Synthesis and structure-activity relationships of N-(1-benzylpiperidin-4-yl)arylacetamide analogues as potent σ1receptor ligands

Article abstract of DOI:10.1021/jm010384j

A series of N-(1-benzylpiperidin-4-yl)arylacetamides were synthesized and evaluated for their binding properties for σ₁ and σ₂ receptors. In agreement with previously reported σ₁/σ₂ receptor binding data for N-(1-benzylpiperidin-4-yl)phenylacetamide, all of the N-(1-benzylpiperidin-4-yl)arylacetamide compounds reported below displayed higher affinity for σ₁ vs σ₁ receptors. Replacement of the phenyl ring of the phenylacetamide moiety with a thiophene, naphthyl, or indole aromatic ring had no significant effect on the σ₁ receptor affinity. Replacement of the phenyl ring with an imidazole or pyridyl aromatic ring resulted in a >60-fold loss in affinity for σ₁ receptors and no significant binding affinity for σ₂ receptors. Substitution on the aromatic ring of the benzyl group showed a similar or slightly decreased affinity for σ₁ receptors. Substitution on the aromatic rings of both the phenylacetamide moiety and the benzyl group with a halogen resulted in a similar affinity for σ₁ receptors and a significantly increased affinity for σ₂ receptors. Comparative molecular field analysis revealed that electrostatic properties of the substituents in the phenylacetamide aromatic ring strongly influenced binding to σ₁ receptors. Compounds 1, 10, 18, 22, 37, and 40 showed the highest selectivity for σ₁ receptors with K_i (σ₂) to K_i (σ₁) ratios of 100, >92, >122, 77, 74, and 80, respectively. In agreement with previously reported results, the phenylacetamide analogues had no binding affinity for dopamine receptors (D₂/D₃).

Full text of DOI:10.1021/jm010384j

4404
J . Med. Chem. 2001, 44, 4404-4415
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of
N-(1-Ben zylp ip er id in -4-yl)a r yla ceta m id e An a logu es a s P oten t σ1 Recep tor
Liga n d s
Yunsheng Huang,†,‡ Philip S. Hammond,† Li Wu,† and Robert H. Mach*,†,§,‡
Department of Radiology and Department of Physiology and Pharmacology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina 27157, and Anasazi BioMedical Research, Inc., Winston-Salem, North Carolina 27101
Received August 13, 2001
A series of N-(1-benzylpiperidin-4-yl)arylacetamides were synthesized and evaluated for their
binding properties for σ1 and σ2 receptors. In agreement with previously reported σ1/σ2 receptor
binding data for N-(1-benzylpiperidin-4-yl)phenylacetamide, all of the N-(1-benzylpiperidin-
4-yl)arylacetamide compounds reported below displayed higher affinity for σ1 vs σ2 receptors.
Replacement of the phenyl ring of the phenylacetamide moiety with a thiophene, naphthyl, or
indole aromatic ring had no significant effect on the σ1 receptor affinity. Replacement of the
phenyl ring with an imidazole or pyridyl aromatic ring resulted in a >60-fold loss in affinity
for σ1 receptors and no significant binding affinity for σ2 receptors. Substitution on the aromatic
ring of the benzyl group showed a similar or slightly decreased affinity for σ1 receptors.
Substitution on the aromatic rings of both the phenylacetamide moiety and the benzyl group
with a halogen resulted in a similar affinity for σ1 receptors and a significantly increased affinity
for σ2 receptors. Comparative molecular field analysis revealed that electrostatic properties of
the substituents in the phenylacetamide aromatic ring strongly influenced binding to σ1
receptors. Compounds 1, 10, 18, 22, 37, and 40 showed the highest selectivity for σ1 receptors
with Ki (σ2) to Ki (σ1) ratios of 100, >92, >122, 77, 74, and 80, respectively. In agreement with
previously reported results, the phenylacetamide analogues had no binding affinity for dopamine
receptors (D2/D3).
