Structure-activity relationship studies of novel 4-[2-[bis(4- fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine analogs: Synthesis and biological evaluation at the dopamine and serotonin transporter sites

Article abstract of DOI:10.1021/jm9506581

Several analogs of the potent dopamine (DA) transporter ligand 4-[2- [bis(4-fluorophenyl)-methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl)piperidine.

Full text of DOI:10.1021/jm9506581

J . Med. Chem. 1996, 39, 749-756
749
Str u ctu r e-Activity Rela tion sh ip Stu d ies of Novel
4-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-1-(3-p h en ylp r op yl)p ip er id in e An a logs:
Syn th esis a n d Biologica l Eva lu a tion a t th e Dop a m in e a n d Ser oton in
Tr a n sp or ter Sites
Aloke K. Dutta,*,† Cen Xu,‡ and Maarten E. A. Reith‡
Organix Inc., 65 Cummings Park, Woburn, Massachusetts 01801, and Department of Basic Sciences, University of Illinois,
Peoria, Illinois 61656
Received September 5, 1995X
Several analogs of the potent dopamine (DA) transporter ligand 4-[2-[bis(4-fluorophenyl)-
methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their
binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl
chain lengths and substitutions were introduced in these molecules to generate an optimum
activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted
compounds were the most active and selective for the DA transporter. The compound 4-[2-
(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a , showed high potency and was the most selective
for the DA transporter (5HT/DA ) 49) in this series of compounds. Some of these novel analogs
were found to be more selective in binding at the DA transporter than the original GBR 12909
molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperidine.
The dopamine (DA) transporter, a presynaptically
located macromolecule, terminates dopaminergic neu-
rotransmission by reaccumulation of released dopamine
into presynaptic neurons1 and plays an important role
in some pathophysicological processes in the central
nervous system (CNS). Cocaine, a powerful drug of
abuse,2 is known to bind to various neurotransporter
systems in the brain,3-5 but the reinforcing effect of
cocaine is believed to be initiated by binding to the DA
transporter causing inhibition of DA transport;6-8 im-
portant factors also are the rapid uptake and clearance
of cocaine.9 Phenylcyclidine (PCP), a psychoactive drug
of abuse, exhibits some of its behavioral effects through
binding to the DA transporter.10,11 This transporter also
plays a crucial role in the neurotoxic action of 1-methyl-
4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which in-
duces idiopathic Parkinsonian syndrome in humans.12,13
The DA transporter, which is localized presynaptically,
is found to be absent in tissue sections of Parkinson’s
diseased putamen, and its measurement can be used
as a probe for this disease.14,15
F igu r e 1.
Different classes of compounds have been developed
in the past to characterize cocaine-3,16,17 and PCP18,19
-
DA transporter. Similarly the modification of PCP
molecule, which induces behavioral effect in the CNS,
led to the development of a more potent compound,
BTCP (Figure 1), and its analogs for the DA trans-
porter.18,19,27
binding sites at the DA transporter. Extensive studies
on structure-activity relationships (SAR) in the series
of cocaine 3â-(aryltropanyl)-2â-(carboxylic acid methyl
ester) analogs resulted in the development of some very
potent and selective tropane derivatives for the DA
transporter.20-22 Some of the well-known compounds
in this class are CFT (WIN 35, 428) and RTI-55 (Figure
1), and they are more potent and selective than cocaine
in their action at the DA transporter.3,23,24 Recent
reports describe the discovery of some even more potent
and selective tropane classes of compounds for this
transporter.25,26 Such analogs will help to establish and
characterize the putative binding site of cocaine at the
The GBR classes of compounds, originally developed
by Van der Zee et al.,28 are known for their unusual high
selectivity and potency for the DA transporter. Two of
the most widely used GBR compounds, GBR 12909 and
12935 (Figure 1), have affinities in the low-nanomolar
range.29,30 An extensive SAR study was conducted in
the GBR series of compounds by Van der Zee et al.
which produced some very potent compounds for the DA
transporter. Consequently some of these potent com-
pounds have been radiolabeled, and detailed neuro-
pharmacological actions have been carried out with
these radioligands.31-33 GBR 12909 dissociates very
slowly from the DA transporter,34 attenuates the in-
* To whom correspondence should be addressed.
† Organix Inc.
‡ University of Illinois.
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
0022-2623/96/1839-0749$12.00/0 © 1996 American Chemical Society

750 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Dutta et al.
Sch em e 1
crease in extracellular dopamine level induced by
cocaine as measured in microdialysis experiments,34,35a
and exhibits nonstimulant properties in human volun-
teers.35b It is also shown recently that GBR 12909
selectively blocks cocaine self-administration behavior
in rhesus monkey.35c These intriguing results have
raised the possibility that a suitable GBR derivative or
related compounds can act as a cocaine antagonist.34,35a
Our interest in GBR molecules began with the explo-
ration and identification of molecular determinants
needed in these molecules to confer their strong selective
affinity for the DA transporter. In our previous study,
we demonstrated that the replacement of the piperazine
ring of GBR 12909 by a piperidine group maintains the
same activity of GBR 12909 in the new molecule, 1b
(Figure 1), when the nitrogen atom is in the correct
position.36 In addition, this new molecule was shown
to have more selectivity since it did not have the
nonselective piperazine binding activity37 which con-
tributes as much as 30% to binding of conventional GBR
compounds to brain preparations under commonly used
assay conditions.29 In this regard it has been shown
by other workers that changing the piperazine ring to
a homopiperazine moiety in the GBR 12935 molecule
produces a highly selective compound for the DA
transporter.38
characterization of a series of analogs from the struc-
tural modifications of the lead compound 1b.
Ch em istr y
The synthesis of 7a -c, 8a -e, and 9a ,b is described
in Scheme 1. The commercially available ketal 2 was
N-alkylated with 1-bromo-3-phenylpropane in the pres-
ence of K2CO3 to give compound 3a in excellent yield.
