Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis and biological evaluation of 1-(arylalkynyl)-4-benzylpiperidines

Article abstract of DOI:10.1021/jm990148x

A search of our compound library for compounds with structural similarity to ifenprodil (5) and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B potency, while addition of hydrogen bond donors in the para position of the phenyl group enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine group slightly reduced NR1A/2B potency while reducing α-1 adrenergic and dopamine D2 receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl > pentynyl >> propynyl. For the para methanesulfonamide or hydroxyl groups, the order was butynyl ? propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA in the 6-hydroxydopamine-lesioned rat, a model of Parkinson's disease, dosed at 10 mg/kg ip, but 48 was not active at 30 mg/kg po.

Full text of DOI:10.1021/jm990148x

J . Med. Chem. 1999, 42, 2469-2477
2469
Su btyp e-Selective N-Meth yl-D-a sp a r ta te Recep tor An ta gon ists: Syn th esis a n d
Biologica l Eva lu a tion of 1-(Ar yla lk yn yl)-4-ben zylp ip er id in es
J on L. Wright,* Tracy F. Gregory, Christopher F. Bigge, Peter A. Boxer, Kevin Serpa, Leonard T. Meltzer, and
Lawrence D. Wise
Departments of Chemistry and Therapeutics, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company,
Ann Arbor, Michigan 48105
Sui Xiong Cai, J on E. Hawkinson, Christopher S. Konkoy, Edward R. Whittemore, Richard M. Woodward, and
Zhang-Lin Zhou
CoCensys, Inc., 201 Technology Drive, Irvine, California 92618
Received March 29, 1999
A search of our compound library for compounds with structural similarity to ifenprodil (5)
and haloperidol (7) followed by in vitro screening revealed that 4-benzyl-1-(4-phenyl-3-butynyl)-
piperidine (8) was a moderately potent and selective antagonist of the NR1A/2B subtype of
NMDA receptors. Substitution on the benzyl group of 8 did not significantly affect NR1A/2B
potency, while addition of hydrogen bond donors in the para position of the phenyl group
enhanced NR1A/2B potency. Addition of a hydroxyl moiety to the 4-position of the piperidine
group slightly reduced NR1A/2B potency while reducing R-1 adrenergic and dopamine D2
receptor binding affinities substantially, resulting in improved overall selectivity for NR1A/2B
receptors. Finally, the butynyl linker was replaced with propynyl or pentynyl. When the phenyl
was para substituted with amine or acetamide groups, the NR1A/2B potency order was butynyl
> pentynyl . propynyl. For the para methanesulfonamide or hydroxyl groups, the order was
butynyl ≈ propynyl > pentynyl. The hydroxyl propyne (48) and butyne (23) were among the
most potent NR1A/2B antagonists from this study. They both potentiated the effects of L-DOPA
in the 6-hydroxydopamine-lesioned rat, a model of Parkinson’s disease, dosed at 10 mg/kg ip,
but 48 was not active at 30 mg/kg po.
In tr od u ction
acutely life-threatening situation of stroke, they are
unacceptable in the treatment of neurodegenerative
diseases where chronic drug administration is required.
Mammalian NMDA receptors are ligand-gated ion
channels composed of hetero-oligomeric combinations of
NR1 subunits (found in eight splice variants) and at
least one of four NR2 subunits, designated NR2A-
NR2D.9 The existence of distinct NMDA receptor sub-
types offers potential new classes of NMDA receptor
modulators. Subtype-selective NMDA antagonists might
retain therapeutic utility without the side effects as-
sociated with nonselective NMDA receptor antagonists.
The R-1 adrenergic antagonist ifenprodil (5) was
discovered to be neuroprotective both in vitro and in
animal models of stroke.10 Ifenprodil was later shown
to be an antagonist at native NMDA receptors and at
the NR1A/2B combination of subunits expressed in
Xenopus oocytes. Unfortunately, ifenprodil’s activity at
R-1 adrenergic receptors meant that its neuroprotective
properties were compromised by hypotension, an unde-
sirable side effect in stroke patients.
The excitatory neurotransmitter L-glutamic acid
(glutamate) plays a key role in the neuronal death
associated with stroke and head trauma.1 High levels
of glutamate released during such events hyperactivate
glutamate receptors, allowing toxic increases in calcium
ion flux into neurons. In addition, glutamate receptor
overstimulation may also be involved in chronic neuro-
degenerative conditions, such as Alzheimer’s disease2
and Parkinson’s disease.3
There is strong evidence that much of the toxicity
associated with high levels of glutamate is mediated by
N-methyl-D-aspartate (NMDA) receptors. For example,
NMDA receptor antagonists have been shown to protect
neurons in vitro, both in response to neurotoxic levels
of L-glutamic acid or N-methyl-D-aspartic acid. In ad-
dition, NMDA receptor antagonists offer neuroprotec-
tion in models of focal ischemia in animals.4
First-generation NMDA receptor antagonists fall into
three main classes: competitive antagonists at the
glutamate binding site, such as CGS 19755 (selfotel)5
(1) (see Chart 1); noncompetitive antagonists at a
channel site, such as MK 801 (dizocilpine)6 (2) and PCP
(phencyclidine)7 (3) (“ion-channel blockers”); and glycine
site antagonists, such as ACEA 1021 (licostinel)8 (4).
Antagonists acting at these sites are neuroprotective;
however, many of them cause psychotomimetic side
effects. While these side effects may be tolerable in the
Using ifenprodil as a starting point, Pfizer developed
CP-101,606 (6).11 This compound is a potent NR1A/2B
antagonist with weak R-1 adrenergic antagonist activity.
CP-101,606 is neuroprotective in vitro, confirming that
selective NR1A/2B antagonists can act as neuropro-
tectants. More significantly, 6 reduced neuronal damage
in a cat model of stroke.12 In addition, 6 does not appear
to show PCP-like psychotomimetic behavioral effects.13
10.1021/jm990148x CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/05/1999

2470 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Wright et al.
Ch a r t 1
Sch em e 1
dine as solvent. The use of pyrrolidine accelerated the
rate of the couplings compared to alternate conditions,
such as Pd(PPh3)4/n-BuNH2. In most cases, the aryl
iodide was used; coupling proceeded at room tempera-
ture and was complete in a few hours. Yields were
variable, and often several purification steps were
necessary to produce pure product. In most cases, a
crystallization was performed as the last step; this
usually ensured that the material would pass elemental
analysis, but decreased yields. Optimization of the
reaction conditions and purification schemes was not
attempted and would likely increase many of the yields
reported.
The Pd(PPh3)4/pyrrolidine conditions also worked
with aryl bromides, although elevated temperatures
were needed for coupling to proceed. Stirring at 50 °C
overnight was sufficient in most cases for complete
consumption of starting materials. In some cases, the
nucleophilicity of the pyrrolidine solvent was an issue.
If the halide was activated toward displacement, such
as in 4-bromonitrobenzene, or the aryl group contained
displaceable functional groups, such as esters, then the
Pd(PPh3)4/pyrrolidine conditions could not be used.
Instead, the less reactive Pd(PPh3)4/n-BuNH2 conditions
were employed. The temperatures had to be further
elevated to reflux (80 °C) for coupling to occur.
The dopamine antagonist haloperidol (7) is also a
NR1A/2B receptor antagonist.14 To find novel NR1A/2B-
selective ligands, we conducted similarity structure
searches of our compound library based on the struc-
tures of ifenprodil and haloperidol. We identified com-
pounds with varying levels of structural overlap and
tested them in oocytes expressing the various NMDA
receptor subtype combinations. Among others, com-
pound 8 was found to be a moderately potent, selective
NR1A/2B antagonist. In this paper we report the results
of our structure-activity (SAR) studies around 8 de-
signed to optimize NR1A/2B potency and monitor selec-
tivity versus other receptors. We studied the effects of
substitution on the benzyl and phenyl groups, altering
the alkyne chain length, and substituting a hydroxyl
group at the 4-position of the piperidine.