In tr od u ction
compounds to increase the extracellular levels of ace-
tylcholine in rat frontal cortex was positively correlated
with their binding affinities for σ1 receptors, and this
facilitated release was fully reversed by σ1 receptor
antagonists.11 Stimulated dopamine release by NMDA
(N-methyl-D-aspartate) was inhibited by σ receptor
agonists in a concentration-dependent manner, while
this inhibition was reversed by σ1 receptor antago-
nists.7,13 Various σ1 agonists were also shown to potenti-
ate NMDA in a dose-dependent manner, and this effect
was also reversed by selective σ1 receptor antagonists.8,14
σ receptor antagonists have also been shown to block
the development of sensitization to cocaine and other
psychostimulants.15,16 These data suggest that σ1 recep-
tor antagonists may prevent schizophrenics from dete-
riorating or becoming susceptible to relapses.16 Clinical
studies using the σ ligand panamesine in patients with
schizophrenia indicated improvement in psychometric
variables and no extrapyramidal and other side effects
were observed.17
σ receptors are present in high density in both the
central nervous system and many peripheral organs.1
The classification of sigma receptors into two distinct
subtypes, designated σ1 and σ2,1-3 has prompted interest
in developing selective ligands for investigating the
functional differences between σ1 and σ2 receptors. Over
the past several years, tremendous effort has been
focused on studying the physiological functions of σ1 and
σ2 receptors, but the endogenous ligand for these recep-
tors is still unidentified. The σ1 receptor has been cloned
and displays a 30% sequence homology with the enzyme,
yeast sterol isomerase. These data, in concert with the
observation that progesterone possesses a modest af-
finity for σ1 receptors,1,2 suggest that this subtype of the
sigma receptor may play a role in steroid biochemistry.
The σ2 receptor has not been cloned, but evidence
suggests that it is linked to potassium channels in NCB-
20 cells.1,2
Recent evidence has indicated that σ1 receptors may
be involved in regulating a variety of neurotransmitters
in the central nervous system, including cholinergic,4,5
dopaminergic,6,7 and glutamatergic systems.8,9 σ1 recep-
tor agonists have been shown to elevate extracellular
acetylcholine levels in rat frontal cortex without affect-
ing striatal acetylcholine levels.10,12 The ability of these
We have previously reported the N-(1-benzylpiperi-
din-4-yl)phenylacetamide (BP P ; Chart 1) as a σ receptor
ligand with high affinity for σ1 binding sites and
relatively low affinity for σ2 binding sites.18 A structure-
activity relationship (SAR) study of more than 40
derivatives of BP P was conducted with variable sub-
stitutions on the aromatic ring of the phenylacetamide
moiety. Substitution with fluoro at the ortho-position
to afford the N-(1-benzylpiperidin-4-yl)-2-fluorophenyl-
acetamide gave the highest selectivity for σ1 sites over
σ2 sites, while substitution with bromo at the meta-
position to afford the N-(1-benzylpiperidin-4-yl)-3-bro-
* To whom correspondence should be addressed. E-mail: rmach@
wfubmc.edu.
† Department of Radiology, Wake Forest University School of
Medicine.
‡ Anasazi BioMedical Research, Inc.
§ Department of Physiology and Pharmacology, Wake Forest Uni-
versity School of Medicine.
10.1021/jm010384j CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4405
Ch a r t 1
ence of a catalytic amount of dibutyltin diacetate
(method C). Compounds with substitution on the benzyl
group were prepared from BP P by hydrogenation over
a palladium hydroxide catalyst in methanol to give the
corresponding secondary amine (method D). The amine
was then alkylated with different substituted benzyl
halides to afford the corresponding analogues, 17-31.
The disubstituted compounds with halogens on both
aromatic rings (32-43) were prepared by the selective
protection and deprotection of the amino groups of
4-aminopiperidine (method E). Thus, 1-benzyl-4-ami-
nopiperidine was treated with trifluoroacetic anhydride
to give N-(1-benzylpiperidin-4-yl)trifluoroacetamide, fol-
lowed by hydrogenation with palladium hydroxide as
the catalyst to give the debenzylated amine. The de-
benzylated amine was protected with a tert-butoxycar-
bonyl (BOC) group by reacting with di-tert-butyl-
di-carbonate. The bis-protected aminopiperidine was
reacted with ammonium hydroxide to remove the tri-
fluoroacetyl group to generate 1-BOC-4-aminopiperi-
dine, which was then condensed with different substi-
tuted phenylacetic acids to afford the N-(1-BOC-piperidin-
4-yl)phenylacetamides. Deprotection of the BOC group
gave the corresponding amine, which was then alkyl-
ated with different substituted benzyl halides to afford
the desired analogues. 4-Iodobenzyl chloride, which was
used to synthesize compounds 22, 37, 40 and 43, was
prepared from 4-bromobenzyl alcohol in three steps
(Scheme 2).