Deketalization of compound 3a in acidic THF (5% HCl)
produced 4a in good yield (65%). A modified Wittig
reaction of 4a with triethyl phosphonoacetate produced
5a in very good yield, which on reduction with lithium
aluminum hydride gave 6a in quantitative yield. Final
compounds 7a -c were prepared by acid-catalyzed reac-
tion of 6a with commercially available appropriately
substituted benzhydrols via azeotropic distillation.39
Similarly compounds 8a -e and 9a ,b were prepared in
an identical fashion by following the same reaction
conditions applied to prepare 7a -c.
Compound 7d was prepared in a slightly different
way. Here 4,4′-dimethoxybenzhydrol was converted
into the corresponding chloride which was then con-
verted into the final compound by treatment with
alcohol 6a in good yield. The synthesis is shown in
Scheme 2.
Scheme 3 describes the synthesis of 15a ,b, 16a ,b, and
17a ,b. The common commercially available starting
material ethyl isonipecotate was N-alkylated in the
presence of a base with 1-bromo-3-phenylpropane to give
13a in excellent yield. The reduction of ester 13a gave
alcohol 14a which on reaction with benzhydrol fur-
nished 15a in good yield. Compounds 15b, 16a ,b, and
17a ,b were also made by following the same procedure.
We embarked upon several structural modifications
of our lead compound 1b in an effort to establish a SAR
among these compounds. One of our goals is to develop
potent and selective compounds for the DA transporter
which will help to characterize the molecular structure
of this macromolecule further. A suitable compound
found in these studies might also be developed as a
radioligand to study the DA transporter; it would have
the advantage of lacking the nonspecific piperazine
binding activity relative to [3H]GBR 12935. Such a
compound might also be tested for use as a potential
cocaine antagonist in treatment programs. In this
report, we are describing the synthesis and biological
Bioch em istr y
Biological studies of the newly synthesized compounds
were carried out with rat brain striatal membrane
tissue. Binding analyses were performed to determine

SAR of Novel Piperidine Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 751
Ta ble 1. Affinity and Receptor Selectivity of Drugs at the
Dopamine and Serotonin Transporters in Rat Striatum
connectivities attached to the 1 and 4 positions of the
piperidine ring in these molecules. Various substitu-
tions in the aromatic rings were also tried to determine
the role of electronic and steric environments in the
potency of these molecules for the DA transporter. In
order to assess their dopaminergic selectivity, we tested
the compounds also for their activity at the 5HT
transporter.
Compounds 7a -d represent the analogs of 1b with
different halogens and methoxy substitutions in the
diphenylmethoxy moiety. The most potent and selective
compound in this particular series was 7a (R ) H, 5HT/
DA ) 20) where the F atoms of 1b were replaced by H
atoms. In this case, due to the changes in aromatic
substitution, the selectivity of 7a increased by 6-fold
when compared to 1b (5HT/DA ) 3.3). It is noteworthy
to mention that 1b showed higher selectivity for the DA
transporter when measured originally in monkey (Maca-
ca fascicularis) brain striatum ([3H]CFT IC50 ) 24 nM,
5HT/DA ) 10).36 Among the other substitutions, the
dichloro compound 7b showed 3.4 times less potency
than 1b, while the dibromo and dimethoxy compounds
7c (R ) Br) and 7d (R ) OCH3) were much less potent
and selective for the DA transporter which might
indicate the involvement of unfavorable steric and
electronic interactions of these compounds with the
receptor.
IC50 (nM)a
DA,
5HT,
5-HT/
DA
compd
R
n
n′
[3H]CFT
[3H]citalopram
GBR 12909
1b
F
F
3
3
3
3
3
3
2
2
2
2
2
1
1
3
3
2
2
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
6.0 ( 0.7
16.7 ( 4.0
12.0 ( 0.4
65 ( 12
82 ( 4
13.7
3.3
20
55 ( 10
7a
7b
7c
7d
8a
8b
8c
8d
H
Cl
Br
OCH3
H
232 ( 28
224 ( 10
835 ( 142
340 ( 24
102 ( 5
3.5
5.2
1.3
9.7
1.6
3.6
1.6
2.8
49
159 ( 56
255 ( 32
10.6 ( 0.85
19.9 ( 9.5
115 ( 22
382 ( 167
311 ( 71
15.2 ( 2.8
9.7 ( 0.4
14.5 ( 1.9
13.0 ( 2.5
108 ( 14
13.5 ( 2.6
702 ( 34
126 ( 13
F
31.9 ( 7.1
414 ( 32
638 ( 71
888 ( 58
743 ( 6
Cl
Br
Me
H
8e
9a
9b
F
H
F
H
F
H
F
198 ( 7
20
4
15a
15b
16a
16b
17a
17b
58 ( 7
112 ( 4
8.6
4.2
17.5
0.7
6
456 ( 90
237 ( 53
544 ( 91
761 ( 101
Replacement of the propyl side chain connected to the
N atom in compound 7a by an ethyl linkage resulted in
the development of the next series of compounds, 8a -
e. Their pattern of biological activities was parallel to
that of 7a -d . Compounds 8a (R ) H) and 8b (R ) F)
exhibited almost the same potency when compared with
their counterparts 7a and 1b. Thus, the IC50 values of
8a ,b for displacing [3H]CFT at the DA transporter, 10.6
and 19.9 nM, are comparable with the values of 12.0
and 16.7 nM for 7a and 1b. But the selectivity of 8a ,b
for the DA transporter was lower than that of 7a and
1b (5HT/DA, 9.7 and 1.6 vs 20 and 3.3). These results
reflect the fact that the replacement of the propyl chain
by an ethyl chain did not alter the potency in these
compounds at the DA transporter but enhanced the
affinity for the 5HT transporter by ca. 2-fold. Reduced
dopaminergic selectivity of the substituted compounds
8c-e may be due again to a combination of unfavorable
electronic and steric interactions with the receptors.