P h a r m a cology
All compounds were tested for inhibitory activity at
NR1A/2A, NR1A/2B, and NR1A/2C receptors expressed
in Xenopus oocytes using electrophysiological tech-
niques.15 Compounds that possessed good activity and
selectivity for the NR1A/2B receptor were further pro-
filed in R-1 adrenergic (displacement of [3H]prazosin
from rat brain cortical membranes)16 and dopamine D2
(displacement of [3H]raclopride from rat brain striatal
membranes)17 receptor binding assays. Compounds with
potency and selectivity for NR1A/2B receptors were
tested in the 6-hydroxydopamine-lesioned rat, a model
of Parkinson’s disease, for increases in the number of
Ch em istr y
The compounds in Tables 1-3 were most conveniently
prepared via the general synthesis outlined in Scheme
1. The benzylpiperidines 9a -g were reacted with com-
mercially available alkynyl tosylates or chlorides. The
palladium-assisted coupling of aryl halides to benzylpi-
peridine alkynes 13a , 14a -g, and 15a was most reliably
accomplished using Pd(PPh3)4 as catalyst with pyrroli-

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2471
Ta ble 1. NMDA Receptor Activity for Phenyl Analogues of Compound 8
IC50 (µM)
compd
R2
NR1A/2Aa
NR1A/2B
NR1A/2C
R-1b
DA D2c
e
8
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
35
H
4-NO2
4-Cl
3-Cl
2-Cl
4-F
4-Me
4-MeO
4-OH
>100 (1)d
>100 (1)
47 (1)
4.7 ( 1.5 (3)
5.0 ( 0.7 (3)
4.0 (2)
>100 (1)
>100 (1)
>100 (1)
>100 (2)
>100 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (2)
>100 (4)
>100 (2)
>100 (1)
>100 (1)
>100 (2)
>100 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (2)
>100 (1)
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
>100 (1)
3.8 ( 1.0 (4)
1.2 ( 0.1 (3)
2.7 ( 1.0 (3)
4.2 ( 1.8 (3)
2.6 ( 0.4 (3)
0.17 ( 0.03 (3)
0.43 ( 0.1 (6)
0.46 ( 0.08 (3)
15 (2)
0.26 ( 0.05 (3)
0.24 ( 0.04 (4)
1.1 (2)
1.1 (2)
2.0 (2)
85 (1)
>100 (1)
42 (1)
>100 (1)
>100 (2)
>100 (3)
84 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (1)
70 (1)
0.58 ( 0.07
0.29 ( 0.03
4-NH2
1.0
1.0
-
1.1
1.2
-
0.8
0.3
-
0.1
0.2
-
-
-
4-NHMe
4-NMe2
4-NHAc
4-NHSO2Me
3-NH2
2-NH2
-
-
4-CONH2
4-SO2NH2
3-CH2NH2
3,4-(NH2)2
>100 (1)
22 (1)
0.31 ( 0.08 (3)
0.52 ( 0.1 (5)
0.19 ( 0.03 (3)
1.4
0.8
1.0
0.1
0.3
1.1
15 (1)
>100 (2)
a
IC50 values for inhibition of NMDA reponses at cloned NMDA receptors expressed in Xenopus oocytes. Number of determinations (n)
b
shown in parentheses. Data are presented as mean ( SEM. Compounds were evaluated at nine concentrations for the displacement of
[3H]prazosin from rat brain cortices and an IC50 was calculated; n ) 1 for screening data, n ) 3 for key compounds ((95% confidence
limits). c Compounds were evaluated at nine concentrations for the displacement of [3H]raclopride from rat brain striata, and an IC50 was
calculated; n ) 1 for screening data, n ) 3 for key compounds ((95% confidence limits). Less than 50% inhibition at 100 µM. e Not
d
tested.
contraversive (to the side of lesion) rotations produced
by L-DOPA over a 6-h period.18
para-aniline 24. Comparing the phenol 23 with the less
active methoxy analogue 22 suggested that the hydro-
gen bond-donating ability of 23 was responsible for the
improved NR1A/2B potency. This was confirmed by
comparison of the N-methylaniline 25 and dimethyl-
aniline 26. Monomethyl compound 25 was equipotent
with aniline 24, while the dimethyl aniline 26, which
does not contain a hydrogen bond donor, was 100-fold
less potent as a NR1A/2B antagonist. While the phenol
23 might be slightly more potent than the aniline 24 at
the NR1A/2B receptor, we studied the aniline 24 in more
detail as we could not derivatize the phenol 23 while
maintaining a hydrogen bond donor. Initially we pre-
pared the acetamide (compound 27) and sulfonamide
(compound 28) derivatives of 24; the increased NH
hydrogen bond-donating ability of 27 and 28 versus 24
is reflected by their increased NR1A/2B potency.
The location of this hydrogen bond donor was impor-
tant; moving the amino group of 24 to the meta
(compound 29) or ortho (compound 30) positions reduced
NR1A/2B potency. Extending the hydrogen bond donor
away from the phenyl as in carboxamide 31 reduced
potency. However, the sulfonamide 32 and meta-ben-
zylamine 33 were similar or better in potency to aniline
24; the meta attachment of the aminomethyl group of
33 may allow the amine to occupy the same space as
the aniline at the NR1A/2B receptor. Addition of a
second hydrogen bond donor (the diamino analogue 35)
did enhance activity slightly; the potency was similar
to that of phenol 23.
Resu lts a n d Discu ssion
Our goals were to identify analogues of 8 with potent
activity at NR1A/2B receptors (IC50 < 1 µM) and weak
activity at NR1A/2A and NR1A/2C receptors (IC50’s >
10 µM). This requirement would increase confidence
that these compounds were acting at the NR1A/2B site
in vivo. As these structures were related to ifenprodil
(R-1 adrenergic receptor antagonist) and haloperidol
(dopamine D2 antagonist), we determined R-1 adren-
ergic and dopamine D2 receptor affinity for key ana-
logues. To reduce the chances that we would see R-1
adrenergic or dopaminergic effects in vivo, the goal was
to attain IC50’s in these assays greater than 1 µM.
Our initial studies explored the effects of changing
electron density of the acetylenic phenyl group of 8.
Compounds 16, 17, and 20 contain a para-electron-
withdrawing substituent. These compounds had NR1A/
2B potencies similar to that of the phenyl parent 8.
Moving the chloro substituent to the meta or ortho
positions (compounds 18 and 19) also did not produce a
significant change in potency.
The 4-methyl analogue 21 and the 4-methoxy ana-
logue 22 were synthesized to explore the effects of
electron-donating groups. Again neither analogue showed
significant differences from 8, and we concluded that
NR1A/2B potency of 8 was not sensitive to the relative
electron density of the phenyl group.
Key compounds in Table 1 were tested for their R-1
adrenergic and dopamine D2 receptor affinities. The R-1
IC50’s were clustered around 1 µM, and D2 IC50’s were
The first analogues synthesized that had submicro-
molar NR1A/2B IC50 values were the para-phenol 23 and

2472 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Wright et al.
Ta ble 2. NMDA Receptor Activity for Benzyl and Piperidinyl
Analogues of 24
The final study optimized the length of the alkynyl
chain connecting the piperidine to the aromatic ring.
Again we used aniline 24 as a standard template. As
several other compounds from Table 1 showed similar
NR1A/2B potency, we also studied the chain length effect
on the potency of acetamide 27, sulfonamide 28, and
phenol 23. This would include compounds that may
orient the hydrogen bond donor slightly differently at
NR1A/2B receptors and may therefore behave differently
as the chain length was altered. As the butyne moiety
of aniline 24 was shortened to propyne (compound 42,
Table 3), the NR1A/2B potency reduced sharply. How-
ever, when it was lengthened to pentyne (compound 43),
the NR1A/2B potency was essentially the same. A
similar trend was seen with the acetamide 27; the
shorter analogue 44 lost NR1A/2B potency sharply. In
this case, however, the longer analogue 45 was signifi-
cantly weaker. The sulfonamide series, 46, 28, and 47,
showed no sensitivity to chain length; the NR1A/2B
potency remained below 1 µM for all three compounds.
Finally, the phenol propynyl and butynyl analogues 48
and 23 had similar potency at NR1A/2B receptors.
The two phenolic compounds 48 and 23 were among
the most potent NR1A/2B antagonists tested from this
series. The propynylphenol 48 had moderately weak R-1
and dopamine D2 binding activity. These two com-
pounds were tested in the 6-hydroxydopamine-lesioned
rat, a model of Parkinson’s disease (see Figure 1). After
intraperitoneal administration at 10 mg/kg, they both
caused significant potentiation of the contraversive
rotations produced by L-DOPA at 10 mg/kg sc, but 48
did not show significant potentiation at 30 mg /kg orally.
In summary, we have developed a new series of
NMDA subtype-selective antagonists derived from ifen-
prodil and haloperidol. Substitution on the benzyl group
of 8 had little effect on NR1A/2B potency; however
addition of hydrogen bond donors to the 4-position of
the phenyl group caused large increases in potency. Two
of the most potent NR1A/2B antagonists showed sig-
nificant activity in a rat model of Parkinson’s disease
after intraperitoneal administration.
IC50 (µM)
compd R1
X
NR1A/2Aa
NR1A/2B
NR1A/2C R-1b DA D2c
24
36
37
38
39
40
41
H
Cl
F
Me
H
F
H
>100 (3)d 0.43 ( 0.1 (6) >100 (4) 1.0
0.8
-
0.4
0.8
15
e
H
H
H
>100 (1) 1.2 (2)
>100 (1)
-
70 (1) 0.26 ( 0.03 (3) >100 (1) 0.7
75 (1) 0.31 ( 0.03 (3) 27 (2) 1.2
OH >100 (1) 0.83 ( 0.12 (9) >100 (1) 63
OH 29 (1) 0.65 (2) >100 (1) 31
68 (1) 0.37 ( 0.06 (3) >100 (2) 85
7.9
10
Me OH
a-e For notes, see Table 1.
in the 0.1-0.3 µM range. While weaker than ifenprodil
or haloperidol, it was expected that reducing these
binding affinities would minimize the possibility of
seeing dopamine D2 or R-1 adrenergic side effects in
vivo. Hence compound 24, containing a 4-amino sub-
stituent on the phenyl group, was chosen as a template
for study of structure changes elsewhere in the mol-
ecule.
The compounds in Table 2 are examples of anilines
that have substituents on the benzyl group and/or a
4-hydroxy substituent on the piperidine group. Placing
a chloro group para on the benzyl (compound 36)
reduced NR1A/2B potency, while a fluoro or methyl
group (compounds 37 and 38, respectively) did not
significantly change the NR1A/2B potency. Addition of
a hydroxyl group to the 4-position of the piperidine of
compounds 24 and 37 gave compounds 39 and 40. While
they showed a modest 2-3-fold drop in NR1A/2B
potency, the affinities at R-1 and D2 receptors for 40
versus 37 have dropped over 10-fold. Comparison of
4-methylbenzyl pair 38 and 41 revealed that addition
of the 4-hydroxy group does not effect NR1A/2B potency
while again reducing the R-1 and D2 affinities over 10-
fold. Thus substitution on the benzyl group did not
improve NR1A/2B potency significantly while addition
of a 4-hydroxyl group onto the piperidine ring appeared
to increase selectivity for NR1A/2B receptors over R-1
adrenergic and dopamine D2 receptors.
