Further SAR studies of piperidine-based analogues of cocaine. 2. Potent dopamine and serotonin reuptake inhibitors

Article abstract of DOI:10.1021/jm9905561

The synthesis and monoamine transporter activity of additional members of a series of 3,4-disubstituted piperidines (truncated analogues of the WIN series) are described. All members of this series were prepared from arecoline hydrobromide in optically pure form and were evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds prepared in this series are reasonably potent DAT inhibitors (K(i) values of 4-400 nM) and have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to the DAT (?25-fold). In the present series, (-)-methyl 1-methyl-4β-(2-naphthyl)piperidine-3β- carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting K(i)'s of 21 nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6 is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in their stereochemistry, show different degrees of selectivity for the three transporters. Consistent with results reported in the literature for the tropane analogues, removal of the methyl group from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the in vivo effects of these piperidines, preliminary behavioral screening was carried out on piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was found to be about 2.5-fold less potent in increasing distance traveled in mice. However, consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based ligands may provide valuable insights into the pharmacological mechanisms underlying the enhancement in distance traveled versus stereotypic movements. The present results have important implications for better understanding the structural motifs required in the design of agents with specific potency and selectivity at monoamine transporters.

Full text of DOI:10.1021/jm9905561

J . Med. Chem. 2000, 43, 1215-1222
1215
F u r th er SAR Stu d ies of P ip er id in e-Ba sed An a logu es of Coca in e. 2. P oten t
Dop a m in e a n d Ser oton in Reu p ta k e In h ibitor s
Amir P. Tamiz,† J ianrong Zhang,† J udith L. Flippen-Anderson,§ Mei Zhang,‡ Kenneth M. J ohnson,‡
Olivier Deschaux,† Srihari Tella,† and Alan P. Kozikowski†,*
Drug Discovery Program, Institute of Cognitive and Computational Science, Georgetown University Medical Center,
3970 Reservoir Road, NW, Washington, DC 20007-2197, Department of Pharmacology and Toxicology,
University of Texas Medical Branch, Galveston, Texas 77555-1031, and Laboratory for the Structure of Matter,
Code 6030, Naval Research Laboratory, 4555 Overlook, SW, Washington, DC 20275-5000.
Received November 8, 1999
The synthesis and monoamine transporter activity of additional members of a series of 3,4-
disubstituted piperidines (truncated analogues of the WIN series) are described. All members
of this series were prepared from arecoline hydrobromide in optically pure form and were
evaluated for their ability to inhibit high affinity uptake of dopamine (DA), serotonin (5-HT)
and norepinephrine (NE) into rat brain nerve endings (synaptosomes). Most of the compounds
prepared in this series are reasonably potent DAT inhibitors (Ki values of 4-400 nM) and
have selectivity for the 5-HT transporter relative to both the NE transporter (3-9-fold) and to
the DAT (≈25-fold). In the present series, (-)-methyl 1-methyl-4â-(2-naphthyl)piperidine-3â-
carboxylate (6) was found to be the most potent piperidine-based ligand, exhibiting Ki’s of 21
nM and 7.6 nM at the DAT and 5-HTT, respectively. While the 5-HTT activity of compound 6
is comparable to that of the antidepressant medication fluoxetine, it is less selective. As is
apparent from the data presented, the naphthyl substituted piperidines 6-9, which differ in
their stereochemistry, show different degrees of selectivity for the three transporters. Consistent
with results reported in the literature for the tropane analogues, removal of the methyl group
from the nitrogen atom of 9 leads to a further enhancement in 5-HTT activity. To examine the
in vivo effects of these piperidines, preliminary behavioral screening was carried out on
piperidine 14. Despite its 2.5-fold greater DAT activity compared to cocaine, piperidine 14 was
found to be about 2.5-fold less potent in increasing distance traveled in mice. However,
consistent with its DAT activity, piperidine 14 was found to be about 2.5-fold more potent
than cocaine in enhancing stereotypic movements. Further studies of these piperidine-based
ligands may provide valuable insights into the pharmacological mechanisms underlying the
enhancement in distance traveled versus stereotypic movements. The present results have
important implications for better understanding the structural motifs required in the design
of agents with specific potency and selectivity at monoamine transporters.
In tr od u ction
serotonergic systems have been implicated in compul-
sive cocaine seeking behavior (craving). Accordingly,
5-HT-based agents are being investigated as possible
medications for the treatment of cocaine abuse as well.7
Interestingly, serotonin inhibitors lacking dopaminergic
activity do not produce reward or euphoria in primates.8
Selective monoamine reuptake inhibitors of dopamine
(DA), serotonin (5-HT), and norepinephrine (NE) have
been developed to treat a variety of neurological disor-
ders. For example, selective norepinephrine transporter
(NET) inhibitors such as desipramine1 and serotonin
transporter (5-HTT) inhibitors such as paroxetine2 and
fluoxetine3 are currently being used for the treatment
of depression (Chart 1).4 Selective dopamine transporter
(DAT) antagonists are clinically used for the treatment
of Parkinson’s disease and attention deficit disorders.5
There has also been considerable interest in recent years
in the development of DA reuptake inhibitors as sub-
stitute medications for the treatment of cocaine abuse.
Various studies have shown that the ability of cocaine
to bind to the DAT and inhibit the reuptake of DA is
likely responsible for the reinforcing properties of this
drug.6 Cocaine also inhibits serotonin reuptake, and
Serotonin selective reuptake inhibitors (SSRIs) are
widely used not only in major depression but also in
severe anxiety disorders, including panic-agoraphobia
syndrome, and obsessive compulsive disorder (OCD).9
There is an implied correlation between craving and
OCD. However, clinical trials would suggest that the
use of SSRI alone would not likely result in significant
efficacy for the treatment of cocaine withdrawal.10 Yet,
there has been some reported success in polytherapy
(combination of DA reuptake inhibitor and 5-HT re-
leaser) in recent studies for cocaine withdrawal therapy.11
The pilot studies conducted using such a polytherapeutic
approach report little to no side effects associated with
the combination of DA reuptake inhibitor and 5-HT
releaser regimen. Therefore, it is possible that the
combination of 5-HT and DAT reuptake inhibitory
properties into a single molecule may offer a more
* To whom correspondence should be addressed. Tel: 202-687-0686.
Fax: 202-687-5065. E-mail: kozikowa@pop3.odr.georgetown.edu.
† Georgetown University Medical Center.
‡ University of Texas Medical Branch.
§ Naval Research Laboratory.
10.1021/jm9905561 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/25/2000

1216 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Tamiz et al.