The DA transporter was labeled with [3H]CFT, and the 5HT
transporter was labeled with [3H]citalopram. Results are average
( SEM of three to five (DA) or two to three (5-HT) independent
experiments assayed in triplicate.
a
Sch em e 2
Continuing along the same experimental pathways,
compounds 9a (R ) H) and 9b (R ) F) were synthesized
where the N-propylphenyl side chain of the original
compound 1b was replaced by a benzyl group. This
modification resulted in compounds with potent activity
at the DA transporter and the highest selectivity for the
DA transporter as compared with 5HT observed in the
present series. Thus, compound 9a , which had an IC50
value of 15.2 nM and a 5HT/DA ratio of 49, showed 15
and 2.5 times more selectivity when compared to our
previous lead compound 1b and the compound 7a in the
current series, whereas compound 9b turned out to be
as selective as 7a . Compound 9a , when compared to
the original GBR 12909, was much more selective at
the DA transporter (Table 1, see also ref 36). In
addition, while the potencies of compounds 9a ,b at the
DA transporter did not change significantly, like their
previous counterparts 7a , 1b, and 8a ,b, their affinities
their activity at the DA and serotonin (5HT) transport-
ers in the brain tissues. The DA transporter in the rat
striatal tissue was labeled with a tritiated analog of a
potent cocaine analog, [3H]CFT, and the 5HT trans-
porter was labeled with [3H]citalopram. Table 1 shows
the IC50 values of the compounds, i.e., the concentrations
needed to inhibit binding by 50%.
Resu lts a n d Discu ssion
Some of the modifications of our lead compound 1b
(R ) F) involve the variations of the length of methylene

752 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Dutta et al.
Sch em e 3
for the 5HT transporter were reduced significantly.
Enhanced selectivity of 9a ,b for the DA transporter
could not be rationalized completely since initial reduc-
tion in chain length from N-propyl to N-ethyl yielded
less selective compounds. A further structure-activity
exploration of 9a currently is in progress to develop
more selective compounds in this category.
piperidine for the piperazine ring in the current series
of compounds. It is known that the pKa value of the
piperazine derivative is lower than that of the piperidine
derivative which might be responsible for the better
selectivity for the DA transporter in the case of the
current piperidine derivatives.
Our present work is an extension of our initial work
on the modification of the piperazine ring in these
molecules. Some of these new analogs were shown to
have more DA transporter selectivity than GBR 12909
(5HT/DA, 13.7 for GBR 12909 vs 49, 20, 20, and 17.5
for 9a ,b, 7a , and 16b). In addition, it was shown by us
previously that these new analogs lacked the nonspecific
piperazine site binding activity unlike conventional GBR
compounds.37 It is interesting to observe that variations
of the alkyl chain length were allowed without compro-
mising the activity of these compounds appreciably. This
is encouraging since one of our goals is to reduce the
lipophilicity in these new molecules in the light of the
fact that high lipophilicity imposes considerable dif-
ficulty in handling GBR compounds. Further SAR
studies in these classes of compounds in the future will
enable us to characterize the DA transporter complex
in greater detail.
The next series of compounds, 15a ,b, 16a ,b, and
17a ,b, represents the structural modifications in the
alkyl chain length connected to the O atom of diaryl-
methoxy moiety as well as to the N atom of the
piperidine ring. It was observed that the reduction of
ethylene linkage connected to O atom of the diphenyl-
methoxy moiety into a methylene unit, as shown in
these structures, did not change the high potency of the
compounds 15a ,b and 16b (R ) F) at the DA trans-
porter. On the other hand, compounds 17a ,b turned
out to be much less potent at the DA transporter which
reflects the low tolerance of the DA transporter for
N-benzyl substitution in these molecules. The most
potent and selective compound in this particular series
was found to be 16b (5HT/DA ) 17.5). These results
suggest that the activities in this series of molecules
with a connection of one methylene unit (n′ ) 1) were
more dependent on the variation of the N-alkyl chain
length showing the weakest activity for compounds with
the shortest chain length (n ) 1, 17a ,b). There was an
interesting contrast between the effect of fluorination
in all these compounds and that in 1b/7a and 8a /8b.
Only in the latter pairs were the fluoro-substituted
compounds slightly less potent than their hydrogen
counterparts in inhibiting the DA transporter, suggest-
ing a complex interaction between substitutions at one
end of the molecule and alkyl chain length changes at
distal portions. A similar complexity probably underlies
the abrupt drop in potency in the unsubstituted com-
pounds 16a (R ) H) and 17a (R ) H).
Exp er im en ta l Deta ils
Analytical silica gel-coated TLC plates (Si 250F) were
purchased from Baker, Inc., and visualized with UV light or
by treatment with phosphomolybdic acid (PMA). Flash chro-
matography was carried out on Baker silica gel (40 µM). 1H
NMR spectra were routinely obtained at 100 MHz on a
Brucker WP-100-SY spectrometer. The NMR solvents used
were CDCl3 and CD3OD as indicated; resonances are reported
in δ units. TMS was used as an internal standard. Elemental
analyses were performed by Atlantic Microlab, Inc., and are
within (0.4% of the theoretical values.
[3H]CFT (84.5 Ci/mmol) and [3H]citalopram (81 Ci/mmol)
were obtained from DuPont-New England Nuclear (Boston,
MA). Cocaine hydrochloride was purchased from Mallinckrodt
Chemical Corp. (St. Louis, MO). CFT naphthalenesulfonate
was from Research Biochemicals, Inc. (Natick, MA).
Con clu sion
P r oced u r e A: Syn th esis of 1-(3-P h en ylp r op yl)-4-p ip -
er id on e Eth ylen e Keta l (3a ). 4-Piperidone ethylene ketal
(3 g, 20.8 mmol) and 1-bromo-3-phenylpropane (5 g, 24.2 mmol)
were dissolved in 35 mL of DMF. Potassium carbonate (8 g)
was then added, and the mixture was warmed 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 , 4.8 g
(88% yield), as a colorless liquid. 1H NMR (CDCl3): 1.62-
2.00 (6H, complex m), 2.30-2.75 (8H, complex m), 3.92 (4H,
s, -2O-(CH2)-), 7.20 (5H, bs, Ph). Anal. (C16H23NO2) C, H, N.
In this report we describe the development of novel
potent and selective compounds for the DA transporter.