Exp er im en ta l Section
Melting points were determined on a Gallenkamp capillary
melting point apparatus and are uncorrected. 1H NMR spectra
were determined on Varian Unity 400 spectrometers. Mass
Ta ble 3. NMDA Receptor Activity for Chain Length Analogues
IC50 (µM)
compd
R2
NH2
NH2
NH2
NHAc
NHAc
NHAc
NHSO2Me
NHSO2Me
NHSO2Me
OH
n
NR1A/2Aa
NR1A/2B
NR1A/2C
R-1b
DA D2c
e
42
24
43
44
27
45
46
28
47
48
23
1
2
3
1
2
3
1
2
3
1
2
>100 (1)d
>100 (3)
12 (1)
12 ( 2 (4)
>100 (1)
>100 (4)
>100 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (2)
>100 (1)
>100 (2)
>100 (2)
-
-
0.43 ( 0.1 (6)
1.0
-
0.8
0.38 (2)
-
-
56 (1)
13 (2)
-
>100 (1)
>100 (1)
>100 (1)
>100 (1)
>100 (2)
>100 (2)
>100 (2)
0.26 ( 0.05 (3)
1.4 ( 0.2 (3)
0.15 ( 0.03 (7)
0.24 ( 0.04 (4)
0.28 ( 0.05 (3)
0.10 ( 0.01 (5)
0.17 ( 0.03 (4)
1.1
-
2.2
1.1
1.1
0.1
-
12
0.2
2.3
1.7 ( 0.1
0.29 ( 0.03
1.5 ( 0.5
0.58 ( 0.07
OH
a-e For notes, see Table 1.

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2473
2H), 7.36 (d, J ) 6.0 Hz, 2H), 7.26 (d, J ) 8.0 Hz, 2H), 7.11 (d,
J ) 8.0 Hz, 2H), 6.08 (d, J ) 3.6 Hz, 2H), 5.68 (d, J ) 3.6 Hz,
1H), 2.25 (s, 3H).
This solid (11 g) was hydrogenated (50 psi H2) in MeOH
(200 mL) with concentrated HCl (5 mL) and 20% Pd/C (2 g)
for 16 h. The mixture was filtered and evaporated to leave a
white solid (11.2 g): 1H NMR (CDCl3) δ 7.02 (ABq, J ) 8.1
Hz, δν ) 20.7 Hz, 4H), 3.01 (d, J ) 12.5 Hz, 2H), 2.49 (dt, J )
1.7, 12.0 Hz, 2H), 2.44 (d, J ) 6.6 Hz, 2H), 2.28 (s, 3H), 1.51-
1.60 (m, 3H), 1.12 (m, 2H).
4-(4-F lu or oben zyl)-4-h yd r oxyp ip er id in e (9f). A stirred
slurry of Mg turnings (12 g, 0.49 mol) in 1,2-dibromoethane
(2 mL, 23.2 mmol) and THF (150 mL) was warmed slightly
and 4-fluorobenzyl chloride (Aldrich; 57.4 mL, 0.48 mol) in
THF (75 mL) added slowly. Occasional gentle heating was
required to keep the reaction going. After addition was
complete, the mixture was allowed to cool to room temperature
and stirred for 30 min. The mixture was diluted with THF
(150 mL) and cooled to -40 °C. N-Benzyl-4-piperidone (Aldrich;
25.3 mL, 0.14 mol) in THF (75 mL) was added dropwise and
the mixture allowed to warm to room temperature with
stirring overnight. The mixture was cooled in an ice bath and
saturated aqueous NH4Cl (250 mL) added. Once the mixture
had warmed to room temperature with stirring, water (500
mL) was added and the mixture extracted with EtOAc (3 ×
200 mL). The extracts were washed with brine (300 mL), dried
over MgSO4, filtered, and evaporated to leave a yellow solid.
This solid was purified by MPLC (400 g silica gel) loading in
CH2Cl2 and eluting with 100:8:1 CH2Cl2:EtOH:0.880 NH4OH
to give a yellow oil (29.5 g, 72%): 1H NMR (CDCl3) δ 7.19-
7.32 (m, 5H), 7.11 (m, 2H), 6.95 (t, J ) 8.7 Hz, 2H), 3.48 (s,
2H), 2.69 (s, 2H), 2.61 (m, 2H), 2.26 (t, J ) 10.6 Hz, 2H), 1.68
(dt, J ) 4.4, 12.6 Hz, 2H), 1.45 (d, J ) 12.0 Hz, 2H); HPLC
(70% pH 3 buffer:30% MeCN) 5.13 min (100%).
A portion of the oil (6.5 g, 21.7 mmol) was stirred in EtOH
(100 mL) and AcOH (1 mL) with 10% Pd/C (1 g) under H2
overnight. The mixture was filtered and evaporated. The
residue was purified by MPLC (200 g silica gel) eluting with
100:8:1 f 50:8:1 CH2Cl2:EtOH:0.880 NH4OH to give 9f as a
pale-yellow oil (3.48 g, 77%): 1H NMR (CDCl3) δ 7.12 (t, J )
8.3 Hz, 2H), 6.96 (t, J ) 8.7 Hz, 2H), 2.78-2.90 (m, 4H), 2.69
(s, 2H), 1.52-1.59 (m, 4H), 1.43 (d, J ) 12.5 Hz, 2H); HPLC
(80% 0.1% aqueous CF3CO2H:20% MeCN) 3.72 min (100%).
4-(4-Meth ylben zyl)-4-h yd r oxyp ip er id in e (9g). A proce-
dure identical to that described for the preparation of 9f using
4-methylbenzyl chloride gave 9g, which was isolated as the
HCl salt: 1H NMR (DMSO-d6) δ 9.02 (br s, 1H), 8.56 (br s,
1H), 7.03 (AA′BB′, 4H), 4.71 (br s, 1H), 2.86-2.99 (m, 4H),
2.61 (s, 2H), 2.21 (s, 3H), 1.59 (dt, J ) 4.6, 13.9 Hz, 2H), 1.45
(d, J ) 13.4 Hz, 2H).
4-Ben zyl-1-bu t-3-yn ylp ip er id in e (14a ). A mixture of
3-butyn-1-yl p-toluenesulfonate (11) (Lancaster; 29.9 g, 0.13
mol), 4-benzylpiperidine (9a ) (Aldrich; 21.2 mL, 0.12 mol), and
NaHCO3 (12.2 g, 0.15 mol) in DMF (300 mL) was stirred at
80 °C under N2 overnight. The DMF was evaporated under
high vacuum on a rotary evaporator and the residue treated
with water (500 mL) and extracted with ether (2 × 300 mL).
The combined extracts were washed with saturated brine (500
mL), dried over MgSO4, filtered, and evaporated to leave 14a
as a brown oil (24.8 g, 90%): 1H NMR (CDCl3) δ 7.23 (m, 2H),
7.11 (m, 3H), 2.85 (d, J ) 11.5 Hz, 2H), 2.50 (m, 4H), 2.33 (m,
2H), 1.85-1.95 (m, 3H), 1.60 (d, J ) 12.9 Hz, 2H), 1.47 (m,
1H), 1.28 (m, 2H).
4-(4-Ch lor oben zyl)-1-bu t-3-yn ylp ip er id in e (14b). A pro-
cedure identical to that described for the preparation of 14a
using 4-(4-chlorobenzyl)piperidine19 (9b) gave 14b: 1H NMR
(CDCl3) δ 7.26 (d, J ) 8.1 Hz, 2H), 7.04 (d, J ) 8.1 Hz, 2H),
2.88 (d, J ) 11.1 Hz, 2H), 2.55 (m, 2H), 2.48 (m, 2H), 2.38 (m,
2H), 1.96 (m, 3H), 1.59 (m, 2H), 1.50 (m, 1H), 1.31 (m, 2H); EI
MS m/z 261 (M+, 35Cl, 2%), 222 (100%), 194 (50%), 188 (82%),
125 (30%), 91 (25%).
F igu r e 1. Interaction of compounds 23 and 48 on L-DOPA-
induced rotations in 6-hydroxydopamine-lesioned rats. A base-
line response to L-DOPA (10 mg/kg sc) alone was established
for groups of rats (n ) 8). The compounds were administered
at the same time as L-DOPA (10 mg/kg sc), and the total
number of full contraversive rotations over 6 h was compared
to the L-DOPA baseline for that group. *P < 0.05 (paired t-test).
spectra were obtained on Finnigan 4500 or VG Analytical
7070E/HF mass spectrometers. IR spectra were recorded as
KBr disks on a Nicolet MX-1 FT spectrophotometer. Elemental
analyses were performed by Robertson Laboratories. TLC was
performed on 0.25-mm silica gel F254 (E. Merck) glass plates.
Medium-pressure liquid chromatography (MPLC) was per-
formed on self-packed Michel-Miller 40-mm i.d. × 350-mm
(∼200 g of silica gel) or 51-mm i.d. × 450 mm (∼400 g of silica
gel) glass columns using 32-63-µm, 60-A pore silica gel. HPLC
was performed on Beckman Ultrasphere 5-µm 4.6-mm × 25-
cm C-18 columns eluting with pH 3 buffer:acetonitrile mix-
tures (unless otherwise noted) at 1.5 mL/min, and compounds
were detected using UV absorption at 214 nm. pH 3 buffer
was prepared by adjusting a 0.05 M solution of Et3N in water
to pH 3 with phosphoric acid. Ether refers to diethyl ether.