Ch a r t 1
Sch em e 1a
a
Reagents and conditions: (a) 2-naphthylMgBr, ether, -10 °C;
(b) HCl (6 N); (COCl)2, CH2Cl2; 8-phenylmenthol, n-BuLi, ether;
(c) HCl (6 N); HCl/MeOH (1 M); (d) NaOMe (cat.), MeOH; (e)
1-naphthylMgBr, ether, -10 °C.
particular, based upon results reported in the tropane
series, we wished to examine related structural modi-
fications to the piperidines which might lead to im-
proved 5-HTT activity while maintaining the DAT
potency.18 The present structure-activity relationship
(SAR) studies in this series of piperidines have led us
to the identification of a series of cis disubstituted
piperidines that exhibit high potency at 5-HTT and
DAT. Synthesis and monoamine uptake activity of these
novel compounds are described.
effective approach to OCD management than conven-
tional monotherapies targeting the DAT or 5-HTT alone.
Recently mild DA reuptake inhibitors, such as bu-
propion, have proven beneficial in treatment of depres-
sion.12 The mesolimbic DA system is believed to underlie
the common mechanism of current antidepressant
treatment by a mechanism which enhances the endo-
genous reward system. Therefore, compounds with a
strong 5-HT inhibitory activity combined with a moder-
ate DA reuptake inhibiting property have been argued
to be most beneficial as antidepressants with a rapid
onset of action. Clinical studies with roxindole (a DA
receptor agonist with 5-HT reuptake activity) have
shown potent antidepressant properties with a rapid
onset of action.13 Recent clinical studies suggest that
fluoxetine can be safely and usefully combined with
bupropion (DAT IC50 ) 2 µM) in partial responders to
monotherapy of depression.14 In a related study, Lab-
bate and co-workers have shown that the SSRIs associ-
ated sexual dysfunction in patients can be diminished
using an adjunctive bupropion treatment.15 It has
become apparent that the combination of a SSRI and a
DAT reuptake inhibitor may offer a safer and possibly
more effective treatment than conventional monother-
apy.16
Ch em istr y
The route of chemical synthesis of the 2-naphthylpi-
peridines 6-9 shown in Table 1 is outlined in Scheme
1. Reaction of arecoline as its free base with 2-naphth-
ylmagnesium bromide19 resulted in a mixture of cis and
trans disubstituted piperidines 2 and 3, which was
separated by flash chromatography on silica gel. The
(()-cis isomer 2 was converted to its acid chloride
(structure not shown) in two steps and reacted with
8-phenylmenthol to give diastereomers 4 and 5 that
were readily separated by flash chromatography. The
absolute stereochemistry of 4 was established by crys-
tallographic methods (Figure 1). Hydrolysis of the
diastereomeric phenyl menthyl esters 4 and 5 followed
by their treatment with HCl (catalyst) in methanol
yielded the cis enantiomers (-)-6 and (+)-8, respectively.
The optically pure enantiomers (-)-6 and (+)-8 were
converted to their respective trans enantiomers (+)-7
and (-)-9 using a catalytic amount of NaOMe in MeOH.
The 4-(1-naphthyl)piperidine analogues 10 and 11 were
also prepared using the Grignard method. We were
unable to separate the individual enantiomers of the cis
Less is known about the neurochemical and physi-
ological actions of compounds that exhibit dual DA and
5-HT transporter potency, especially as cocaine treat-
ment medications, possibly due to the limited number
of studies of such agents. We recently reported on a
series of piperidine-based analogues of cocaine that bind
to the cocaine recognition site and inhibit DA reuptake
with potencies comparable to that of cocaine.17 In

SAR Studies of Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1217
Sch em e 2a
F igu r e 1. ORTEP drawing of piperidine (-)-4 which estab-
lishes its absolute stereochemistry.
piperidine 10 using classical methods of chemical reso-
lution. The p-phenyl substituted piperidines 14-18
were prepared as shown in Scheme 2. Here, 4-(4-
iodophenyl)piperidine 13 prepared in one step from
piperidine 12 was used as a key intermediate for the
synthesis of piperidines 14-18. Stille’s palladium cou-
pling methodology originally described for the WIN
series by Carroll and co-workers was used to prepare
piperidines 14 and 16-18.20 N-Demethylation of pip-
eridine 9 using R-chloroethyl chloroformate followed by
subsequent heating of the carbamate intermediate
(structure not shown) in MeOH gave piperidine 19
which was isolated as its HCl salt.
Str u ctu r e-Activity Rela tion sh ip s
All compounds were tested for their ability to inhibit
high affinity uptake of DA, 5-HT, and NE into nerve
endings (synaptosomes).21 The uptake data and selec-
tivity profiles (based on the Ki values) of these com-
pounds are listed in Table 1. All data are mean values
( range or SEM of two to five separate experiments,
each conducted with six drug concentrations in tripli-
cate. Using piperidine 20 as a starting point for this
work, we examined the effect of structural modifications
to this compound that are similar to those reported by
Carroll in the WIN series (Chart 2) and, specifically,
modifications known to improve the 5-HTT inhibitory
potency. Replacement of the 4-chloro group in 20 with
a vinyl group gave piperidine 14 which showed a 3-fold
increase in potency at the 5-HTT. Replacement of the
4-chloro group in 20 with a ethynyl group gave piperi-
dine 17 that exhibited a 2-fold increase in its 5-HTT
potency. Piperidine 17 has a lower potency at the NET
than does piperidine 14. Catalytic hydrogenation of
piperidine 14 gave the ethyl bearing ligand 15 which
showed a reduced affinity for all three transporters. The
allyl bearing piperidine 17, on the other hand, has a
5-HTT potency similar to that of the parent piperidine
20, while its DAT potency is diminished by more than
13-fold. Replacement of the 4-chloro group in 20 with a
4-phenyl group gave piperidine 18. This compound
showed a 6-fold improvement in potency at the 5-HTT
compared to 20. Piperidine 18 is approximately 3-fold
a
Reagents and conditions: (a) HClO4, HgO, AcOH, I2; (b)
Bu3SnCHdCH2, (Ph3P)4Pd, dioxane; (c) Pd/C (10%), H2 (1 atm),
MeOH; (d) Bu3SnCH2CHdCH2, (Ph3P)4Pd, dioxane; (e) trimeth-
ylsilylacetylene, CuI, (Ph3P)2PdCl2, [(CH3)2CH]2NH; TBAF, THF;
(f) PhSnMe3, (Ph3P)4Pd, PPh3, dioxane; (g) CH3CH(Cl)OCOCl, 1,2-
dichloroethane; MeOH, reflux; HCl/ether (1 M).
more selective for the 5-HTT versus the DAT and the
NET. Introduction of a 2-naphthyl group gave piperidine
(-)-6; this analogue showed improved potency for all
three transporters, with the highest potency (7.6 nM)
being displayed at the 5-HTT. As is apparent from the
data (Table 1), the 4-(2-naphthyl)piperidines 6-9 in-
teract stereoselectively with the respective transporters,
with analogue 8 showing the highest NET activity,
while analogue 7 exhibits the best selectivity for the
5-HTT versus the DAT and NET. N-Demethylation of
piperidine 9 gave 19 and resulted in a 3-fold increase
in potency at the 5-HTT. This result is consistent with
related work in the WIN series.22 In the present series,
piperidine (-)-6 exhibits a 5-HTT potency that is
comparable to that of fluoxetine (Ki ) 7 nM); however,
fluoxetine has lower affinity for the DAT and the NET.