Compound 9a turned out to be the most DA transporter
selective compound in this series, while 9b was the most
potent at the DA transporter. These results reflect that
the benzyl substitution at the N atom of the piperidine
ring in 9a ,b is optimally tolerated and recognized
potently and selectively by the DA transporter. This,
however, stands in contrast to the work of Van der Zee
et al., where the 3-phenylpropyl substitution was shown
to confer maximum potency.28 Most likely, the factor
underlying this difference is the substitution of a

SAR of Novel Piperidine Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 753
P r oced u r e B: Syn th esis of 1-(3-P h en ylp r op yl)-4-p ip -
er id on e (4a ). N-(3-Phenylpropyl)-4-piperidone ethylene ket-
al, 3a (4.6 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 excess amount of solid NaHCO3, and
the crude product was extracted into ethyl acetate (250 mL)
layer. The organic layer was dried over Na2SO4. The crude
product was purified by flash column chromatography over a
silica gel column, and the pure product 4a was eluted with
EtOAc/hexane (1:1), 2.47 g (64.6% yield), as an oil. 1H NMR
(CDCl3): 1.65-2.05 (2H, m), 2.32-2.82 (12H, complex m), 7.20
(5H, bs, Ph). Anal. (C14H19NO) C, H, N.
P r oced u r e C: Syn t h esis of 1-(3-P h en ylp r op 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, 0.41 g, 0.90 mmol) in 25
mL of THF was added triethyl phosphonoacetate (1.9 g, 0.86
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 (1.5 g, 6.9 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. Or-
ganic layer was dried over Na2SO4, and the crude material
was flash chromatographed (silica gel). The pure compound
5a was eluted with EtOAc/hexane (1:1), 1.14 g (74% yield), as
an oil. 1H NMR (CDCl3): 1.15-1.36 (3H, t, J ) 4.5 Hz, (CH3)-
CH2-O-), 1.65-2.00 (2H, m), 2.25-2.75 (10H, complex m),
2.90-3.10 (2H, t, J ) 3 Hz, -N-(CH2)-CH2), 4.00-4.25 (2H, q,
J ) 4.5 Hz, CH3-(CH2)-O-), 5.65 (1H, s, d(CH)-COOEt), 7.20
(5H, bs, Ph). Anal. (C18H25NO2) C, H, N.
P r oced u r e D: Syn th esis of 1-(3-P h en ylp r op yl)-4-(2-
h yd r oxyeth yl)p ip er id in e (6a ). Lithium aluminum hydride
(LAH) (0.09 g, 2.37 mmol) was suspended in 25 mL of dry THF,
and the solution was cooled in an ice bath. The ester 5a (0.22
g, 0.76 mmol), dissolved in 10 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 excess amount of 10% NaOH solution. The solution
was filtered, and THF was removed in vacuo. The product
was partioned between water and ether layer. Organic layer
was dried over Na2SO4, and the product 6a was collected, 0.17
g (91% yield). This product was used in the next reaction
without any further purification. 1H NMR (CDCl3): 1.20-2.05
(9H, complex m), 2.10-3.20 (9H, complex m), 3.50-3.72 (2H,
t, J ) 3 Hz, -(CH2)-O-), 7.20 (5H, bs, Ph). MS (CI): m/e 248.2
(M + H)+.
Free base was converted into its hydrochloride salt, mp
164.5-165.8 °C. Anal. (C29H34NOCl3) C, H, N.
Syn th esis of 4-[2-[Bis(4-br om op h en yl)m eth oxy]eth yl]-
1-(3-p h en ylp r op yl)p ip er id in e Hyd r och lor id e (7c). An
excess amount of 4,4′-dibromobenzhydrol (1 g, 3 mmol) was
reacted with alcohol 6a (0.4 g, 1.6 mmol) to give product 7c,
0.24 g (42% yield), as a viscous oil (procedure E). 1H NMR
(CDCl3): 1.10-2.00 (11H, complex m), 2.25-2.45 (2H, m),
2.50-2.74 (2H, t, J ) 4.5 Hz, -(CH2)-Ph), 2.78-3.00 (2H, m),
3.35-3.55 (2H, t, J ) 3 Hz, CH2-(CH2)-O-), 5.20 (1H, s, -(CH)-
O-), 7.05-7.55 (13H, m, Ph + 2(Ph)-Br).
Free base was converted into its solid hydrochloride salt,
mp 94.6-96.9 °C. Anal. (C29H34NOClBr2) C, H, N.
Syn th esis of 1-(2-P h en yleth yl)-4-p ip er id on e Eth ylen e
Keta l (3b). 4-Piperidone ethylene ketal (5 g, 35 mmol) was
reacted with (2-bromoethyl)benzene (7.4 g, 40 mmol) to yield
3b, 6.28 g (73% yield), as a colorless oil (procedure A). 1H NMR
(CDCl3): 1.66-1.90 (4H, t, J ) 4.5 Hz, 2-(CH2)-C-O-), 2.50-
2.95 (8H, complex m), 3.95 (4H, s, 2-O-(CH2)-), 7.25 (5H, bs,
Ph). Anal. (C15H21NO2) C, H, N.
Syn th esis of 1-(2-P h en yleth yl)-4-p ip er id on e (4b). Ket-
al 3b (5.38 g, 21.7 mmol) after hydrolysis furnished 3.6 g (81%
yield) of 4b as a colorless solid, mp 79-82 °C (procedure B).
1H NMR (CDCl3): 2.35-2.58 (4H, t, J ) 4.5 Hz, 2-(CH2)-CdO),
2.60-3.00 (8H, complex m), 7.12-7.45 (5H, m, Ph). Anal.
(C13H17NO) C, H, N.