mophenylacetamide (BBP ) had the highest affinity for
both σ1 and σ2 binding sites.18 These compounds exhib-
ited no detectable binding affinity for dopamine D2 and
D3 receptors, which distinguish these analogues from
benzamides and some other σ ligands that showed high
affinity for both σ and dopamine receptors.19
As a continued effort to further characterize the SARs
within this class of compounds,18 we report herein the
preparation and in vitro evaluation of a series of N-(1-
benzylpiperidin-4-yl)arylacetamide analogues as selec-
tive σ1 ligands. In this study, SAR studies were con-
ducted on three different regions of the template
compound, BP P , by (a) replacing the phenyl ring of the
phenylacetamide moiety with other aromatic rings, such
as thiophene, pyridyl, naphthyl, etc. (1-15); (b) substi-
tuting the aromatic ring of the benzyl group with
different substituents (17-30); and (c) substituting
either a fluorine or an iodine on the aromatic ring of
the benzyl group (32-43) to find suitable compounds
for the development of 125I- and 18F-labeled imaging
agents to be used with the functional imaging tech-
niques, positron emission tomography (PET), and single
photon emission computed tomography (SPECT). The
in vitro binding affinities for σ1 and σ2 receptors were
measured for all compounds, and selected compounds
were also tested for their binding to dopamine D2 and
D3 receptors. Also reported is a comparative molecular
field analysis (CoMFA) study on 79 compounds from a
combined trial set taken from this and our previous SAR
study. The CoMFA model developed provides new
insight into both steric and electrostatic influences that
affect binding in both aromatic regions of BP P and its
structural congeners.
In Vitr o Bin d in g. Examination of the σ receptor
affinities of those compounds with the phenylacetyl
moiety being replaced by various types of arylacetyl
moieties (1-15) reveals that lipophilicity of the aromatic
moiety has a great impact on σ receptor binding affinity
(Table 1). Compounds 1 and 2 had a thiophene ring
replacement of the phenyl ring as compared to BP P .
Both maintained high σ1 receptor affinities and rela-
tively low σ2 receptor affinities. The 2-substituted
thiophene, 1, exhibited higher σ1 to σ2 selectivity (100-
fold) than did both the BP P (62-fold) and the 3-substi-
tuted thiophene, 2 (47-fold). Compounds 3-6 have one
basic nitrogen in the aryl aromatic ring and are more
hydrophilic than compounds 1 and 2 and BP P . Their
Ki values indicated that they had much lower affinities
for σ1 receptors as compared to BP P and no significant
affinity for σ2 receptors (Ki > 1000). It is possible that
compounds 3-6 may be protonated in the binding
environment of the σ receptors, which may generate an
unfavorable interaction with the protein and result in
a decreased binding affinity. Compounds 7-9 have a
naphthyl group replacement of the phenyl ring. The
1-naphthylacetyl compound, 7, had the highest σ1
receptor affinity among the three naphthyl analogues,
with a σ1 receptor affinity that is comparable to that of
BP P . The 2-naphthylacetyl compound, 9, had a 13-fold
decrease in σ1 receptor affinity as compared to com-
pound 7. The urea analogue, 8, displayed a moderate
affinity for σ1 and σ2 receptors, which was in agreement
with our previous results of the N-(1-benzylpiperidin-
4-yl)-4-methylthiophenylacetamide and 1-(4-methyl-
thiophenyl)-3-(1-benzylpiperidin-4-yl)urea.18 All three
compounds, 7-9, had higher σ2 receptor affinities as
compared to BP P . Compounds 10-13 have an indole
(10-12) or an indanone moiety (13) in place of the
Resu lts
Ch em istr y. The desired compounds were prepared
according to the reactions outlined in Schemes 1 and 2.
Various N-(1-benzylpiperidin-4-yl)arylacetamides were
prepared directly by a simple coupling reaction using
either DCC (1,3-dicyclohexylcarbodiimide) (method A)
or BOP (benzotriazol-1-yloxy)tris(dimethylamino)phos-
phonium hexafluorophosphate) (method B).20,21 Com-
pound 8 was obtained by reacting the corresponding
isocyanate with 1-benzyl-4-aminopiperidine in the pres-

4406 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Huang et al.