Compounds 36, 38, and 41 were not submitted for microanaly-
sis but had 1H NMR and mass spectra that were consistent
with the assigned structure.
4-Ben zyl-1-(4-p h en yl-3-bu tyn yl)p ip er id in e Oxa la te (8).
A mixture of 4-benzyl-1-(3-butynyl)piperidine (14a ; 454 mg, 2
mmol), iodobenzene (408 mg, 2 mmol), and Pd(PPh3)4 (116 mg,
0.1 mmol) was stirred in pyrrolidine (5 mL) at room temper-
ature under N2 overnight. The solvent was evaporated and the
residue purified by MPLC (120 g silica gel) eluting with CH2-
Cl2 f 200:8:1 CH2Cl2:EtOH:0.880 NH4OH to give a brown oil
(540 mg). This was further purified by MPLC (90 g silica gel)
eluting with 20% f 50% EtOAc/hexanes to give a pale-brown
oil (313 mg). This oil was stirred in EtOH (10 mL), and oxalic
acid‚2H2O in EtOH (3 mL) added. The oxalate salt precipitated
on standing overnight in the freezer as a white solid (268
mg): mp 157-158 °C; IR 1721, 1626, 1604, 1491, 1454, 1405,
1189, 760, 701 cm-1; 1H NMR (DMSO-d6) δ 7.30-7.36 (m, 5H),
7.24 (t, J ) 7.4 Hz, 2H), 7.14 (m, 3H), 3.34 (d, J ) 11.4 Hz,
2H), 3.13 (t, J ) 7.4 Hz, 2H), 2.80 (t, J ) 7.6 Hz, 2H), 2.74 (t,
J ) 11.2 Hz, 2H), 2.49 (d, J ) 6.6 Hz, 2H), 1.66 (d, J ) 12.0
Hz, 3H), 1.37 (m, 2H); APCI MS m/z 304.2 (100%, MH+); HPLC
(50% 0.1% aqueous CF3CO2H:50% MeCN) 3.75 min (100%).
Anal. (C22H25N‚C2H2O4) C, H, N, water.
4-(4-Meth ylben zyl)p ip er id in e (9d ). n-Butyllithium (1.6
M in hexanes, 49.3 mL, 79 mmol) was added to 4-bromotoluene
(9.3 mL, 75 mmol) in THF (250 mL) at -78 °C under N2 and
stirred at -78 °C for 75 min. 4-Pyridinecarboxaldehyde (7.16
mL, 75 mmol) was added and the mixture allowed to warm to
-20 °C over 2 h with stirring. The mixture was quenched with
saturated aqueous NH4Cl (300 mL) and stirred for 30 min and
the THF evaporated. The aqueous layer was diluted with 0.1%
aqueous NaHCO3 (300 mL) and extracted with CHCl3 (600
mL). The extract was dried over K2CO3, filtered, and evapo-
rated to a solid. This solid was triturated with ether to give
11.9 g of a solid: 1H NMR (DMSO-d6) δ 8.47 (d, J ) 4.6 Hz,
4-(4-F lu or oben zyl)-1-bu t-3-yn ylp ip er id in e (14c). A pro-
cedure identical to that described for the preparation of 14a
using 4-(4-fluorobenzyl)piperidine20 (9c) gave 14c: 1H NMR

2474 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Wright et al.
(CDCl3) δ 7.03 (m, 2H), 6.91 (t, J ) 8.7 Hz, 2H), 2.85 (m, 2H),
2.53 (t, J ) 7.7 Hz, 2H), 2.45 (d, J ) 7.1 Hz, 2H), 2.33 (dt, J
) 2.7, 7.7 Hz, 2H), 1.92 (m, 3H), 1.57 (d, J ) 12.9 Hz, 2H),
1.41 (m, 1H), 1.26 (dq, J ) 3.7, 12.5 Hz, 2H).
2.87 (m, 2H), 2.70 (m, 2H), 2.48 (d, J ) 6.3 Hz, 2H), 1.66 (d, J
) 11.7 Hz, 3H), 1.38 (m, 2H); APCI MS m/z 349.5 (100%, MH+);
HPLC (60% pH 3 buffer:40% MeCN) 6.53 min (99.45%). Anal.
(C22H24N2O2‚C2H2O4‚0.1H2O) C, H, N, water.
4-Ben zyl-1-[4-(4-ch lor op h en yl)b u t -3-yn yl]p ip er id in e
(17). A mixture of 4-benzyl-1-(3-butynyl)piperidine (14a ; 454
mg, 2 mmol), 4-chloroiodobenzene (715 mg, 3 mmol), and Pd-
(PPh3)4 (116 mg, 0.1 mmol) was stirred in pyrrolidine (5 mL)
at room temperature under N2 for 3 days. The solvent was
evaporated and the residue purified by MPLC (200 g silica gel)
eluting with 25% f 50% EtOAc/hexanes to give a pale-yellow
oil (577 mg). This oil was stirred in EtOH (15 mL) and oxalic
acid‚2H2O (215 mg) in EtOH (2 mL) added. The salt precipi-
tated on standing; it was collected, washed with cold EtOH,
and dried at 50 °C under high vacuum overnight to give 17 as
an off-white solid (449 mg, 52%): mp 155-158 °C; IR 1489,
1404, 1198, 1090, 721 cm-1; 1H NMR (DMSO-d6) δ 7.38 (s, 4H),
7.24 (m, 2H), 7.13 (m, 3H), 3.33 (d, J ) 12.0 Hz, 2H), 3.12 (t,
J ) 7.4 Hz, 2H), 2.81 (t, J ) 7.6 Hz, 2H), 2.72 (br t, J ) 11.2
Hz, 2H), 2.48 (d, J ) 6.8 Hz, 2H), 1.65 (d, J ) 12.2 Hz, 3H),
1.36 (m, 2H); APCI MS m/z 338.5 (100%, 35Cl MH+), 340.5
(35%, 37Cl MH+); HPLC (60% pH 3 buffer:40% MeCN) 11.12
min (100%). Anal. (C22H24ClN‚C2H2O4‚0.15H2O) C, H, N, Cl,
water.
4-(4-Meth ylben zyl)-1-bu t-3-yn ylp ip er id in e (14d ). A pro-
cedure identical to that described for the preparation of 14a
using 9d gave 14d :1H NMR (CDCl3) δ 7.02 (ABq, J ) 8.1 Hz,
δν ) 22.8 Hz, 4H), 2.84 (d, J ) 11.5 Hz, 2H), 2.53 (t, J ) 7.3
Hz, 2H), 2.45 (d, J ) 7.1 Hz, 2H), 2.33 (dt, J ) 2.7, 8.5 Hz,
2H), 2.28 (s, 3H), 1.86-1.93 (m, 3H), 1.59 (d, J ) 12.9 Hz,
2H), 1.44 (m, 1H), 1.24 (dq, J ) 3.7, 12.2 Hz, 2H).
4-Ben zyl-4-h ydr oxy-1-bu t-3-yn ylpiper idin e (14e). A pro-
cedure identical to that described for the preparation of 14a
using commercially available 4-benzyl-4-hydroxypiperidine
(9e) gave 14e as a brown oil (81% yield): 1H NMR (CDCl3) δ
7.15-7.30 (m, 5H), 2.71 (s, 2H), 2.56-2.65 (m, 4H), 2.28-2.36
(m, 4H), 1.93 (t, J ) 1.3 Hz, 1H), 1.70 (dt, J ) 3.9, 13.4 Hz,
2H), 1.50 (m, 2H).
4-(4-F lu or oben zyl)-1-b u t -3-yn yl-4-h yd r oxyp ip er id in e
(14f). A procedure identical to that described for the prepara-
tion of 14a using 4-hydroxy-4-(4-fluorobenzyl)piperidine (9f)
gave 14f as a yellow oil: 1H NMR (CDCl3) δ 7.11 (m, 2H), 6.95
(t, J ) 8.5 Hz, 2H), 2.68 (s, 2H), 2.55-2.64 (m, 4H), 2.27-2.36
(m, 4H), 1.93 (m, 1H), 1.66 (dt, J ) 4.4, 13.4 Hz, 2H), 1.46 (d,
J ) 12.0 Hz, 2H).
The following analogues were prepared using the procedure
outlined for 17 above.
4-(4-Me t h y lb e n zy l)-1-b u t -3-y n y l-4-h y d r o x y p ip e r i-
d in e (14g). A procedure identical to that described for the
preparation of 14a using 4-hydroxy-4-(4-methylbenzyl)piperi-
dine (9g) gave 14g as a brown oil: 1H NMR (CDCl3) δ 7.06
(ABq, J ) 7.5 Hz, δν ) 15.8 Hz, 4H), 2.67 (s, 2H), 2.55-2.65
(m, 4H), 2.25-2.38 (m, 7H including s at 2.29), 1.93 (m, 2H),
1.68 (dt, J ) 3.9, 12.5 Hz, 2H), 1.48 (d, J ) 13.2 Hz, 2H).