Syn th esis of 1-(2-P h en yleth yl)-4-[(eth oxyca r bon yl)-
m eth ylen e]p ip er id in e (5b). 4b (5.5 g, 27 mmol) was
converted into the product 5b, 1.7 g (24% yield), as an oil
(procedure C). 1H NMR (CDCl3): 1.15-1.40 (3H, t, J ) 4.5
Hz, (CH3)-CH2-O-), 2.25-2.90 (10H, complex m), 2.95-3.15
(2H, t, J ) 4.5 Hz, -N-(CH2)-), 4.00-4.30 (2H, q, J ) 4.5 Hz,
-O-(CH2)-CH3), 5.65 (1H, s, d(CH)-COOEt), 6.10-6.40 (5H, m,
Ph). Anal. (C17H23NO2) C, H, N.
Syn th esis of 1-(2-P h en yleth yl)-4-(2-h yd r oxyeth yl)p i-
p er id in e (6b). Ester 5b (1.67 g, 6.1 mmol) was converted into
6b, 1.31 g (92% yield), mp 79-81 °C (procedure D). 1H NMR
(CDCl3): 1.10-3.10 (15H, complex m), 3.60-3.80 (2H, t, J )
4.5 Hz, -CH2-(CH2)-O-), 7.05-7.40 (5H, m, Ph). MS (CI): m/e
234.1 (M + H)+.
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-(2-p h en -
yleth yl)p ip er id in e Hyd r och lor id e (8a ). Benzhydrol (0.51
g, 2.7 mmol) and alcohol 6b (0.26 g, 1.1 mmol) were reacted
to give 8a , 0.18 g (42% yield), as a viscous liquid (procedure
E). 1H NMR (CDCl3): 1.10-2.15 (9H, complex m), 2.42-3.10
(6H, complex m), 3.40-3.58 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-),
5.32 (1H, s, -(CH)-O-), 7.10-7.45 (15H, m, 3Ph).
P r oced u r e E : Syn t h esis of 4-[2-(Dip h en ylm et h oxy)-
eth yl]-1-(3-p h en ylp r op yl)p ip er id in e Hyd r och lor id e (7a ).
Benzhydrol (0.17 g, 0.92 mmol), N-(3-phenylpropyl)-4-(2-
hydroxyethyl)piperidine (0.17 g, 0.68 mmol), and p-tolune-
sulfonic acid (0.17 g, 0.85 mmol) were mixed together in 65
mL of benzene, and the solution was heated to reflux under
azeotropic distillation conditions overnight, under nitrogen.
Benzene was removed in vacuo, and the residue was parti-
tioned between ether (100 mL) and saturated NaHCO3. The
ether layer was seperated and dried over Na2SO4. Crude
mixture was chromatographed over a silica gel column, and
7a was eluted with EtOAc/hexane (1:1) mixture, 0.05 g (17%
yield), as a viscous oil. 1H NMR (CDCl3): 1.00-2.05 (11H,
complex m), 2.24-2.45 (2H, m), 2.50-2.75 (2H, t, J ) 4.5 Hz,
-(CH2)-Ph), 2.80-3.00 (2H, m), 3.40-3.60 (2H, t, J ) 3 Hz,
-CH2-(CH2)-O-), 5.35 (1H, s, -(CH)-O-), 7.12-7.45 (15H, m,
3Ph).
Free base was converted into its solid hydrochloride salt,
mp 172-174.2 °C. Anal. (C28H34NOCl) C, H, N.
Syn th esis of 4-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-
1-(2-p h en yleth yl)p ip er id in e Hyd r och lor id e (8b). 4,4′-
Difluorobenzhydrol (0.55 g, 2.5 mmol) was reacted with alcohol
6b (0.24 g, 1.3 mmol) to furnish 8b, 0.2 g (45% yield), as a
viscous liquid (procedure E). 1H NMR (CDCl3): 1.05-2.15 (9H,
complex m), 2.45-3.10 (6H, complex m), 3.35-3.55 (2H, t, J
) 3 Hz, -CH2-(CH2)-O-), 5.25 (1H, s, -(CH)-O-), 6.85-7.40 (13H,
m, Ph + 2(Ph)-F).
Free base was converted into its solid hydrochloride salt,
mp 146.9-148.8 °C. Anal. (C28H32NOF2Cl) C, H, N.
Syn th esis of 4-[2-[Bis(4-ch lor op h en yl)m eth oxy]eth yl]-
1-(2-p h en yleth yl)p ip er id in e Hyd r och lor id e (8c). 4,4′-
Dichlorobenzhydrol (0.75 g, 3 mmol) and alcohol 6b (0.28 g,
1.2 mmol) were reacted to give compound 8c, 0.33 g (59%
yield), as a viscous liquid (procedure E). 1H NMR (CDCl3):
1.10-2.20 (9H, complex m), 2.45-3.15 (6H, complex m), 3.35-
3.55 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-), 5.25 (1H, s, -(CH)-O-),
7.10-7.40 (13H, m, Ph + 2(Ph)-Cl).
Free base was converted into its hydrochloride salt, mp
125.9-126.4 °C. Anal. (C29H36NOCl) C, H, N.
Syn th esis of 4-[2-[Bis(4-ch lor op h en yl)m eth oxy]eth yl]-
1-(3-p h en ylp r op yl)p ip er id in e Hyd r och lor id e (7b). Start-
ing from 4,4′-dichlorobenzhydrol, the final compound 7b was
synthesized (procedure E). Thus an excess amount of 4,4′-
dichlorobenzhydrol (1 g, 3.9 mmol) was reacted with alcohol
6a (0.4 g, 1.6 mmol) to produce 7b, 0.68 g (88% yield), as an
oil. 1H NMR (CDCl3): 1.10-2.05 (11H, complex m), 2.25-2.45
(2H, m), 2.50-2.70 (2H, t, J ) 4.5 Hz, -(CH2)-Ph), 2.75-3.00
(2H, m), 3.30-3.54 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-), 5.25 (1H,
s, -(CH)-O-), 7.05-7.35 (13H, m, Ph + 2(Ph)-Cl).
Free base was converted into its solid hydrochloride salt,
mp 123-126.5 °C. Anal. (C28H32NOCl3) C, H, N.