Sch em e 1a
aReagents: (a) DCC/THF; (b) BOP/CH2Cl2; (c) dibutyltin diacetate/CH2Cl2; (d) H2/Pd-C/MeOH; (e) Br(CH2)nAr/CH2Cl2; (f) (CF3CO)2/
CH2Cl2; (g) (BOC)2O/CH2Cl2; (h) NH4OH/MeOH; (i) YC6H4CH2COOH/DCC/CH2Cl2; (j) CF3COOH/CH2Cl2; (k) ZCH2C6H4X (Z ) Br, Cl).
Sch em e 2a
receptor affinities were either decreased with ortho (17)
and meta (18) substitution or increased with para
substitution (19) when compared to that of BP P . The
3-fluoro-substituted analogue, 18, showed no significant
σ2 receptor affinity and had the highest σ1:σ2 selectivity
ratio (>122). The iodo-substituted compounds, 20-22,
displayed a slightly different pattern of binding to σ
receptors. The 2-iodo-substituted analogue, 20, had a
low affinity for σ1 receptors, whereas both the 3-iodo-
and the 4-iodo-substituted analogues maintained a σ1
receptor affinity that is comparable to that of BP P . The
σ2 receptor affinities of 2-iodo- and 4-iodo-substituted
analogues were decreased as compared to that of BP P ,
while the σ2 receptor affinity of the 3-iodo-substituted
analogue was similar to that of BP P . As a result, the
4-iodo-substituted analogue 22 had the highest σ1 to σ2
selectivity (σ1:σ2 ratio ) 77) among the three com-
pounds. Substitution with a trifluoromethyl group (23-
25) resulted in a significant reduction in σ1 receptor
affinity and a slight to significant reduction of σ2
receptor affinity. The 4-nitro-substituted analogue (26)
had a 5-fold lower σ1 receptor affinity than BBP ,
whereas the σ2 receptor affinity was only slightly
reduced. All three 3,4-disubstituted analogues (27-29)
maintained similar σ1 and σ2 receptor affinities to that
of BP P . Replacement of the benzyl group with a
aReagents: (a) BuLi/THF, Bu3SnCl; (b) Ph3P/CCl4; (c) I2/CH2Cl2.
phenyl ring. These compounds displayed a minor to
significant decrease in σ1 receptor affinity, with Ki
values in the rank order of 10 < 11 < 12 < 13.
Compound 10 had a high σ1 receptor affinity and
possessed a σ1:σ2 selectivity ratio of >92. Substitution
with a bromo (11) or methoxy (12) group decreased σ1
receptor affinity, and replacement with an indanone
ring (13) further reduced σ1 receptor affinity. Compound
14, which contained a 7-hydroxycoumarin ring, had no
measurable affinity for σ1 and σ2 receptors. Compound
15, which had a 2-pyrimidylthio moiety replacement of
the phenyl ring, showed a significant decrease in σ1
receptor affinity and no σ2 receptor affinity.
Substitution on the phenyl ring of the benzyl group
also showed some impact on σ1 and σ2 receptor affinity.
Compounds 17-19 contained a 2-, 3-, and 4-fluoro-
substituted benzyl group, respectively. Their σ1 receptor
affinities were similar to that of BP P , but their σ2

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4407
Ta ble 1. σ Receptor Binding Profiles of N-(1-Benzylpiperidin-4-yl)arylacetamides and Analogues in Cell Membranes
Ki(nM)a
b
c
d
no.