Beh a vior a l Stu d ies
Piperidine 14 was selected as a representative mem-
ber of this series for preliminary behavioral screening
for its effect on locomotor activity in mice. The primary

1218 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Ta ble 1. Activity at Monoamine Transporters, Ki ( SE (nM)
Tamiz et al.
b,c
a
b
Data are mean ( standard error of at least three experiments performed in triplicate. See ref 5. c E ) COOMe.
mechanism underlying cocaine’s behavioral effects in-
cluding locomotor stimulation is thought to be due to
its ability to bind to dopamine transporters and thereby
inhibit dopamine reuptake. In agreement with the
dopamine hypothesis, both cocaine and piperidine 14
inhibited dopamine reuptake and increased motor ef-
fects. Employing the standard locomotor assay, both
cocaine (3-56 mg/kg) and piperidine 14 (10-56 mg/kg)
produced dose-dependent enhancements in the distance
traveled and stereotypic movements (Figure 2). How-
ever, cocaine is about 2.5-fold (95% confidence limits:
1.56-4.6) more potent (by parallel lines bioassay test)
than piperidine 14 in increasing the distance traveled.
In contrast, piperidine 14 is about 2.4-fold (95% confi-
dence limits: 1.46-4.37) more potent than cocaine in
enhancing stereotypic movements. Cocaine is also sig-
nificantly (P < 0.01) more efficacious than piperidine
14 in increasing distance at the maximal dose (56 mg/
kg) tested. Both cocaine and piperidine 14 had a similar
time-course of locomotor effects (data not shown). For
example, the stimulant effects on horizontal distance
of both cocaine and piperidine 14 at 56 mg/kg dose
lasted about 2 h.
piperidine 14 in inhibiting dopamine uptake. Unlike its
effects on stereotypic movements, piperidine 14 is about
2.5 times less potent than cocaine in increasing the
distance traveled. This suggests that besides the inhibi-
tion of dopamine uptake, other mechanisms might also
play a modulatory role in enhancing the distance
traveled. The inhibition of norepinephrine and serotonin
uptake are unlikely to be involved, since both com-
pounds had similar potencies at these transporters.
Thus, the piperidine 14 may serve as a useful biological
tool to understand the differences in the pharmacologi-
cal mechanisms underlying the cocaine-induced en-
hancements in the distance traveled versus stereotypic
movements.
Con clu sion s
The chemical synthesis and monoamine transporter
activity of a series of piperidine-based monoamine
reuptake inhibitors are presented. While these mol-
ecules lack the tropane nucleus which is characteristic
of the WIN series of cocaine analogues, some members
of the present series are potent inhibitors of the
monoamine transporters. The naphthyl bearing ligand
6 represents the most potent ligand at the DAT and the
5-HTT. As in the WIN series, N-demethylation of the
piperidine in the case of 9 leads to a compound 19 of
Piperidine 14 is about 2.5-fold more potent than
cocaine in enhancing stereotypic movements (Figure 2).
This is consistent with the 3-fold higher potency of

SAR Studies of Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1219
at 30-40 °C. All reactions were performed under inert
atmosphere (Ar or N2) unless otherwise noted. Diethyl ether
was freshly distilled under nitrogen from sodium benzophen-
one. IR spectra were collected on an ATI Mattson Genesis
1
spectrometer. H and 13C NMR spectra were obtained with a
Varian Unity Inova instrument at 300 and 75.46 MHz,
respectively. 1H chemical shifts (δ) are reported in ppm
downfield from internal TMS. 13C chemical shifts are referred
to CDCl3 (central peak, δ ) 77.0 ppm). Melting points were
taken in Pyrex capillaries with a Thomas-Hoover Unimelt
apparatus and are not corrected. Mass spectra were measured
in the EI mode at an ionization potential of 70 eV. TLC was
performed on Merck silica gel 60 F254 glass plates; column
chromatography was performed using Merck silica gel (60-
200 mesh). Yields are of purified product and are not opti-
mized.
(()-Meth yl 1-Meth yl-4-(2-n a p h th yl)p ip er id in e-3-ca r -
boxyla te (2, 3). To a stirred suspension of Mg (240 mg, 10.0
mmol) in ether (10 mL) were added 2-bromonaphthalene (2.07
g, 10.0 mmol) in ether (3.0 mL) followed by 1,2-dibromoethane
(140 mg, 0.750 mmol), and the mixture was heated at reflux
until all of the Mg had disappeared. Arecoline (630 mg, 4.10
mmol) in ether (15 mL) was added dropwise to the 2-naphthyl
Grignard solution with stirring at -20 °C, and the resulting
suspension was stirred at -15 °C for 0.5 h. The mixture was
cooled to -40 °C and treated with HCl (10% aqueous, 30 mL).
The aqueous layer was separated, washed with ether (20 mL),
and neutralized with saturated sodium bicarbonate solution
while being cooled in an ice bath. The aqueous phase was
extracted with ether (3 × 30 mL). The combined organic phases
were washed with brine (30 mL), dried over Na2SO4, and
concentrated under reduced pressure to give an oil. Flash
chromatography (ether/Et3N, 99:1) gave the faster moving cis
isomer 2 (259 mg, 20%) then the trans isomer 3 (120 mg, 9%).