Syn th esis of 4-[2-[Bis(4-br om op h en yl)m eth oxy]eth yl]-
1-(2-p h en yleth yl)p ip er id in e Hyd r och lor id e (8d ). 4,4′-
Dibromobenzhydrol (1.02 g, 3 mmol) and alcohol 6b (0.28 g,
1.2 mmol) were reacted to give compound 8d , 0.33 g (50%
yield), as a viscous liquid (procedure E). 1H NMR (CDCl3):
1.10-2.15 (9H, complex m), 2.45-3.10 (6H, complex m), 3.35-

754 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3
Dutta et al.
3.60 (2H, t, J ) 3 Hz, -CH2-(CH2)-O-), 5.24 (1H, s, -(CH)-O-),
7.05-7.60 (13H, m, Ph + 2(Ph)-Br).
Free base was converted into its hydrochloride salt, mp
121.8-125 °C. Anal. (C28H32NOClBr2) C, H, N.
Hz, (CH3)-CH2-O-), 1.60-2.45 (11H, complex m), 2.54-2.72
(2H, t, J ) 4.5 Hz, -(CH2)-Ph), 2.76-3.00 (2H, m), 4.00-4.25
(2H, q, J ) 4.5 Hz, -O-(CH2)-CH3), 7.05-7.40 (5H, m, Ph). Anal.
(C16H23NO2) C, H, N.
Syn th esis of 4-[2-[Bis(4-m eth ylp h en yl)m eth oxy]eth yl]-
1-(2-p h en yleth yl)p ip er id in e Hyd r och lor id e (8e). Reac-
tion between 4,4′-dimethylbenzhydrol (0.87 g, 4.1 mmol) and
alcohol 6b (0.3 g, 1.2 mmol) was carried out to give 8e, 0.25 g
(49% yield), as a viscous liquid (procedure E). 1H NMR
(CDCl3): 1.20-2.15 (9H, complex m), 2.30 (6H, s, 2(CH3)-Ph),
2.40-3.10 (6H, complex m), 3.35-3.55 (2H, t, J ) 3 Hz, -CH2-
(CH2)-O-), 5.26 (1H, s, -(CH)-O-), 6.00-6.35 (13H, m, Ph +
2(Ph)-CH3).
Syn th esis of 1-(3-P h en ylp r op yl)-4-(h yd r oxym eth yl)-
p ip er id in e (14a ). Ester 13a (5.17 g, 18.8 mmol) was con-
verted to alcohol 14a , 4 g (93% yield), as an oil (procedure B).
1H NMR (CDCl3): 1.20-2.45 (11H, complex m), 2.50-2.70 (2H,
t, J ) 4.5 Hz, -(CH2)-Ph), 2.80-3.10 (3H, m), 3.30-3.50 (2H,
d, J ) 3 Hz, -(CH2)-O-), 7.00-7.40 (5H, m, Ph). MS (CI): m/e
234.2 (M + H)+.
Syn th esis of 4-[(Dip h en ylm eth oxy)m eth yl]-1-(3-p h en -
ylp r op yl)p ip er id in e Hyd r och lor id e (15a ). Alcohol 14a
(0.7 g, 3 mmol) and benzhydrol (1.6 g, 9 mmol) were reacted
to give product 15a , 0.6 g (50% yield), as a viscous liquid
(procedure E). 1H NMR (CDCl3): 1.20-1.90 (9H, complex m),
2.25-2.46 (2H, m), 2.50-2.72 (2H, t, J ) 4.5 Hz, -(CH2)-Ph),
2.80-3.00 (2H, m), 3.25-3.35 (2H, d, J ) 3 Hz, -(CH2)-O-),
5.30 (1H, s, -(CH)-O-), 7.10-7.45 (15H, m, 3Ph).
Free base was converted into its solid hydrochloride salt,
mp 178-181.2 °C. Anal. (C28H34NOCl‚0.25H2O) C, H, N.
Syn th esis of 4-[[Bis(4-flu or op h en yl)m eth oxy]m eth yl]-
1-(3-p h en ylp r op yl)p ip er id in e Hyd r och lor id e (15b). Al-
cohol 14a (0.7 g, 3 mmol) and 4,4′-difluorobenzhydrol (1.9 g,
8.6 mmol) were reacted to give product 15b, 0.9 g (69% yield),
as an oil (procedure E). 1H NMR (CDCl3): 1.10-2.05 (9H,
complex m), 2.25-2.45 (2H, m), 2.50-2.74 (2H, t, J ) 4.5 Hz,
-(CH2)-Ph), 2.80-3.05 (2H, m), 3.15-3.35 (2H, d, J ) 3 Hz,
-(CH2)-O-), 5.25 (1H, s, -(CH)-O-), 6.85-7.40 (13H, m, Ph +
2Ph-F).
Free base was converted into its hydrochloride salt, mp
159.3-160.9 °C. Anal. (C30H38NOCl) C, H, N.
Syn th esis of 1-Ben zyl-4-[(eth oxyca r bon yl)m eth ylen e]-
p ip er id in e (5c). The compound 4c (1.5 g, 7.9 mmol) was
reacted with triethyl phosphonoacetate (2 g, 9.1 mmol) to give
product 5c, 0.52 g (26% yield), as an oil (procedure C). 1H
NMR (CDCl3): 1.15-1.35 (3H, t, J ) 4.5 Hz, (CH3)-CH2-O-),
2.20-2.60 (6H, complex m), 2.90-3.05 (2H, t, J ) 3 Hz, -N-
(CH2)-), 3.50 (2H, s, -N-(CH2)-Ph), 4.00-4.25 (2H, q, J ) 4.5
Hz, CH3-(CH2)-O-), 5.64 (1H, s, d(CH)-COOEt), 7.30 (5H, bs,
Ph). Anal. (C16H21NO2) C, H, N.
Syn t h esis of 1-Ben zyl-4-(2-h yd r oxyet h yl)p ip er id in e
(6c). The compound 5c (0.4 g, 1.5 mmol) was converted into
alcohol 6c, 0.29 g (91% yield), as an oil (procedure D). 1H NMR
(CDCl3): 1.10-3.00 (12H, complex m), 3.50 (2H, s, -N-(CH2)-
Ph), 3.55-3.75 (2H, t, J ) 3 Hz, -(CH2)-O-), 7.30 (5H, bs, Ph).
