-F). Free base was
converted into its oxalate salt, mp 164.9-165.8 °C. Anal.
(C29H34NFO‚(COOH)2) C, H, N.
Syn th esis of 1-[3-(3′-P yr id yl)p r op yl]-4-(2-h yd r oxyeth -
yl)p ip er id in e (13). Compound 12 (0.5 g, 1.81 mmol) was
converted into 13, 0.40 g (95% yield), as a viscous oil (procedure
C). 1H NMR (CDCl3): δ 1.10-2.55 (13H, m), 2.67 (2H, t, J )
4.5 Hz, -CH2-(CH2)-pyridyl), 2.86-2.98 (2H, m), 3.65 (2H, t, J
) 3.0 Hz, -CH2-(CH2)-O-), 6.98-8.44 (4H, m, pyridyl). MS
(CI): m/e 249.2 (M + H)+.
Syn th esis of 4-[2-[(2-Th ien yl)(4-flu or oph en yl)m eth oxy]-
eth yl]-1-(3-p h en ylp r op yl)p ip er id in e (19b). (4-Fluorophen-
yl)(2-thienyl)methanol (0.5 g, mmol) was reacted with 18 (0.3
g, 1.2 mmol) in the same way as described for 19a to produce
19b, 0.15 g (30% yield). 1H NMR (CDCl3): δ 1.0-1.85 (11H,
m), 2.25-2.42 (2H, m), 2.61 (2H, t, J ) 4.5 Hz, -CH2-(CH2)-
Ph), 2.84-3.00 (2H, m), 3.45 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-),
5.12 (1H, s, -(CH)-O-), 6.72-7.48 (12H, m, Ph + Ph-F +
thienyl). Free base was converted into its oxalate salt, mp
116.1-119.2 °C. Anal. (C27H32NSO‚(COOH)2‚0.5H2O) C, H,
N.
Biologica l Meth od s. The DAT was labeled with [3H]WIN
35,428 and the SERT with [3H]citalopram as described by us
previously.26 Both binding assays were carried out under the
same conditions with striatal tissue from male, young adult
Sprague-Dawley rats, exactly as described in our previous
work.26 All compounds were dissolved in dimethyl sulfoxide
(DMSO) and diluted out in 10% (v/v) DMSO. Additions from
the latter stocks resulted in a final concentration of DMSO of
0.5%, which by itself did not interfere with radioligand binding.
After initial range-finding experiments, at least five concentra-
tions of the test compound were studied spaced evenly around
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-[3-(3′-p y-
r id yl)p r op yl]p ip er id in e (14). Compound 13 (0.2 g, 0.8
mmol) was reacted with benzhydrol (0.5 g, 2.66 mmol) to
produce 14, 0.24 g (72% yield). 1H NMR (CDCl3): δ 1.05-
2.44 (13H, m), 2.64 (2H, t, J ) 4.5 Hz, -CH2-(CH2)-pyridyl),
2.82-2.95 (2H, m), 3.50 (2H, t, J ) 3.0 Hz, -CH2-(CH2)-O-),

Potent and Selective Ligands for the DAT
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curve-fitting procedures as described by us previously.25
Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse, Grant DA08647
(A.K.D.).
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