F igu r e 2. The dose-effect curves for the effect of cocaine and
piperidine 14 on horizontal distance traveled (top panel) and
the stereotypic movements (bottom panel) in male Swiss-
Webster mice. The maximal 30 min total from the original 2
h data for each dose of a given drug was identified and used
for statistical analysis. These 30 min maximal responses were
expressed as the percent of mean of the corresponding saline
control group. The data points in the figure represent the mean
( SEM of these percent changes for different doses of cocaine
and piperidine 14. Both piperidine 14 (F7,110 ) 18.58, P <
0.001) and cocaine (F4,115 ) 61.67, P < 0.001) produced
significant and dose-dependent increases in horizontal distance
traveled. Similarly, piperidine 14 (F7,110 ) 18.57, P < 0.001)
and cocaine (F4,115 ) 7.89, P < 0.001) significantly increased
stereotypic movements. The horizontal activity and stereotypic
movement responses in the saline control group were 3775 (
216 cm and 1833 ( 70, respectively. **P < 0.01; ***P < 0.001
as compared to the corresponding responses in the saline
control group by Tukey’s post hoc test.
Compound 2: mp 100-101 °C; IR (KBr) 758, 1019, 1165,
1
1743, 2783, 2941 cm-1; H NMR (CDCl3) δ 1.92 (dd, 1H, J )
3.0, 12.6 Hz), 2.11 (dt, 1H, J ) 2.7, 11.1 Hz), 2.30 (s, 3H), 2.41
(dd, 1H, J ) 3.6, 11.4 Hz), 2.81 (dq, 1H, J ) 3.6, 11.7 Hz),
2.96-3.08 (m, 2H), 3.12 (d, 1H, J ) 3.3 Hz), 3.23 (dd, 1H, J )
1.8, 11.4 Hz), 3.45 (s, 3H), 7.38-7.48 (m, 3H), 7.70-7.83 (m,
4H); 13C NMR (CDCl3) δ 22.3, 37.4, 41.7, 42.1, 46.8, 51.4, 53.9,
120.9, 121.3, 121.6, 121.9, 123.0, 123.1, 123.4, 127.6, 128.8,
136.0, 168.2; MS m/z% 44 (63), 70 (100), 252 (2), 283 (M+, 16).
Anal. (C18H21NO2) C, H, N.
Compound 3: IR (film) 746, 819, 1194, 1733, 2789, 2939
cm-1; 1H NMR (CDCl3) δ 1.85-2.10 (m, 2H), 2.18 (dt, 1H, J )
3.3, 11.1 Hz), 2.26 (t, 1H, J ) 10.5 Hz), 2.40 (s, 3H), 2.90-
3.20 (m, 4H), 3.38 (s, 3H), 7.36-7.48 (m, 3H), 7.65 (s, 1H),
7.74-7.82 (m, 3H); 13C NMR (CDCl3) δ 33.4, 44.9, 46.4, 49.2,
51.7, 56.1, 58.4, 125.6, 125.9, 126.1, 127.8, 127.9, 128.3, 132.7,
133.7, 141.1, 173.8; MS m/z% 44 (33), 70 (100), 224 (8), 283
(M+, 12).
(2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)cycloh ex-
yl (3R,4S)-1-Meth yl-4-(2-n a p h th yl)p ip er id in e-3-ca r boxyl-
a te (4) a n d (2S,5R)-5-Meth yl-2-(1-m eth yl-1-p h en yleth yl)-
cycloh exyl (3S,4R)-1-Meth yl-4-(2-n a p h th yl)p ip er id in e-3-
ca r boxyla te (5). A solution of piperidine 2 (1.0 g, 3.5 mmol)
in HCl (6 N, 20 mL) was stirred at reflux for 5 h and
concentrated in vacuo to give the acid intermediate as a white
solid. The acid was suspended in CH2Cl2 (10 mL) and treated
with oxalyl chloride (1.0 mL, 12 mmol) with stirring for 2 h at
room temperature. The solvent was removed in vacuo to give
the acid chloride intermediate as a solid. To a solution of (-)-
8-phenylmenthol (2.38 g, 10.2 mmol) in ether (40 mL) was
added n-butyllithium (2.5 M in hexane, 4.0 mL, 10 mmol) at
0 °C. The solution was warmed to room temperature and added
dropwise to a suspension of the acid chloride intermediate in
ether (40 mL), and the resulting mixture was stirred overnight.
The solution was diluted with ether (30 mL), washed with
brine (30 mL), dried over Na2SO4, and concentrated to give
an oil. Flash chromatography (ether/Et3N 99:1) gave the faster
moving isomer 4 (610 mg, 36%) followed by the isomer 5 (620
mg, 36%).
improved 5-HTT activity (3.5 nM). Piperidine 7, on the
other hand, shows the best overall selectivity for the
5-HTT. Locomotor studies with the 4-(4-vinylphenyl)-
piperidine 14 reveals differential effects on distance
traveled versus stereotypic movements, which contrasts
with the effects found for cocaine in the same study. As
a consequence of the potency of some of these pip-
eridines as multitransporter inhibitors combined with
the unexpected results from the locomotor studies,
further in vivo studies of these piperidines as possible
cocaine medications and as antidepressants23 are now
being conducted.
Exp er im en ta l P r oced u r es
Gen er a l. Reagents and solvents were obtained from com-
mercial suppliers and used as received. All starting materials
were commercially available unless otherwise indicated. Sol-
vent removal was routinely performed on a rotory evaporator

1220 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Tamiz et al.
Compound 4: IR (film) 700, 1734, 2783, 2952 cm-1; 1H NMR
(CDCl3) δ 0.66-1.00 (m, 12H), 1.22-1.56 (m, 3H), 1.70-1.94
(m, 3H), 2.00-2.18 (m, 2H), 2.24 (s, 3H), 2.50-2.58 (m, 1H),
2.76-3.02 (m, 4H), 4.55 (dt, 1H, J ) 4.2, 10.8 Hz), 6.94-7.16
(m, 5H), 7.36-7.48 (m, 3H), 7.70-7.84 (m, 4H); 13C NMR
(CDCl3) δ 21.9, 26.0, 26.5, 26.9, 27.2, 31.4, 34.8, 39.7, 41.5,
42.2, 46.5, 46.8, 50.5, 56.1, 58.4, 74.2, 125.0, 125.5, 125.6, 125.9,
126.7, 127.1, 127.6, 127.7, 127.9, 128.0, 132.4, 133.5, 140.9,
151.8, 171.7; MS m/z% 44 (100), 483 (M+, 5).