MS (CI): m/e 220.2 (M + H)+.
Syn th esis of 4-[2-(Dip h en ylm eth oxy)eth yl]-1-ben zylp i-
p er id in e Hyd r och lor id e (9a ). Alcohol 6c (0.15 g, 0.68
mmol) was reacted with benzhydrol (0.44 g, 2.39 mmol) to give
product 9a , 0.12 g (46% yield), as a viscous liquid (procedure
E). 1H NMR (CDCl3): 1.10-1.74 (7H, complex m), 1.78-2.05
(2H, t, J ) 4.5 Hz, -N(CH2)-), 2.75-2.95 (2H, m), 3.35-3.55
(4H, m, -N-(CH2)-Ph + -(CH2)-O-), 5.30 (1H, s, -(CH)-O-), 7.15-
7.40 (15H, m, 3Ph).
Free base was converted into its hydrochloride salt, mp
173.3-176.3 °C. Anal. (C28H32NOF2Cl) C, H, N.
Syn t h esis of 1-(2-P h en ylet h yl)-4-ca r b et h oxyp ip er i-
d in e (13b). Ethyl isonipecotate, 12 (6 g, 38 mmol), and
2-(bromoethyl)benzene (8.47 g, 45 mmol) were treated to
produce 13b, 6.55 g (66% yield), as an oil (procedure A). 1H
NMR (CDCl3): 1.14-1.35 (3H, t, J ) 4.5 Hz, (CH3)-CH2-O-),
1.55-3.10 (13H, complex m), 4.00-4.26 (2H, q, J ) 4.5 Hz,
CH3-(CH2)-O-), 7.05-7.40 (5H, m, Ph). Anal. (C16H23NO2) C,
H, N.
Free base was converted into its foamy hydrochloride salt.
Anal. (C27H32NOCl‚0.2H2O) C, H, N.
Syn th esis of 4-[2-[Bis(4-flu or op h en yl)m eth oxy]eth yl]-
1-ben zylp ip er id in e Hyd r och lor id e (9b). Alcohol 6c (0.24
g, 1.09 mmol) was reacted with 4,4′-difluorobenzhydrol (0.96
g, 4.35 mmol) to give product 9b, 0.1 g (23% yield), as a viscous
liquid (procedure E). 1H NMR (CDCl3): 1.10-1.75 (7H,
complex m), 1.78-2.10 (2H, t, J ) 4.5 Hz, -N-(CH2)-), 2.70-
3.00 (2H, m), 3.30-3.54 (4H, m, -N-(CH2)Ph + -(CH2)-O-), 5.25
(1H, s, -(CH)-O-), 6.85-7.40 (13H, m, Ph + 2Ph-F).
Syn th esis of 1-(2-P h en yleth yl)-4-(h yd r oxym eth yl)p i-
p er id in e (14b). Ester 13b (5 g, 15 mmol) was converted to
alcohol 14b, 3.14 g (95% yield), mp 101-104 °C (procedure
B). 1H NMR (CDCl3): 1.10-2.18 (8H, complex m), 2.45-3.15
(6H, complex m), 3.48-3.58 (2H, d, J ) 3 Hz, CH-(CH2)-O-),
7.10-7.40 (5H, m, Ph). MS (CI): m/e 220.2 (M + H)+.
Syn th esis of 4-[(Dip h en ylm eth oxy)m eth yl]-1-(2-p h en -
yleth yl)p ip er id in e Hyd r och lor id e (16a ). Alcohol 14b (0.7
g, 3.1 mmol) and benzhydrol (1.8 g, 10 mmol) were treated to
give product 16a , 0.7 g (59% yield), as a colorless solid, mp
67.3-68.9 °C (procedure E). 1H NMR (CDCl3): 1.10-2.15 (7H,
complex m), 2.45-3.12 (6H, m), 3.24-3.38 (2H, d, J ) 3 Hz,
-CH-(CH2)-O-), 5.30 (1H, s, -(CH)-O-), 7.10-7.40 (15H, m, 3Ph).
Free base was converted into its hydrochloride salt, mp
220-222.5 °C. Anal. (C27H32NOCl) C, H, N.
Syn th esis of 4-[[Bis(4-flu or op h en yl)m eth oxy]m eth yl]-
1-(2-p h en yleth yl)p ip er id in e Hyd r och lor id e (16b). Alco-
hol 14b (0.7 g, 3 mmol) and 4,4′-difluorobenzhydrol (2.2 g, 9.9
mmol) were reacted to give product 16b, 0.85 g (66% yield),
as a viscous liquid (procedure E). 1H NMR (CDCl3): 1.20-
2.15 (7H, complex m), 2.45-3.14 (6H, complex m), 3.20-3.35
(2H, d, J ) 3 Hz, CH-(CH2)-O-), 5.25 (1H, s, -(CH)-O-), 6.85-
7.40 (13H, m, Ph + 2Ph-F).
Free base was converted into its solid hydrochloride salt,
mp 225.5-226.7 °C. Anal. (C27H30NOClF2) C, H, N.
Syn t h esis of 1-Ben zyl-4-ca r b et h oxyp ip er id in e (13c).
Ethyl isonipecotate, 12 (2.75 g, 17.5 mmol), and benzyl bromide
were reacted to produce 13c, 3 g (70% yield), as an oil
(procedure A). 1H NMR (CDCl3): 1.14-1.35 (3H, t, J ) 4.5
Hz, (CH3)-CH2-O-), 1.60-2.45 (7H, complex m), 2.70-3.00 (2H,
m), 3.50 (2H, s, -N-(CH2)-Ph), 4.00-4.25 (2H, q, J ) 4.5 Hz,
-O-(CH2)-CH3), 7.30 (5H, bs, Ph). Anal. (C14H19NO2) C, H, N.
Syn t h esis of 1-Ben zyl-4-(h yd r oxym et h yl)p ip er id in e
(14c). Ester 13c (2 g, 8 mmol) was converted to alcohol 14c,
1.53 g (93% yield), as a viscous oil (procedure B). 1H NMR
Free base was converted into its oxalate salt, mp 145.5-
147.4 °C. Anal. (C29H32NO6F2‚0.1(COOH)2‚0.8H2O) C, H, N.