4-Ben zyl-1-p r op -2-yn ylp ip er id in e (13a ). A procedure
identical to that described for the preparation of 14a using
4-benzylpiperidine (9a ) (Aldrich) and propargyl p-toluene-
4-Ben zyl-1-[4-(3-ch lor op h en yl)b u t -3-yn yl]p ip er id in e
oxa la t e (18): mp 171-172 °C; IR 1721, 1641, 1591, 1474,
1454, 1405, 1078, 788, 709 cm-1; 1H NMR (DMSO-d6) δ 7.18-
7.30 (m, 7H), 7.08 (d, J ) 7.1 Hz, 2H), 3.74 (d, J ) 12.2 Hz,
2H), 3.22 (t, J ) 7.3 Hz, 2H), 2.89 (t, J ) 7.1 Hz, 2H), 2.56 (m,
4H), 1.71-1.84 (m, 5H); APCI MS m/z 338.6 (100%, 35Cl MH+),
340.6 (39%, 37Cl MH+); HPLC (70% pH 3 buffer:30% MeCN)
11.33 min (99.77%). Anal. (C22H24ClN‚1.07C2H2O4) C, H, N.
4-Ben zyl-1-[4-(2-ch lor op h en yl)b u t -3-yn yl]p ip er id in e
oxa la te (19): mp 165 °C; IR 1717, 1703, 1635, 1498, 1474,
1430, 1068, 953, 760, 722, 699 cm-1; 1H NMR (CDCl3) δ 7.16-
7.37 (m, 7H), 7.08 (d, J ) 7.1 Hz, 2H), 3.77 (d, J ) 11.0 Hz,
2H), 3.26 (m, 2H), 2.94 (t, J ) 6.3 Hz, 2H), 2.54-2.67 (m, 4H),
1.70-1.80 (m, 5H); APCI MS m/z 338.3 (100%, 35Cl MH+),
340.3 (32%, 37Cl MH+); HPLC (60% pH 3 buffer:40% MeCN)
8.50 min (99.22%). Anal. (C22H24ClN‚C2H2O4) C, H, N, Cl.
4-Ben zyl-1-[4-(4-flu or oph en yl)bu t-3-yn yl]piper idin e ox-
a la te (20): mp 148-149 °C; IR 3426, 2924, 2551, 1718, 1600,
1506, 1455, 1403, 1221, 839, 720, 497 cm-1; 1H NMR (DMSO-
d6) δ 7.45-7.48 (m, 2H), 7.28-7.31 (m, 2H), 7.17-7.23 (m, 5H),
3.37 (d, J ) 12.0 Hz, 2H), 3.17 (t, J ) 7.5 Hz, 2H), 2.75-2.87
(m, 4H), 2.53 (d, J ) 6.7 Hz, 2H), 1.70 (br d, J ) 12.5 Hz, 3H),
1.40-1.46 (m, 2H); CI MS m/z 322 (70%). Anal. (C22H24FN‚
C2H2O4‚0.27H2O) C, H, N, F, water.
4-Ben zyl-1-[4-(4-m et h ylp h en yl)b u t -3-yn yl]p ip er id in e
oxa la t e (21): mp 163-164 °C; IR 1717, 1703, 1640, 1509,
1497, 1454, 1404, 954, 815, 722, 699 cm-1; 1H NMR (CDCl3) δ
7.18-7.27 (m, 5H), 7.07 (t, J ) 8.3 Hz, 4H), 3.73 (d, J ) 12.2
Hz, 2H), 3.22 (t, J ) 7.2 Hz, 2H), 2.86 (t, J ) 7.2 Hz, 2H), 2.55
(m, 4H), 2.29 (s, 3H), 1.70-1.83 (m, 5H); APCI MS m/z 318.6
(100%, MH+); HPLC (70% pH 3 buffer:30% MeCN) 10.87 min
(100%). Anal. (C23H27N‚C2H2O4) C, H, N.
4-Be n zyl-1-[4-(4-m e t h oxyp h e n yl)b u t -3-yn yl]p ip e r i-
d in e oxa la te (22): mp 158-161 °C; IR 1715, 1704, 1606,
1289, 1246, 1170, 1033, 954, 826, 700 cm-1; 1H NMR (DMSO-
d6) δ 7.22-7.30 (m, 4H), 7.14 (m, 3H), 6.86 (d, J ) 8.8 Hz,
2H), 3.70 (s, 3H), 3.34 (d, J ) 11.7 Hz, 2H), 3.11 (t, J ) 7.6
Hz, 2H), 2.75 (m, 4H), 2.48 (d, J ) 6.8 Hz, 2H), 1.67 (m, 3H),
1.36 (m, 2H); APCI MS m/z 334.6 (100%, MH+); HPLC (60%
pH 3 buffer:40% MeCN) 8.35 min (98.94%). Anal. (C23H27NO‚
C2H2O4‚0.1H2O) C, H, N, water.
1
sulfonate (Lancaster) (10) gave 13a : H NMR (CDCl3) δ 7.23
(d, J ) 5.9 Hz, 2H), 7.15 (t, J ) 7.3 Hz, 1H), 7.11 (d, J ) 7.3
Hz, 2H), 3.24 (d, J ) 2.4 Hz, 2H), 2.83 (d, J ) 11.5 Hz, 2H),
2.50 (d, J ) 7.1 Hz, 2H), 2.18 (t, J ) 2.4 Hz, 1H), 2.10 (dt, J
) 1.7, 11.5 Hz, 2H), 1.63 (d, J ) 12.9 Hz, 2H), 1.29 (dq, J )
3.7, 12.7 Hz, 2H).
4-Ben zyl-1-p en t-4-yn ylp ip er id in e (15a ). A mixture of
5-chloropentyne (5.4 mL, 33 mmol), 4-benzylpiperidine (9a )
(5.3 mL, 30 mmol), and NaHCO3 (3.0 g, 36 mmol) in DMF (100
mL) was stirred at 80 °C under N2 overnight. Water (500 mL)
was added and the mixture extracted with ether (3 × 150 mL).
The extracts were washed with saturated brine (300 mL), dried
over MgSO4, filtered, and evaporated to leave a brown oil. This
oil was purified by MPLC (400 g of silica gel) eluting with 25%
f 50% EtOAc/hexanes to give a brown oil (6.3 g, 87%): 1H
NMR (CDCl3) δ 7.22-7.25 (m, 2H), 7.09-7.16 (m, 3H), 2.84
(d, J ) 10.7 Hz, 2H), 2.49 (d, J ) 6.8 Hz, 4H), 2.34 (dt, J )
1.2, 7.3 Hz, 2H), 2.17 (tt, J ) 2.4, 7.1 Hz), 1.90 (m, 1H), 1.82
(t, J ) 11.7 Hz, 2H), 1,67 (dquin, J ) 1.2, 7.3 Hz, 2H), 1.59 (d,
J ) 12.0 Hz, 2H), 1.47 (m, 1H), 1.25 (dq, J ) 3.2, 11.5 Hz,
2H).
4-Ben zyl-1-[4-(4-n itr oph en yl)bu t-3-yn yl]piper idin e (16).
A mixture of 4-benzyl-1-(3-butynyl)piperidine (14a ; 909 mg, 4
mmol), 4-iodonitrobenzene (1.49 g, 6 mmol), and Pd(PPh3)4
(347 mg, 0.3 mmol) was stirred in n-BuNH2 (10 mL) and
deoxygenated by bubbling N2 through the mixture for 10 min.
The mixture was stirred at room temperature under N2
overnight. The solvent was evaporated and the residue purified
by MPLC (200 g of silica gel) eluting with 30% f 75% EtOAc/
hexanes to give a red oil (918 mg). This oil was repurified by
MPLC (200 g of silica gel) eluting with 25% f 50% EtOAc/
hexanes to give a red oil (504 mg). This oil was stirred in EtOH
(10 mL) and oxalic acid‚2H2O (182 mg) in EtOH (2 mL) added.
The salt precipitated on standing in the freezer overnight; it
was collected, washed with cold EtOH, and dried at 50 °C
under high vacuum overnight to give 16 as a pink solid (379
mg, 22%): mp 112-115 °C; IR 1594, 1516, 1342 cm-1; 1H NMR
(DMSO-d6) δ 8.16 (d, J ) 8.5 Hz, 2H), 7.62 (d, J ) 8.5 Hz,
2H), 7.24 (m, 2H), 7.14 (m, 3H), 3.32 (m, 2H), 3.13 (m, 2H),
4-Be n zyl-1-[4-(4-h yd r oxyp h e n yl)b u t -3-yn yl]p ip e r i-
d in e (23): mp 124-128 °C; IR 1606, 1511, 1274, 829 cm-1
;
1H NMR (DMSO-d6) δ 7.21 (m, 2H), 7.10 (m, 5H), 6.63 (d, J )
8.8 Hz, 2H), 2.78 (d, J ) 11.5 Hz, 2H), 2.42 (m, 6H), 1.83 (t, J
) 10.5 Hz, 2H), 1.35-1.50 (m, 3H), 1.12 (m, 2H); APCI MS
m/z 320.6 (100%, MH+); HPLC (60% pH 3 buffer:40% MeCN)
3.85 min (99.44%). Anal. (C22H25NO) C, H, N.

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2475
4-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]p h en yla m in e
oxa la te (24): mp 120-121 °C; 1H NMR (DMSO-d6) δ 7.24 (t,
J ) 7.2 Hz, 2H), 7.14 (m, 3H), 6.99 (d, J ) 8.5 Hz, 2H), 6.43
(d, J ) 8.5 Hz, 2H), 3.40 (m, 2H), 3.17 (m, 2H), 2.83 (m, 2H),
2.76 (t, J ) 7.6 Hz, 2H), 2.49 (d, J ) 6.3 Hz, 2H), 1.50-1.80
(m, 3H), 1.38 (m, 2H); APCI MS m/z 319.2 (100%, MH+); HPLC
(70% 0.1% aqueous CF3CO2H:30% MeCN) 4.33 min (93.84%).
Anal. (C22H26N2‚1.72C2H2O4‚0.37H2O) C, H, N, water.