Compound 5: IR (KBr) 700, 1729, 2783, 2934 cm-1; 1H NMR
(CDCl3) δ 0.31 (d, 3H, J ) 6.3 Hz), 0.38-0.56 (m, 1H), 0.76-
1.18 (m, 10H), 1.28-1.42 (m, 2H), 1.62 (dt, 1H, J ) 3.0, 10.2
Hz), 1.82-1.98 (m, 1H), 2.12-2.60 (m, 7H), 2.63-2.96 (m, 3H),
4.57 (dt, 1H, J ) 4.2, 10.8 Hz), 7.10-7.20 (m, 3H), 7.20-7.35
(m, 3H), 7.35-7.48 (m, 2H), 7.56 (s, 1H), 7.64-7.82 (m, 3H);
13C NMR (CDCl3) δ 21.4, 26.0, 26.6, 27.1, 28.6, 30.9, 34.5, 39.9,
40.8, 41.0, 45.5, 46.9, 50.1, 54.4, 56.2, 74.1, 125.1, 125.5, 125.6,
126.0, 126.3, 127.4, 127.5, 127.6, 128.0, 128.1, 132.2, 133.4,
140.6, 152.0, 171.9; MS m/z% 49 (100), 483 (M+, 2).
mL) at such a rate that the reaction proceeded vigorously. The
resulting solution was further refluxed until all of the Mg had
disappeared. The solution was diluted with ether (30 mL) and
cooled to -15 °C at which time a solution of arecoline (1.5 g,
9.7 mmol) in ether (20 mL) was added dropwise. The resulting
mixture was stirred at -15 °C for 1 h, poured onto cracked
ice, and treated with HCl (10%, 22 mL). The aqueous layer
was separated, washed with ether (20 mL), and neutralized
with saturated sodium bicarbonate solution while being cooled
in an ice bath. The aqueous phase was extracted with ether
(3 × 40 mL). The combined organic phases were washed with
brine (30 mL), dried over Na2SO4, and concentrated to give
an oil. Flash chromatography (ether/Et3N, 99:1) gave the cis
isomer 10 (700 mg, 26%) as a white solid: mp 108-109 °C; IR
(KBr) 776, 1157, 1379, 1747, 2792, 2931 cm-1; 1H NMR (CDCl3)
δ 1.78-1.87 (m, 1H), 2.21 (dt, 1H, J ) 2.7, 11.1 Hz), 2.35 (s,
3H), 2.54 (dd, 1H, J ) 3.3, 11.1 Hz), 2.92-3.18 (m, 2H), 3.18-
3.32 (m, 2H), 3.41 (s, 3H), 3.51-3.63 (m, 1H), 7.40-7.56 (m,
3H), 7.61 (d, 1H, J ) 6.9 Hz), 7.72 (d, 1H, J ) 8.1 Hz), 7.86
(dd, 1H, J ) 1.5, 7.2 Hz), 7.97 (d, 1H, J ) 8.4 Hz); 13C NMR
(CDCl3) δ 22.5, 33.7, 40.6, 42.2, 46.6, 52.2, 54.3, 118.0, 120.6,
120.9, 121.0, 121.4, 122.5, 124.8, 126.8, 129.3, 133.5, 168.1;
MS m/z% 44 (83), 70 (100), 283 (M+, 44). Anal. (C18H21NO2) C,
H, N.
(-)-Meth yl 1-Meth yl-4â-(2-n a p h th yl)p ip er id in e-3â-ca r -
boxyla te (6). A solution of piperidine 4 (257 mg, 0.53 mmol)
in HCl (6 N, 25 mL) was stirred at reflux for 24 h. The solvent
was removed in vacuo to give a white solid. This solid was
dissolved in a saturated methanolic solution of HCl (g) (3 mL),
and the resulting solution was stirred at room temperature
overnight. The solvent was removed in vacuo to give a white
solid which was dissolved in saturated NaHCO3 (20 mL), and
the solution was extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were washed with brine (30 mL),
dried over Na2SO4, and concentrated to give an oil. Flash
chromatography (ether/Et3N, 99:1) gave the title compound 6
(80 mg, 53%) as a white solid: mp 77-78 °C; [R]D -13.0° (c
(-)-Meth yl 4â-(4-Iod op h en yl)-1-m eth ylp ip er id in e-3â-
ca r boxyla te (13). Perchloric acid (70%, 5.25 mL) was added
to a stirred slurry of mercuric oxide (975 mg, 4.49 mmol) in
glacial acetic acid (10 mL), and the slurry was stirred until
all of the orange solid had dissolved. To this solution was added
piperidine 12 (1.05 g, 4.51 mmol) followed by acetic acid (5
mL). After 15 min, a solution of iodine (2.85 g, 11.2 mmol) in
acetic acid (21 mL) and CH2Cl2 (41 mL) was added, and the
resulting slurry was stirred at room temperature for 5 h. The
orange solid was removed through a plug of Celite, and the
filtrate was neutralized with concentrated ammonium hydrox-
ide. The mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined extracts were dried over Na2SO4 and concentrated
to give an oil. Flash chromatography gave the title compound
(800 mg, 50%) as a white solid: [R]D -27.1° (c 0.55, CHCl3);
1
0.45, CHCl3); H NMR (CDCl3) δ 1.94 (dd, 1H, J ) 2.7, 12.6
Hz), 2.14 (dt, 1H, J ) 2.7, 11.1 Hz), 2.32 (s, 3H), 2.43 (dd, 1H,
J ) 3.3, 11.4 Hz), 2.81 (dq, 1H, J ) 3.6, 12.0 Hz), 2.94-3.08
(m, 2H), 3.08-3.16 (m, 1H), 3.23 (d, 1H, J ) 11.1 Hz), 3.46 (s,
3H), 7.38-7.48 (m, 3H), 7.70-7.83 (m, 4H). Anal. (C18H21NO2)
C, H, N.
(+)-Meth yl 1-Meth yl-4â-(2-n a p h th yl)p ip er id in e-3â-ca r -
boxyla te (8) was prepared similarly to naphthylpiperidine
(-)-6. From naphthylpiperidine 5 (285 mg, 0.59 mmol) was
obtained piperidine (+)-8 (100 mg, 60%) as a white solid: mp
77-79 °C; [R]D +13.3° (c 0.43, CHCl3); 1H NMR (CDCl3) δ
1.89-2.00 (m, 1H), 2.15 (dt, 1H, J ) 2.7, 11.1 Hz), 2.32 (s,
3H), 2.44 (dd, 1H, J ) 3.3, 11.4 Hz), 2.81 (dq, 1H, J ) 3.6,
11.4 Hz), 2.96-3.08 (m, 2H), 3.09-3.17 (m, 1H), 3.23 (dd, 1H,
J ) 2.1, 11.7 Hz), 3.46 (s, 3H), 7.38-7.48 (m, 3H), 7.69-7.83
(m, 4H). Anal. (C18H21NO2) C, H, N.