Ar1
Ar2
σ1
σ2
σ2/σ1
1
2
3
4
5
6
7
8
2-thiopheneacetyl
3-thiopheneacetyl
4-imidazoleacetyl
2-pyridylacetyl
3-pyridylacetyl
4-pyridylacetyl
1-naphthylacetyl
1-naphthylcarbamoyl
2-naphthylacetyl
3-indoleacetyl
5-bromo-3-indoleacetyl
5-methoxy-3-indoleacetyl
5-methoxy-1-indanone-3-acetyl
7-hydroxycoumarin-4-acetyl
(2-pyrimidylthio)acetyl
4-iodophenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
phenylacetyl
2-fluorophenylacetyl
2-fluorophenylacetyl
2-fluorophenylacetyl
3-fluorophenylacetyl
3-fluorophenylacetyl
3-fluorophenylacetyl
3-chlorophenylacetyl
3-chlorophenylacetyl
3-chlorophenylacetyl
3-bromophenylacetyl
3-bromophenylacetyl
3-bromophenylacetyl
phenylacetyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
benzyl
3.93 ( 0.80
7.20 ( 0.19
248.36 ( 2.42
235.50 ( 3.06
269.15 ( 4.33
298.47 ( 1.45
4.64 ( 1.01
392.82 ( 10.76
336.74 ( 50.65
100
47
>4
>4
>4
>3
9
1
2
>92
13
>8
1
0
>7
4
64
>122
13
2
>1000
>1000
>1000
>1000
39.44 ( 3.81
22.66 ( 1.13
61.77 ( 2.14
10.90 ( 0.02
51.94 ( 3.87
125.41 ( 4.04
298.56 ( 2.13
25.02 ( 1.85
111.57 ( 7.52
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
BBP
>1000
678.28 ( 3.42
>1000
416.41 ( 5.31
>1000
>1000
61.31 ( 1.70
682.70 ( 11.96
>1000
>1000
149.84 ( 10.17
13.82 ( 3.43
10.16 ( 1.92
8.22 ( 0.05
6.59 ( 0.89
346.90 ( 4.66
6.75 ( 0.32
9.03 ( 0.34
2-fluorobenzyl
3-fluorobenzyl
4-fluorobenzyl
2-iodobenzyl
3-iodobenzyl
4-iodobenzyl
2-trifluoromethylbenzyl
3-trifluoromethylbenzyl
4-trifluoromethylbenzyl
4-nitrobenzyl
3,4-dichlorobenzyl
3,4-difluorobenzyl
3,4-methylenedioxybenzyl
2-naphthylmethyl
phenylethyl
4-fluorobenzyl
3-iodobenzyl
4-iodobenzyl
4-fluorobenzyl
3-iodobenzyl
4-iodobenzyl
4-fluorobenzyl
3-iodobenzyl
4-iodobenzyl
4-fluorobenzyl
3-iodobenzyl
4-iodobenzyl
82.89 ( 1.35
631.00 ( 8.34
191.05 ( 3.11
693.54 ( 58.16
28
77
0
4
3
17
58
37
43
8
>1000
>1000
141.36 ( 5.78
87.05 ( 3.50
19.07 ( 0.22
7.24 ( 1.04
6.30 ( 0.01
3.97 ( 0.07
23.88 ( 1.70
31.25 ( 2.04
3.15 ( 0.05
15.41 ( 0.37
4.20 ( 0.84
5.51 ( 0.61
4.29 ( 1.16
2.25 ( 0.60
1.15 ( 0.22
2.31 ( 0.46
3.21 ( 0.14
1.21 ( 0.16
3.49 ( 0.35
1.78 ( 0.20
3.90 ( 0.82
2.53 ( 0.25
14.34 ( 0.08
513.16 ( 5.68
300.41 ( 3.64
319.07 ( 13.78
423.17 ( 4.11
231.61 ( 29.36
171.40 ( 15.68
189.47 ( 8.82
106.87 ( 4.82
139.51 ( 21.89
181.30 ( 15.40
232.53 ( 23.54
31.02 ( 0.18
50.26 ( 3.24
167.63 ( 15.09
9.38 ( 0.27
3
44
12
55
6
12
74
8
13
80
5
17
51
62
11
2
30.34 ( 5.34
256.62 ( 19.04
6.06 ( 1.50
59.32 ( 2.32
90.31 ( 6.79
benzyl
240 ( 30
haloperidol
haloperidol metabolite II
28.52 ( 1.64
28.55 ( 4.17
a
Mean ( SEM, Ki values were determined by at least three experiments. Each inhibition curve consisted of eight points from each
binding assay. Ki values for σ1 receptors were measured on guinea pig brain membranes using [3H](+)-pentazocine as the radioligand.
b
c Ki values for σ2 receptors were measured on rat liver membranes using [3H]-DTG as the radioligand in the presence of (+)-pentazocine.
d
Ki for σ2 receptor/Ki for σ1 receptor.
Ta ble 2. Summary of Results for CoMFA on 76 Compound Set
2-naphthylmethyl (30) or phenethyl (31) group resulted
for σ1 Binding Data
in 6-8-fold loss in σ1 receptor affinity and a similar or
q2
Npc SEOP
0.50
r2
0.91 0.24 116
SEE
F
steric electrostatic
0.54 0.46
slightly reduced σ2 receptor affinity.