δ 7.82 (d, J ) 8.7 Hz, 2H), 7.48 (d, J ) 8.4 Hz, 2H), 7.27 (m,
2H), 7.19 (t, J ) 7.5 Hz, 1H), 7.15 (d, J ) 6.8 Hz, 2H), 4.82 (br
s, 2H), 2.92 (d, J ) 11.3 Hz, 2H), 2.59-2.67 (m, 4H), 2.53 (d,
J ) 7.2 Hz, 2H), 2.00 (t, J ) 11.8 Hz, 2H), 1.49-1.67 (m, 3H),
1.23-1.36 (m, 2H); APCI MS m/z 383 (49%). Anal. (C22H26N2-
O2S‚0.10H2O) C, H, N, S, water.
3-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]b en zyla m in e
oxa la te (33): mp 99-100 °C; IR 3450, 3058, 3026, 2924, 1723,
1624, 1453, 1207, 703, cm-1 1H NMR (DMSO-d6) δ 7.52 (s,
;
{4-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]p h en yl}m eth -
yla m in e oxa la te (25): mp foams at 151 °C; IR 3403, 1610,
1523, 1178, 819 cm-1; 1H NMR (DMSO-d6) δ 7.24 (m, 2H), 7.14
(m, 3H), 7.05 (d, J ) 8.5 Hz, 2H), 6.41 (d, J ) 8.8 Hz, 2H),
3.34 (m, 2H), 3.09 (m, 2H), 2.73 (m, 4H), 2.60 (s, 3H), 2.48 (d,
J ) 6.8 Hz, 2H), 1.66 (m, 3H), 1.36 (m, 2H); APCI MS m/z
333.6 (100%, MH+); HPLC (60% pH 3 buffer:40% MeCN) 5.18
min (96.15%). Anal. (C23H28N2‚C2H2O4) C, H, N, water.
{4-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]ph en yl}dim eth -
yla m in e oxa la te (26): mp 163-164 °C; IR 1608, 1523, 1191,
1H), 7.39-7.45 (m, 3H), 7.29 (t, J ) 7.5 Hz, 2H), 7.17-7.21
(m, 3H), 4.02 (s, 2H), 3.27 (d, J ) 12.0 Hz, 2H), 3.01 (t, J )
7.2 Hz, 2H), 2.52-2.86 (m, 4H), 1.66 (d, J ) 11.3 Hz, 3H), 1.33
(q, J ) 12.5 Hz, 2H); CI MS m/z 333 (100%). Anal. (C23H28N2‚
1.96C2H2O4‚0.82H2O) C, H, N, water.
4-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]-2-n it r ob en -
zen ea m in e Oxa la te (34). A procedure similar to that de-
scribed for 17 on a 10-mmol scale starting with 4-bromo-2-
nitroaniline (Trans World Chemicals) stirring overnight at 50
°C gave 34 as a red oil (3.14 g, 86%). A portion of the oil (340
mg) was converted to the oxalate salt for characterization:
orange solid (200 mg); mp 150-153 °C; IR 1631, 1515, 1253
cm-1; 1H NMR (DMSO-d6) δ 7.91 (d, J ) 2.0 Hz, 1H), 7.63 (br
s, 2H), 7.31 (dd, J ) 2.0, 8.8 Hz, 1H), 7.24 (m, 2H), 7.13 (m,
3H), 6.92 (d, J ) 9.0 Hz, 1H), 3.32 (d, J ) 11.5 Hz, 2H), 3.10
(m, 2H), 2.78 (m, 4H), 2.48 (d, J ) 6.8 Hz, 2H), 1.67 (m, 3H),
1.35 (m, 2H); APCI MS m/z 364.5 (100%, MH+); HPLC (60%
pH 3 buffer:40% MeCN) 4.88 min (98.96%). Anal. (C22H25N3O2‚
C2H2O4‚0.3H2O) C, H, N, water.
4-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]ben zen e-1,2-d i-
a m in e (35). A mixture of 34 (2.56 g, 7.0 mmol), iron powder
(3.75 g), and concentrated HCl (5 drops) in EtOH (52 mL) and
water (8 mL) was stirred at reflux for 2 h. The mixture was
filtered and evaporated. The residue was purified by MPLC
(400 g of silica gel) eluting with 200:8:1 f 100:8:1 CH2Cl2:
EtOH:0.880 NH4OH to give, after drying at 40 °C under high
vacuum overnight, 35 as a beige solid (1.82 g, 77%): mp 141-
142 °C; IR 1517, 1282, 1131 cm-1; 1H NMR (CDCl3) δ 7.22 (m,
2H), 7.11-7.16 (m, 3H), 6.74 (dd, J ) 1.7, 8.1 Hz, 1H), 6.70
(d, J ) 1.5 Hz, 1H), 6.54 (d, J ) 7.8 Hz, 1H), 3.42 (br s, 2H),
3.27 (br s, 2H), 2.89 (d, J ) 11.7 Hz, 2H), 2.59 (m, 2H), 2.50
(m, 4H), 1.94 (dt, J ) 1.7, 11.7 Hz, 2H), 1.60 (m, 2H), 1.48 (m,
1H), 1.28 (m, 2H); APCI MS m/z 334.6 (100%, MH+); HPLC
(70% pH 3 buffer:30% MeCN) 3.02 min (99.05%). Anal.
(C22H27N3‚0.07H2O) C, H, N, water.
1
819 cm-1; H NMR (DMSO-d6) δ 7.24 (m, 2H), 7.13 (m, 5H),
6.59 (d, J ) 9.0 Hz, 2H), 3.34 (m, 2H), 3.08 (m, 2H), 2.85 (s,
6H), 2.74 (m, 4H), 2.49 (d, J ) 6.8 Hz, 2H), 1.66 (m, 3H), 1.35
(m, 2H); APCI MS m/z 347.6 (100%, MH+); HPLC (60% pH 3
buffer:40% MeCN) 7.88 min (100%). Anal. (C24H30N2‚C2H2O4)
C, H, N, water.
N-{4-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]ph en yl}acet-
a m id e (27): mp 161-163 °C; IR 1663, 1598, 1535, 1509, 1320,
1
838 cm-1; H NMR (CDCl3) δ 7.39 (d, J ) 8.5 Hz, 2H), 7.29
(m, 2H), 7.15-7.30 (m, 3H), 7.10 (d, J ) 6.8 Hz, 2H), 2.89 (d,
J ) 11.5 Hz, 2H), 2.50-2.65 (series of m, 6H), 2.13 (s, 3H),
1.95 (dt, J ) 2.0, 11.5 Hz, 2H), 1.61 (d, J ) 14.2 Hz, 2H), 1.49
(m, 1H), 1.28 (m, 2H); APCI MS m/z 361.7 (100%, MH+); HPLC
(70% pH 3 buffer:30% MeCN) 6.97 min (98.87%). Anal.
(C24H28N2O) C, H, N.
N-{4-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]ph en yl}m eth -
a n esu lfon a m id e (28): mp 125-127 °C; IR 1506, 1326, 1152,
1
980, 755 cm-1; H NMR (DMSO-d6) δ 9.88 (br s, 1H), 7.20-
7.30 (m, 4H), 7.06-7.15 (m, 5H), 3.28 (s, 3H), 2.80 (d, J ) 11.5
Hz, 2H), 2.45 (m, 6H), 1.85 (t, J ) 10.7 Hz, 2H), 1.35-1.50
(m, 3H), 1.13 (m, 2H); APCI MS m/z 397.6 (100%, MH+); HPLC
(60% pH 3 buffer:40% MeCN) 10.73 min (99.40%). Anal.
(C23H28N2O2S) C, H, N.
3-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]p h en yla m in e
(29): mp 96 °C; IR (KBr) 3452, 3324, 3201, 2917, 2805, 1638,
1599, 1492, 1120, 858, 786, 747, 702, 689 cm-1 1H NMR
;
(CDCl3) δ 7.22-7.25 (m, 2H), 7.14 (d, J ) 7.3 Hz, 1H), 7.09 (d,
J ) 6.8 Hz, 2H), 7.02 (t, J ) 7.8 Hz, 2H), 6.73 (d, 1H, J ) 7.5
Hz, 1H), 6.67 (s, 1H), 6.54 (d, J ) 8.0 Hz, 1H), 3.58 (br s, 2H),
2.89 (d, J ) 11.4 Hz, 2H), 2.48 (m, 7H), 1.97 (t, J ) 9.8 Hz,
2H), 1.44-1.62 (m, 8H), 1.23-1.33 (m, 2H); CI MS m/z 319
(62%); HPLC (80% pH 3.0 buffer:20% MeCN) 3.02 min (100%).
Anal. (C22H26N2‚0.25H2O) C, H, N, water.
4-{4-[4-(4-Ch lor oben zyl)piper idin -1-yl]bu t-1-yn yl}ph en -
yla m in e (36): 1H NMR (CDCl3) δ 7.20 (m, 4H), 7.05 (m, 2H),
6.53 (d, J ) 6.0 Hz, 2H), 3.75 (br. s, 2H), 2.89 (m, 2H), 2.55
(m, 4H), 2.15 (m, 2H), 1.96 (m, 3H), 1.58 (m, 2H), 1.44 (m,
1H), 1.24 (m, 2H); EI MS m/z 354 (37Cl M+, 3%), 353 (35Cl,
M+, 9%), 222 (100%), 188 (15%), 125 (20%); HRMS calcd for
C
22H2535ClN2 352.1714, found 352.1710.