(+)-Meth yl 1-Meth yl-4â-(2-n a p h th yl)p ip er id in e-3r-ca r -
boxyla te (7). A solution of (-)-6 (0.12 g, 0.42 mmol) and
sodium methoxide (30% in MeOH, 5 drops) in MeOH (5 mL)
was stirred at reflux for 24 h. The solvent was removed in
vacuo to give an oil. Flash chromatography gave the title
compound (110 mg, 93%) as an oil which solidified upon
standing: mp 71-72 °C; [R]D +50.4° (c 0.51, CHCl3); 1H NMR
(CDCl3) δ 1.85-2.10 (m, 2H), 2.18 (dt, 1H, J ) 3.3, 11.1 Hz),
2.26 (t, 1H, J ) 10.8 Hz), 2.38 (s, 3H), 2.90-3.20 (m, 4H), 3.38
(s, 3H), 7.36-7.48 (m, 3H), 7.65 (s, 1H), 7.74-7.82 (m, 3H).
Anal. (C18H21NO2) C, H, N.
(-)-Meth yl 1-Meth yl-4â-(2-n a p h th yl)p ip er id in e-3r-ca r -
boxyla te (9) was prepared similarly to piperidine (+)-7. From
piperidine (+)-8 (0.15 g, 0.53 mmol) was obtained piperidine
(-)-9 (140 mg, 93%) as an oil which solidified upon standing:
mp 71-72 °C; [R]D -51.2° (c 0.33, CHCl3); 1H NMR (CDCl3) δ
1.85-2.10 (m, 2H), 2.18 (dt, 1H, J ) 3.3, 11.4 Hz), 2.26 (t, 1H,
J ) 10.5 Hz), 2.38 (s, 3H), 2.90-3.20 (m, 4H), 3.38 (s, 3H),
7.36-7.48 (m, 3H), 7.65 (s, 1H), 7.74-7.82 (m, 3H). Anal.
(C18H21NO2) C, H, N.
(()-Meth yl 1-Meth yl-4â-(1-n a p h th yl)p ip er id in e-3â-ca r -
boxyla te (10). To a stirred suspension of Mg (480 mg, 20.0
mmol) in ether (20 mL) were added I2 (2-3 crystals) and
R-bromonaphthalene (0.5 mL, 3.6 mmol), and the mixture was
heated until the color of I2 disappeared. To this mixture was
added R-bromonaphthalene (2.30 mL, 16.4 mmol) in ether (20
IR (film) 772, 842, 1168, 1739, 2784, 2942 cm-1 1H NMR
;
(CDCl3) δ 1.73-1.85 (m, 1H), 2.07 (dt, 1H, J ) 2.7, 11.4 Hz),
2.28 (s, 3H), 2.35 (dd, 1H, J ) 3.3, 11.4 Hz), 2.64 (dq, 1H, J )
3.3, 11.7 Hz), 2.72-2.82 (m, 1H), 2.92-3.04 (m, 2H), 3.18 (d,
1H, J ) 11.4 Hz), 3.55 (s, 3H), 7.05 (d, 2H, J ) 8.4 Hz), 7.59
(d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 26.6, 41.7, 46.3, 46.8,
51.6, 56.1, 58.6, 91.7, 130.0, 137.3, 143.0, 172.7; MS m/z% 44
(100), 300 (17), 359 (M+, 13). Anal. (C14H18INO2) C, H, N.
(-)-Meth yl 1-Meth yl-4â-(4-vin ylp h en yl)p ip er id in e-3â-
ca r boxyla te (14). A solution of piperidine (-)-13 (223 mg,
0.720 mmol), a catalytic amount of 4-tert-butylcatechol, tri-
phenylphosphine (18 mg, 0.069 µmol), vinyltributyltin (240 µL,
800 µmol), and Pd(PPh3)4 (30 mg, 0.026 mmol) in dioxane (7
mL) was stirred at reflux for 6 h. The mixture was cooled to
room temperature and then diluted with pyridine-HF (1 M in
THF, 2.0 mL). The resulting solution was stirred at room
temperature for 16 h, diluted with ether (30 mL), and filtered
through a small pad of Celite. The filtrate was washed with
aqueous NH4Cl (20 mL), water (20 mL), and brine (20 mL),
dried over Na2SO4, and concentrated to give an oil. Flash
chromatography (ether/Et3N, 99:1) gave the title compound
(100 mg, 54%) as a crystalline solid: mp 68-69 °C; [R]D -27.6°
(c 0.46, CHCl3); IR (KBr) 850, 1016, 1165, 1241, 1629, 1745,
1
2783, 2942 cm-1; H NMR (CDCl3) δ 1.78-1.88 (m, 1H), 2.09
(dt, 1H, J ) 2.7, 11.1 Hz), 2.29 (s, 3H), 2.37 (dd, 1H, J ) 3.3,
11.4 Hz), 2.68 (dq, 1H, J ) 3.6, 12.0 Hz), 2.78-2.87 (m, 1H),
2.93-3.02 (m, 2H), 3.18 (dd, 1H, J ) 1.5, 11.1 Hz), 3.52 (s,
3H), 5.20 (d, 1H, J ) 10.8 Hz), 5.71 (d, 1H, J ) 17.4 Hz), 6.68
(dd, 1H, J ) 10.8, 17.4 Hz), 7.25 (d, 2H, J ) 8.1 Hz), 7.34 (d,
2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 26.9, 41.8, 46.4, 46.9,
51.5, 56.2, 58.6, 113.4, 126.2, 128.0, 135.7, 136.8, 143.0, 172.9;
MS m/z% 44 (100), 200 (16), 259 (M+, 14). Anal. (C16H21NO2)
C, H, N.