Syn th esis of 4-[2-[Bis(4-m eth oxyph en yl)m eth oxy]eth yl]-
1-(3-p h en ylp r op yl)p ip er id in e Hyd r och lor id e (7d ). A 50
mL flask equipped with a magnetic stirrer was charged with
4,4′-dimethoxybenzhydrol (1 g, 4 mmol) dissolved in 20 mL of
dry benzene. Excess amount of thionyl chloride (1 g, 8 mmol)
was added, and the solution was refluxed for 1 h. After cooling
benzene and excess thionyl chloride were removed in vacuo.
The crude chloride was used in the next reaction without any
further purification. Chloride 11 (4 mmol) and the alcohol 6a
(0.3 g, 1.2 mmol) were dissolved in 25 mL of toluene, and the
solution was refluxed for 3 h. Toluene was removed in vacuo,
and the residue was partitioned between EtOAc (100 mL) and
excess saturated NaHCO3 solution. Crude product was chro-
matographed over a silica gel column, and the pure product
7d was eluted with EtOAc/hexane (1:1) mixture, 0.36 g (64%
yield), as a solid, mp 74-75.8 °C. 1H NMR (CDCl3): 1.10-
2.20 (11H, complex m), 2.25-2.45 (2H, m), 2.50-2.74 (2H, t,
J ) 4.5 Hz, -(CH2)-Ph), 2.76-3.00 (2H, m), 3.35-3.54 (2H, t,
J ) 3 Hz, -O-(CH2)-), 3.80 (6H, s, -2OCH3), 5.24 (1H, s, -O-
(CH)-), 6.75-7.35 (13H, m, Ph + 2Ph-OCH3). Anal. (C31H39
O3N) C, H, N.
-
Syn th esis of 1-(3-P h en ylp r op yl)-4-ca r beth oxyp ip er i-
d in e (13a ). Ethyl isonipecotate, 12 (6 g, 38 mmol), and
1-bromo-3-phenylpropane (9.5 g, 47 mmol) were reacted in the
presence of K2CO3 to furnish 13a , 9.1 g (87% yield), as an oil
(procedure A). 1H NMR (CDCl3): 1.14-1.32 (3H, t, J ) 4.4

SAR of Novel Piperidine Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 3 755
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in the nucleus accumbens and phencyclidine-induced hyperac-
tivity are decreased following lesions of the mesolimbic dopamine
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(CDCl3): 1.10-2.10 (6H, m), 2.70-3.00 (4H, m), 3.35-3.50
(4H, m), 7.30 (5H, bs, Ph). MS (CI): m/e 206.1 (M + H)+.
Syn th esis of 4-[(Dip h en ylm eth oxy)m eth yl]-1-ben zylp i-
p er id in e Hyd r och lor id e (17a ). Alcohol 14c (0.4 g, 1.9
mmol) and benzhydrol (1.07 g, 5.8 mmol) were reacted to give
product 17a , 0.6 g (85% yield), as a viscous liquid (procedure
E). 1H NMR (CDCl3): 1.10-2.10 (7H, complex m), 2.75-3.00
(2H, m), 3.22-3.35 (2H, d, J ) 3 Hz, -CH-(CH2)-O-), 3.45 (2H,
s, -N-(CH2)-Ph), 5.25 (1H, s, -(CH)-O-), 7.25 (15H, bs, 3Ph).
Free base was converted into its oxalate salt, mp 175.6-
177.1 °C. Anal. (C28H31NO5) C, H, N.
Syn th esis of 4-[[Bis(4-flu or op h en yl)m eth oxy]m eth yl]-
1-ben zylp ip er id in e Hyd r och lor id e (17b). Alcohol 14c (0.4
g, 1.9 mmol) and 4,4′-difluorobenzhydrol (1.3 g, 5.8 mmol) were
reacted to give product 17b, 0.6 g (78% yield), as a viscous
liquid (procedure E). 1H NMR (CDCl3): 1.04-2.10 (7H,
complex m), 2.76-3.00 (2H, m), 3.15-3.30 (2H, d, J ) 3 Hz,
-CH-(CH2)-O-), 3.48 (2H, s, -N-(CH2)-Ph), 5.25 (1H, s, -(CH)-
O-), 6.85-7.40 (13H, m, Ph + 2Ph-F).
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Free base was converted into its oxalate salt, mp 161.5-
162.9 °C. Anal. (C28H29NF2O5‚0.4H2O) C, H, N.
Biological Meth ods. Binding of [3H]CFT (2â-carbomethoxy-
3â-(4-fluorophenyl)tropane, also known as WIN 35, 428) to the
DA transporter and of [3H]citalopram to the 5HT transporter
was measured in rat striatal P2 membrane preparations as
described previously.40 Briefly, rat striatal tissue was homog-
enized in 0.32 M sucrose, the P2 pellet was polytronned in ice-
cold 35 mM sodium phosphate buffer (final [Na+] of 35 mM
by mixing 35 mM NaH2PO4 and 17.5 mM Na2HPO4 to obtain
a pH of 7.4 at room temperature), and the binding assays were
carried out for 2 h on ice at a final sodium phosphate
concentration of 30 mM. The compounds were dissolved in
dimethyl sulfoxide and diluted out into 10% (v/v) dimethyl
sulfoxide solution. Additions from the later stocks resulted
in a final concentration of dimethyl sulfoxide of 0.5%, which
by itself did not interfere with the binding of [3H]CFT or [3H]-
citalopram. After initial range-finding experiments, typical
inhibition curves consisted of five different concentrations of
compounds spaced evenly around the IC50 value. Computation
of IC50 values was carried out with the equation of the ALLFIT
program41 entered into the Biosoft ORIGIN curve-fitting and
plotting software.
Ack n ow led gm en t. This work was supported by the
National Institute on Drug Abuse Grant No. DA08647.
We thank Lori L. Coffey for excellent assistance.
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