2-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]p h en yla m in e
4-{4-[4-(4-Flu or oben zyl)piper idin -1-yl]bu t-1-yn yl}ph en -
oxa la te (30): mp 112-113 °C; IR (KBr) 3444, 3376, 3026,
yla m in e (37): mp 83-84 °C; IR 3406, 3345, 3225, 2943, 2916,
2923, 2853, 1723, 1617, 1493, 1454, 749, 702, 487 cm-1 1H
;
1
2834, 1639, 1606, 1511, 1217, 828 cm-1; H NMR (CDCl3) δ
NMR (DMSO-d6) δ 7.28 (d, J ) 7.5 Hz, 2H), 7.17-7.22 (m,
3H), 7.07 (d, J ) 7.7 Hz, 1H), 7.00 (t, J ) 8.4 Hz, 1H), 6.66 (d,
J ) 7.7 Hz, 1H), 6.44 (t, J ) 8.4 Hz, 1H), 3.36-3.40 (m, 2H),
3.16-3.18 (m, 2H), 2.87 (t, J ) 7.5 Hz, 2H), 2.63-2.77 (m, 2H),
2.54 (d, J ) 6.8 Hz, 2H), 1.69-1.73 (m, 3H), 1.40-1.46 (m,
2H); CI MS m/z 319 (100%). Anal. (C22H26N2‚1.1C2H2O4‚
0.05H2O) C, H, N, water.
7.17 (d, J ) 8.7 Hz, 2H), 7.08 (m, 2H), 6.96 (t, J ) 8.7 Hz,
2H), 6.58 (d, J ) 8.7 Hz, 2H), 3.72 (s, 2H), 2.93 (m, 2H), 2.50-
2.65 (m, 6H), 2.00 (m, 2H), 1.39-1.72 (m, 3H), 1.19-1.31 (m,
2H); CI MS m/z 337 (M+, 100); HPLC (80% pH 3.0 buffer:20%
MeCN) 3.52 min (95.02%). Anal. (C22H25FN2‚0.59H2O) C, H,
N, F, water.
4-{4-[4-(4-Meth ylben zyl)piper idin -1-yl]bu t-1-yn yl}ph en -
yla m in e (38): 1H NMR (CDCl3) δ 7.12 (d, J ) 8.4 Hz, 2H),
7.04 (q, J ) 7.8 Hz, 4H), 6.54 (d, J ) 8.4 Hz, 2H), 3.73 (br s,
2H), 2.91 (d, J ) 11.1 Hz, 2H), 2.48-2.64 (m, 6H), 2.32 (s,
3H), 1.99 (t, J ) 12.0 Hz, 2H), 1.62 (d, J ) 12.0 Hz, 2H), 1.50
(m, 1H), 1.31 (m, 2H); EI MS m/z 332 (M+, 10%), 202 (100%),
189 (30%), 105 (32%); HRMS calcd for C23H28N2 332.2252,
found, 332.2260.
4-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]ben zam ide (31):
prepared using 4-iodobenzamide;21 mp 179-182 °C; IR 3412,
1
1648, 1614, 1410, 1395, 1132, 856 cm-1; H NMR (CDCl3) δ
7.65 (d, J ) 8.3 Hz, 2H), 7.37 (d, J ) 8.3 Hz, 2H), 7.20 (m,
2H), 7.08 (m, 3H), 6.00 (br s, 1H), 5.64 (br s, 1H), 2.87 (d, J )
11.7 Hz, 2H), 2.57 (m, 4H), 2.47 (d, J ) 7.1 Hz, 2H), 1.94 (dt,
J ) 2.3, 11.7 Hz, 2H), 1.58 (d, J ) 12.9 Hz, 2H), 1.46 (m, 1H),
1.24 (m, 2H); APCI MS m/z 347.6 (100%, MH+); HPLC (65%
pH 3 buffer:35% MeCN) 3.48 min (98.34%). Anal. (C23H26N2O)
C, H, N.
1-[4-(4-Am in op h en yl)bu t-3-yn yl]-4-ben zylp ip er id in -4-
ol (39): mp 89-92 °C; IR 1620, 1606, 1513, 1118, 828, 700
1
4-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]ben zen esu lfon -
a m id e (32): mp 171-172 °C; IR 3359, 2937, 2829, 1594, 1327,
1152, 1096, 839, 749, 700, 644, 614, 555 cm-1; 1H NMR (CDCl3)
cm-1; H NMR (DMSO-d6) δ 7.10-7.21 (m, 5H), 6.94 (d, J )
8.3 Hz, 2H), 6.41 (d, J ) 8.5 Hz, 2H), 2.59 (s, 2H), 2.44 (m,
4H), 2.24 (t, J ) 10.7 Hz, 2H), 1.41 (m, 2H), 1.29 (m, 2H); APCI

2476 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13
Wright et al.
MS m/z 335.0 (100%, MH+); HPLC (80% pH 3 buffer:20%
MeCN) 4.65 min (100%). Anal. (C22H26N2O) C, H, N.
8.8 Hz, 2H), 3.34 (s, 2H), 2.74 (d, J ) 11.2 Hz, 2H), 2.44 (m,
2H), 2.02 (t, J ) 10.5 Hz, 2H), 1.32-1.55 (m, 3H), 1.15 (m,
2H); APCI MS m/z 306.0 (100%, MH+); HPLC (70% pH 3
buffer:30% MeCN) 7.75 min (100%). Anal. (C21H23NO) C, H,
N.
1-[4-(4-Am in op h en yl)bu t-3-yn yl]-4-(4-flu or oben zyl)p i-
p er id in -4-ol (40): mp 113.5 °C; IR 1621, 1607, 1511, 1218,
1
829 cm-1; H NMR (CDCl3) δ 7.10-7.17 (m, 4H), 6.96 (t, J )
P h a r m a cologica l Meth od s. Electr op h ysiology. Oocytes
were obtained from mature female Xenopus laevis and were
prepared and maintained as described previously.22 Individual
oocytes were microinjected with a mixture of NMDA receptor-
encoding cRNAs, provided by Dr. P. H. Seeburg (Heidelberg
University, Heidelberg, Germany).23 NR1A and NR2A were
injected at a 1:4 ratio; all other binary subunit combinations
were injected 1:1 (1-10 ng of each subunit). Oocytes were
stored in Barth’s medium containing (in mM): NaCl, 88; KCl,
1; CaCl2, 0.41; Ca(NO3)2, 0.33; MgSO4, 0.82; NaHCO3, 2.4;
HEPES, 5; pH 7.4, with 0.1 mg/mL gentamycin sulfate.
Standard two electrode voltage-clamp recordings were made
at -70 mV in nominally Ca2+-free Ringer (in mM): NaCl, 115;
KCl, 2; BaCl2, 1.8; HEPES, 5; pH 7.4.15 All drugs were diluted
in Ringer and applied via bath perfusion (7-10 mL/min) in a
conventional flow-through chamber (volume ∼ 0.2 mL). Test
drugs were initially dissolved in DMSO and diluted into Ringer
just prior to application (final [DMSO] ) 0.1-1%). IC50 values
were obtained by fitting the partial (3-5 point) concentration-
inhibition curves to the following equation using Origin
(Microcal):
8.5 Hz, 2H), 6.53 (d, J ) 8.5 Hz, 2H), 3.69 (br s, 2H), 2.69 (s,
2H), 2.50-2.70 (m, 6H), 2.35 (m, 2H), 1.69 (m, 2H), 1.48 (m,
2H); APCI MS m/z 353.1 (100%, MH+); HPLC (80% pH 3
buffer:20% MeCN) 5.85 min (92.4%). Anal. (C22H25FN2O) C,
H, N, water.
1-[4-(4-Am in op h en yl)bu t-3-yn yl]-4-(4-m eth ylben zyl)p i-
p er id in -4-ol (41): 1H NMR (CDCl3) δ 7.11-7.19 (m, 6H), 6.58
(m, 2H), 3.73 (s, 2H), 3.45 (m, 4H), 2.71 (m, 4H), 2.59 (m, 2H),
2.33 (s, 3H), 2.05 (m, 2H), 1.88 (m, 2H), 1.65 (m, 3H); HRMS
calcd for C23H28N2O + H 349.2279, found 348.2280.
4-[3-(4-B e n zy lp ip e r id in -1-y l)p r o p -1-y n y l]p h e n y l-
a m in e (42): mp 99-101 °C; IR 3445, 3325, 2936, 2922, 1634,
1607, 1515, 1302, 699 cm-1; 1H NMR (CDCl3) δ 7.13-7.52 (m,
7H), 6.57 (d, J ) 10.8 Hz, 2H), 3.76 (s, 2H), 3.47 (s, 2H), 2.94
(d, J ) 11.3 Hz, 2H), 2.53 (d, J ) 7.0 Hz, 2H), 2.2 (m, 2H),
1.2-1.7 (m, 5H); APCI MS m/z 305 (99%, MH+). Anal.
(C21H24N2‚0.15H2O) C, H, N, water.
4-[5-(4-B e n zy lp ip e r id in -1-y l)p e n t -1-y n y l]p h e n y l-
a m in e oxa la te (43): mp 148-150 °C; IR 1720, 1609, 1515,
1202, 1177, 703 cm-1; 1H NMR (DMSO-d6) δ 7.24 (m, 2H), 7.13
(m, 2H), 6.98 (d, J ) 8.5 Hz, 2H), 6.42 (d, J ) 8.3 Hz, 2H),
3.35 (m, 2H), 2.98 (m, 2H), 2.77 (m, 2H), 2.48 (d, J ) 6.3 Hz,
2H), 2.37 (t, J ) 6.8 Hz, 2H), 1.60-1.90 (m, 5H), 1.36 (m, 2H);
APCI MS m/z 333.4 (100%, MH+); HPLC (70% pH 3 buffer:
30% MeCN) 6.33 min (100%). Anal. (C23H28N2‚C2H2O4‚
0.10H2O) C, H, N, water.