(-)-Meth yl 4â-(4-Eth ylp h en yl)-1-m eth ylp ip er id in e-3â-
ca r boxyla te (15). A suspension of piperidine (-)-14 (200 mg,

SAR Studies of Piperidine-Based Analogues of Cocaine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1221
0.772 mmol) and Pd/C (10%, 20 mg) in MeOH (10 mL) was
stirred at room temperature under H2 (1 atm) for 2 h. The
catalyst was removed by filtration, and the filtrate was
concentrated to afford the title compound (195 mg, 97%) as
an oil which solidified upon standing: [R]D ) -26.3° (c 0.48,
CHCl3); IR (film) 778, 843, 1017, 1164, 1241, 1379, 1515, 1746,
for 16 h, diluted with ether (30 mL), and filtered through a
small pad of Celite. The filtrate was washed with NH4Cl (20
mL), dried over Na2SO4, and concentrated to give a solid. Flash
chromatography (ether/Et3N, 99:1) gave the title compound (32
mg, 41%) as a white solid: mp 120-121 °C; [R]D -25.3° (c 0.47,
1
CHCl3); IR (film) 764, 1170, 1738, 2782, 2954 cm-1; H NMR
1
2782, 2963 cm-1; H NMR (CDCl3) δ 1.21 (t, 3H, J ) 7.5 Hz),
(CDCl3) δ 1.87 (dd, 1H, J ) 3.0, 12.3 Hz), 2.11 (dt, 1H, J )
2.7, 11.1 Hz), 2.30 (s, 3H), 2.40 (dd, 1H, J ) 3.6, 11.7 Hz),
2.73 (dq, 1H, J ) 3.3, 12.0 Hz), 2.82-2.94 (m, 1H), 2.94-3.09
(m, 2H), 3.18 (dd, 1H, J ) 1.8, 11.4 Hz), 3.55 (s, 3H), 7.28-
7.47 (m, 5H), 7.48-7.61 (m, 4H); 13C NMR (CDCl3) δ 26.9, 41.8,
46.4, 46.9, 51.5, 56.2, 58.7, 127.0, 127.2, 127.3, 128.3, 128.9,
139.2, 141.1, 142.4, 173.0; MS m/z (%) 44 (100), 250 (5), 309
(M+, 6). Anal. (C20H23NO2) C, H, N.
1.76-1.87 (m, 1H), 2.08 (dt, 1H, J ) 2.7, 11.1 Hz), 2.28 (s,
3H), 2.37 (dd, 1H, J ) 3.6, 11.7 Hz), 2.61 (q, 2H, J ) 7.5 Hz),
2.64-2.75 (m, 1H), 2.76-2.86 (m, 1H), 2.92-3.04 (m, 2H), 3.16
(dd, 1H, J ) 2.1, 11.4 Hz), 3.52 (s, 3H), 7.11 (d, 2H, J ) 8.1
Hz), 7.21 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3) δ 15.6, 27.0,
28.5, 41.6, 46.4, 46.8, 51.3, 56.2, 58.5, 127.7, 140.4, 142.1, 173.0;
MS m/z% 44 (75), 70 (100), 202 (25), 261 (M+, 22). Anal.
(C16H23NO2) C, H, N.
(-)-Meth yl 4â-(2-Na p h th yl)p ip er id in e-3r-ca r boxyla te
Hyd r och lor id e (-)-19. A suspension of piperidine (-)-9 (30
mg, 0.11 mmol), 1,8-bis-(dimethylamino)naphthalene (50 mg,
0.23 mmol), and R-chloroethyl chloroformate (0.10 mL) in 1,2-
dichloroethane (6 mL) was stirred at reflux for 3 h. The
mixture was cooled to room temperature, diluted with HCl/
ether (1.0 M, 20 mL), and the resulting suspension was passed
through a short path of silica gel. The silica gel was washed
with CH2Cl2, and the combined fractions were evaporated in
vacuo to give an oil. The oil was dissolved in MeOH (14 mL),
and the solution was stirred at reflux for 3 h. The solvent was
removed in vacuo to give an oil. This oil was dissolved in ether
(3 mL) and treated with HCl/ether (1.0 M, 1 mL), and the
resulting suspension was stirred at room temperature for 1
h. The solid was removed by filtration and washed with ether
(2 × 5 mL) to give the title compound (24 mg, 71%) as a white
solid: mp 78-80 °C; [R]D -55° (c 0.25, CHCl3); 1H NMR (CD3-
OD) δ 2.18 (m, 2H), 3.2-3.4 (m, 3H), 3.40 (s, 3H), 3.56 (d, 1H,
J ) 12.6 Hz), 3.70 (d, 1H, J ) 12.2 Hz), 3.29 (dd, 1H, J ) 3.6,
12.0 Hz), 7.30-7.40 (m, 3H), 7.73 (s, 1H), 7.89 (m, 3H). Anal.
(C17H19NO‚1.1HCl) C, H, N.
Biologica l Meth od s. Syn a p tosom a l Up ta k e of [3H]-
Dop a m in e. The effect of candidate compounds in antagonizing
dopamine high affinity uptake was determined using a method
previously employed. For [3H]DA uptake, dissected rat striata
were homogenized with a Teflon-glass pestle in ice-cold 0.32
M sucrose and centrifuged for 10 min at 1000g. The superna-
tant was centrifuged at 17500g for 20 min. This P2 synapto-
somal pellet was resuspended in 30 volumes of ice-cold
modified KRH buffer. An aliquot of the synaptosomal suspen-
sion was preincubated with the buffer and drug for 30 min at
37 °C, and uptake was initiated by the addition of [3H]-
dopamine (3-5 nM, final concentration). After 5 min, uptake
was terminated by adding 5 mL of cold buffer containing
glucosamine as a substitute for NaCl and then finally by rapid
vacuum filtration over GF-C glass fiber filters, followed by
washing with two 5 mL volumes of ice-cold, sodium-free buffer.
Radioactivity retained on the filters was determined by liquid
scintillation spectrometry. Specific uptake was defined as that
which is sensitive to inhibition by 30 µM cocaine. It is identical
to that calculated by subtracting the mean of identical tubes
incubated at 0 °C. The Km for [3H]DA uptake in this assay is
50 nM.
Syn a p tosom a l Up ta k e of [3H]5-Hyd r oxytr yp ta m in e
a n d [3H]Nor ep in ep h r in e. [3H]5-HT and [3H]NE uptake were
measured in an entirely analogous fashion using synaptosomes
prepared from rat midbrain or parietal and occipital cortices,
respectively. The same buffer was used in all uptake and
binding assays. The specific uptake of [3H]5-HT and [3H]NE
was defined with 10 µM fluoxetine or 3 µM desipramine,
respectively. The Km values and substrate concentrations used
for calculating Ki from IC50 values in uptake experiments were
53 nM and 4-5 nM for [3H]5-HT and 54 nM and 8-10 nM for
[3H]NE.