I/Icontrol ) {(1 - min)/{1 + ([antagonist]/IC50)n}} + min
where Icontrol is the current in the absence of antagonist, min
(minimum) is the residual fractional response at saturating
concentration of antagonist, and IC50 is the concentration of
drug that causes one-half this level of inhibition. To fit the
curves for NR1A/2B, ‘min’ was fixed at 0.15.24 Data in the text
are mean ( standard error (SE).
R a d ioliga n d Bin d in g Assa ys. Test compounds were
evaluated at nine concentrations in duplicate added in 5-µL
aliquots (1% DMSO final) to 96-well, 1.0-mL volume assay
plates and incubated in a total volume of 500 µL for 60 min at
room temperature as described below. Assays were terminated
by filtration through GF/B filter plates (Packard, Meriden, CT),
and the filter plates were rinsed three times with ∼0.8 mL of
assay buffer/well. Microscint-20 scintillation cocktail (50 µL/
well; Packard) was added to the dried filter plates, which were
then counted on a TopCount (Packard) scintillation counter
for 8 min/well. IC50 values were determined by fitting the data
to the sigmoidal equation using Prism (GraphPad, SanDiego,
CA).
N-{4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]p h en yl}-
a ceta m id e (44): mp 185-188 °C; IR 1670, 1599, 1526, 1513,
1
1320, 839 cm-1; H NMR (DMSO-d6) δ 10.01 (s, 1H), 7.50 (d,
J ) 8.3 Hz, 2H), 7.27 (dd, J ) 1.7, 6.8 Hz, 2H), 7.21 (t, J ) 7.4
Hz, 2H), 7.11 (m, 3H), 3.37 (s, 2H), 2.75 (d, J ) 11.5 Hz, 2H),
2.44 (m, 2H), 2.03 (t, J ) 9.8 Hz, 2H), 1.98 (s, 3H), 1.50 (d, J
) 12.5 Hz, 2H), 1.40 (m, 1H), 1.14 (m, 2H); APCI MS m/z 347.1
(100%, MH+); HPLC (70% pH 3 buffer:30% MeCN) 6.15 min
(98.55%). Anal. (C23H26N2O) C, H, N.
N-{4-[5-(4-Ben zylp ip er id in -1-yl)p en t -1-yn yl]p h en yl}-
a ceta m id e (45). A procedure similar to that described for 17
on a 2-mmol scale starting with 4-iodoacetanilide and 15a gave
a yellow oil (588 mg). The material was triturated with EtOH
to give a brown solid (139 mg, 18%): mp 142-143 °C; IR 1669,
1600, 1526, 1513, 1320, 837 cm-1; 1H NMR (CDCl3) δ 7.39 (d,
J ) 8.5 Hz, 2H), 7.29 (d, J ) 8.5 Hz, 2H), 7.23 (m, 1H), 7.09-
7.22 (m, 4H), 2.87 (d, J ) 11.5 Hz, 2H), 2.49 (d, J ) 7.1 Hz,
2H), 2.38 (m, 4H), 2.13 (s, 3H), 1.79 (dt, J ) 1.7, 11.7 Hz, 2H),
1.73 (quin, J ) 7.3 Hz, 2H), 1.59 (d, J ) 12.2 Hz, 2H), 1.48
(m, 1H), 1.20-1.31 (m, 2H); APCI MS m/z 375.4 (100%, MH+);
HPLC (70% pH 3 buffer:30% MeCN) 9.20 min (100%). Anal.
(C25H30N2O‚0.10H2O) C, H, N, water.
r-1 Ad r en er gic Recep tor Bin d in g. The [3H]prazosin
binding assay was modified from previously described meth-
ods.16 Frozen Sprague-Dawley rat cortices obtained from ABS
(Wilmington, DE) were thawed, homogenized in 10 volumes
of ice-cold 0.25 M sucrose/10 mM Tris-HCl (pH 7.4) buffer, and
centrifuged at 1000g for 10 min at 4 °C. The supernatant was
centrifuged at 40,000g for 30 min; the pellet was resuspended
in 10 volumes of ice-cold 140 mM NaCl/5 mM MgCl2/50 mM
Tris-HCl (pH 7.4) buffer (prazosin binding buffer) and centri-
fuged at 40000g for 30 min. The pellet was resuspended in
prazosin binding buffer and centrifuged twice more for a total
of three wash steps, and the final pellet was stored at -80 °C.
On the day of the binding assay, the membrane pellets were
thawed and resuspended in prazosin binding buffer, and 200
µg of membrane protein was incubated with 0.8 nM [3H]-
prazosin (∼80 Ci/mmol; NEN, Boston, MA). Nonspecific bind-
ing was determined in the presence of 10 µM phentolamine.
Dop a m in e D2 Recep tor Bin d in g. The [3H]raclopride
binding assay was modified from previously described meth-
ods.17 Frozen Sprague-Dawley rat striata obtained from ABS
(Wilmington, DE) were thawed, homogenized in ice-cold 50
mM Tris-HCl (pH 7.4) buffer (8-9 pairs of striata/10 mL), and
centrifuged at 20000g for 10 min at 4 °C. The pellet was
resuspended in 10 mL of ice-cold 50 mM Tris-HCl (pH 7.4)
buffer and centrifuged at 20000g for 10 min. The pellet was
resuspended in 120 mM NaCl/5 mM KCl/50 mM Tris-HCl (pH
N-{4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]p h en yl}-
m eth a n esu lfon a m id e (46): mp 141-142 °C; IR 3448, 3023,
2933, 2918, 2814, 1605, 1508, 1331, 1149 cm-1 1H NMR
;
(CDCl3) δ 7.38 (d, J ) 6.8 Hz, 2H), 7.26 (m, 2H), 7.13-7.20
(m, 5H), 3.47(s, 2H), 2.96-3.01 (m, 5H), 2.54 (d, J ) 7.0 Hz,
2H), 2.17 (t, J ) 11.3 Hz, 2H), 1.68 (d, J ) 13.0 Hz, 2H), 1.50-
1.57 (m, 1H), 1.32-1.41 (m, 2H); APCI MS m/z 383 (100%);
HPLC (80% pH 3.0 buffer:20% MeCN) 3.22 min (100%). Anal.
(C22H26N2O2S) C, H, N, S.
N-{4-[5-(4-Ben zylp ip er id in -1-yl)p en t -1-yn yl]p h en yl}-
m eth a n esu lfon a m id e oxa la te (47): mp 207-208 °C; IR
1608, 1595, 1509, 1329, 1150 cm-1; 1H NMR (DMSO-d6) δ 7.29
(d, J ) 6.8 Hz, 2H), 7.22 (d, J ) 7.6 Hz, 2H), 7.11 (m, 5H),
3.13 (m, 2H), 2.95 (s, 3H), 2.72 (m, 2H), 2.48 (m, 4H), 2.40 (t,
J ) 6.8 Hz, 2H), 1.73 (m, 2H), 1.59 (m, 3H), 1.25 (m, 2H); APCI
MS m/z 411.6 (100%, MH+); HPLC (60% pH 3 buffer:40%
MeCN) 4.05 min (100%). Anal. (C24H30N2O2S‚0.61C2H2O4‚
0.04H2O) C, H, N, water.
4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]p h en ol (48):
mp 139-140 °C; IR 1606, 1511, 1284, 1238, 836 cm-1; 1H NMR
(DMSO-d6) δ 9.76 (br s, 1H), 7.09-7.23 (m, 7H), 6.66 (d, J )

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7.4) buffer (raclopride binding buffer) (1 mL/pair of striata)
and was stored at -80 °C. On the day of the binding assay,
the membrane suspensions were thawed and diluted in
raclopride binding buffer, and 200 µg of membrane protein was
incubated with 3 nM [3H]raclopride (∼80 Ci/mmol; NEN).
Nonspecific binding was determined in the presence of 300 µM
sulpiride.
6-Hyd r oxyd op a m in e-Lesion ed Ra t.18 Adult male
Sprague-Dawley rats were anesthetized with chloral hydrate,
and unilateral lesions of the nigrostriatal dopamine system
were accomplished by infusion of 8 µg of 6-hydroxydopamine
HBr (6-OHDA) into the right medial forebrain bundle. Rats
were pretreated 30 min before surgery with desipramine HCl
(25 mg/kg ip) to protect noradrenergic neurons and pargyline
(25 mg/kg ip) to potentiate the effects of 6-OHDA. A minimum
of 3 weeks after surgery, the rotational behavior induced by
apomorphine HCl (50 µg/kg sc) was assessed. Only rats
demonstrating more than 100 contraversive turns/hour to
apomorphine were used for the present experiments. Rota-
tional behavior was measured using an automated rotometer
system (Rotorat Rotational Activity System, MED Associates,
Georgia, VT). Anti-parkinsonian activity was assessed as the
ability of the compound to potentiate the contraversive rotation
induced by L-DOPA methyl ester (10 mg/kg sc) over a 6-h
period. Experiments were conducted using a crossover para-
digm where each rat received either a vehicle plus L-DOPA,
or the test compound plus L-DOPA in randomized order. Rats
were tested at 7-day intervals. In experiments in which the
compound was tested orally, rats were food deprived for 16 h.
Statistical analysis between treatment groups was performed
using a paired t-test.
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