Locom otor Stu d ies. Locomotor activity of male Swiss-
Webster mice was recorded using Truscan activity monitors
(Coulbourn Instruments, Allentown, PA) and a computer. The
activity monitors consist of acrylic chambers which are placed
inside the sensor ring. The sensor ring is equipped with light-
sensitive detectors and infrared light beams. The X-Y coor-
(-)-Meth yl 1-Meth yl-4â-[4-(2-p r op en yl)p h en yl]-p ip er i-
d in e-3â-ca r boxyla te (16). A solution of piperidine (-)-13 (90
mg, 0.24 mmol), 4-tert-butylcatechol (catalytic), triphenylphos-
phine (37 mg, 0.14 mmol), allyltributyltin (0.11 mL, 0.35
mmol), and Pd(PPh3)4 (40 mg, 0.034 mmol) in dioxane (5 mL)
was stirred at reflux for 1.5 h. The solvent was removed in
vacuo to give an yellow oil which was dissolved in ether (30
mL) and extracted with hydrochloric acid (1 M, 3 × 10 mL).
The combined aqueous layers were neutralized with saturated
aqueous sodium bicarbonate and extracted with CH2Cl2 (3 ×
30 mL). The combined organic extract was dried over Na2SO4
and concentrated to give a solid. Flash chromatography (ether/
Et3N, 99:1) gave the title compound (51 mg, 75%) as an oil
that solidified upon standing: [R]D -30.0° (c 0.45, CHCl3); IR
(film) 913, 1017, 1164, 1638, 1746, 2782, 2941 cm-1; 1H NMR
(CDCl3) δ 1.82 (dd, 1H, J ) 2.7, 12.3 Hz), 2.11 (dt, 1H, J )
2.4, 10.8 Hz), 2.29 (s, 3H), 2.38 (dd, 1H, J ) 3.3, 11.4 Hz),
2.67 (dq, 1H, J ) 3.3, 12.0 Hz), 2.76-2.88 (m, 1H), 2.92-3.04
(m, 2H), 3.16 (dd, 1H, J ) 2.1, 11.4 Hz), 3.34 (d, 2H, J ) 6.6
Hz), 3.55 (s, 3H), 5.00-5.12 (m, 2H), 5.88-6.02 (m, 1H), 7.11
(d, 2H, J ) 7.8 Hz), 7.22 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3)
δ 27.0, 40.0, 41.7, 46.4, 46.8, 51.5, 56.2, 58.5, 115.8, 127.9,
128.5, 137.7, 138.0, 141.0, 173.0; MS m/z% 44 (100), 214 (8),
258 (1), 273 (M+, 7). Anal. (C17H23NO2) C, H, N.
(-)-Meth yl 4â-(4-Eth yn ylp h en yl)-1-m eth ylp ip er id in e-
3â-ca r boxyla te (17). To a solution of piperidine 13 (223 mg,
0.620 mmol) in diisopropylamine (7.0 mL) in a pressure tube
were added CuI (7.0 mg, 0.037 mmol), and bis(triphenyl-
phosphine)palladium(II) chloride (44 mg, 0.062 mmol) followed
by trimethylsilylacetylene (0.11 mL, 0.77 mmol), and the
mixture was stirred for 3 h at 100 °C. The residue was diluted
with EtOAc (20 mL), filtered through a plug of silica gel, and
concentrated under reduced pressure to give an oil. The oil
was dissolved in THF (6 mL) and added to tetrabutylammo-
nium fluoride (1.0 M in THF, 0.8 mL) dropwise at 0 °C. The
solution was stirred for 5 min and diluted with saturated
aqueous sodium bicarbonate (20 mL), and the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL). The combined extracts
were dried over Na2SO4 and concentrated to give an oil.
Column chromatography (ether/Et3N, 99:1) gave the title
compound (126 mg, 79%) as a white solid: mp 48-50 °C; [R]D
) -29.8° (c 0.57, CHCl3); IR (film) 849, 1017, 1168, 1741, 2785,
2943, 3289 cm-1 1H NMR (CDCl3) δ 1.82 (dd, 1H, J ) 3.3,
;
12.9 Hz), 2.11 (dt, 1H, J ) 2.7, 11.1 Hz), 2.28 (s, 3H), 2.38 (dd,
1H, J ) 3.6, 11.7 Hz), 2.66 (dq, 1H, J ) 3.9, 11.7 Hz), 2.82 (dt,
1H, J ) 3.9, 12.0 Hz), 2.92-3.00 (m, 2H), 3.03 (s, 1H), 3.16
(dd, 1H, J ) 1.8, 11.4 Hz), 3.55 (s, 3H), 7.25 (d, 2H, J ) 8.1
Hz), 7.42 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3) δ 26.6, 41.9,
46.2, 46.8, 51.5, 56.0, 58.5, 77.0, 83.9, 120.0, 127.8, 132.1, 144.3,
172.7; MS m/z% 44 (100), 198 (9), 257 (M+, 6). Anal. (C16H19
-
NO2) C, H, N.
(-)-Meth yl 1-Meth yl-4â-(4-p h en ylp h en yl)-p ip er id in e-
3â-ca r boxyla te (18). A suspension of piperidine (-)-13 (78
mg, 0.25 mmol), a few crystals of 4-tert-butylcatechol, tri-
phenylphosphine (approximately 5 mg), trimethylphenyltin (72
mg, 0.30 mmol), and Pd(PPh3)4 (20 mg, 0.017 mmol) in dioxane
(4.0 mL) was heated at reflux for 12 h. The solution was cooled
to room temperature and diluted with pyridine-HF (1 M, 0.5
mL). The resulting solution was stirred at room temperature

1222 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Tamiz et al.
P. W.; Maidment, K.; Pheleps, M. E.; Baxter, L. R., J r. FDG-
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dinates of the body center of the subject are sampled by
scanning the beams, and then the successive locations of
coordinates are compared. The sum of distances between
successive coordinates is measured as the distance traveled,
while the total number of coordinate changes are recorded as
the stereotypic movements. Following 1 h of habituation to
test arenas, several groups of mice were injected intraperito-
neally with different doses of cocaine, piperidine 14, or saline
in a volume of 10 mL/kg. Locomotor activity was recorded in
10 min bins for the next 2 h. The raw data were converted to
30 min totals. The maximal 30 min activity, occurring within
the 2 h session following test drug injection, was determined
for each dose level and used for plotting dose-response curves.
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Baldessarini, R. J . Combining Serotonin Reuptake Inhibitors
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therapy. J . Clin. Psychiatry 1997, 58, 137-145.
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Ack n ow led gm en t. We are indebted to the National
Institute of Health, National Institute of Drug Abuse
(DA10458), for their support of these studies.
Su p p or tin g In for m a tion Ava ila ble: Analytical data for
compounds listed in Table 1 and tables of crystal data, atomic
coordinates, bond lengths, bond angles, anisotropic displace-
ment parameters, hydrogen coordinates, and isotropic dis-
placement parameters for (-)-4. This material is available free
of charge via the Internet at http://pubs.acs.org.
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