0.61
6
CoMF A Mod el. The initial analysis for the full set
2
of 79 compounds gave a moderate crossvalidated rcv
value (q2) of 0.47 using six components. Examination
of residuals showed that three compounds, i.e., N-(1-
benzylpiperidin-4-yl)-2-methoxyphenylacetamide, N-(1-
benzylpiperidin-4-yl)-3-hydroxyphenylacetamide, and
N-(1-benzylpiperidin-4-yl)-3-pyridylacetamide, 5, were
not well fit by the model. Dropping these three com-
pounds markedly improved the analysis. Analysis of the
remaining set of 76 compounds gave a satisfactory
nents recommended and a standard error of prediction
(SEOP) of 0.49. Examination of the crossvalidated rcv
2
values (q2) and the SEOPs indicated that the optimum
number of components was six since addition of a
seventh component increased the final non-crossvali-
dated r2 value by less than 5%. The final model (six
components) showed a crossvalidated q2 ) 0.61 (SEOP
) 0.50), with a final non-crossvalidated r2 ) 0.91.
CoMFA analyses of the σ1 binding data (log 1/Ki) are
crossvalidated rcv value (q2) of 0.64 with seven compo-
2

4408 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Huang et al.
and 43). In addition to the 2-fluorophenylacetyl and
3-bromophenylacetyl analogues, the 3-fluorophenyl-
acetyl (35-37) and 3-chlorophenylacetyl (38-40) ana-
logues were prepared for comparison. The results of in
vitro binding studies showed that compounds 32-43
maintained an affinity for the σ1 receptor that is similar
to that of the corresponding N-benzyl phenylaceta-
mide.18 However, the σ2 receptor affinities were all
increased as compared to that of the corresponding
N-benzyl phenylacetamide, resulting in a lower selectiv-
ity for σ1 vs σ2 receptors. Compounds 38 and 41 had
very high affinities for both σ1 and σ2 receptors, whereas
32 had a high affinity and high selectivity for σ1 vs σ2
receptors. Compounds 22, 34, 37, 40, and 43, which
contain a 4-iodobenzyl group, all showed high affinity
and selectivity for σ1 receptors. These compounds can
be labeled with iodine-125 and used in in vitro and in
vivo studies of the σ1 receptor. Similarly, 32 can be
labeled with fluorine-18 and be used in PET imaging
studies of the σ1 receptor. These compounds are cur-
rently under evaluation, and the results will be reported
elsewhere.30,31
F igu r e 1. Rotatable bonds used in conformational searches,
substituent orientations, and critical distances in BP P and
related compounds.
summarized in Table 2. Analyses were also carried out
using single-point AM1 charges rather than those
calculated by the Gasteiger-Hu¨ckel method but showed
no improvement in the model.
Similar CoMFA analyses of affinity data for the σ2
binding data gave only low crossvalidated rcv2 (q2) values
and indicated that further work will be needed to derive
a predictive model for those binding data.
Figure 2a,b shows the steric and electrostatic contour
plots, respectively, for the final σ1 CoMFA model. Figure
3 shows a plot of the predicted vs actual pKi values,
spanning three orders of magnitude, for the σ1 binding
affinities of the 76 phenylacetamides used in this model.
In general, binding affinities were well fit, and the
CoMFA model should be of use in the prediction of
binding affinities for new compounds.
Only one CoMFA study of σ1 ligands has been
published to date.33 This study utilized compounds with
limited substitutions on the aromatic ring or rings.
Examining a model based on a more diverse set of
compounds with greater substitution in both the pri-
mary and the secondary hydrophobic sites should be
valuable for identifying the binding requirements of σ1
and σ2 receptors. Initially, conformational search studies
were carried out to identify low energy conformations
as starting points for CoMFA studies. The conformation
chosen for evaluation for parent compound BP P pos-
sessed similar features to the receptor features proposed
originally by Glennon.34 As shown in Figure 1, the
distance from the piperidinyl-nitrogen to the centroid
of the phenylacetamide aromatic ring was 7.9 Å (as
compared to the optimal 8.3 Å proposed by Glennon)
and represents the distance to the proposed primary
hydrophobic site. The distance from the nitrogen to the
centroid of the benzylic aromatic was 3.8 Å and is in
good agreement with the distance to the secondary
hydrophobic binding site proposed by Glennon (2.5-3.9
Å range). One further feature that may be derived from
Discu ssion
Our interest in σ ligands was to discover compounds
having a high affinity and selectivity for both subtypes
of the sigma receptors, σ1 and σ2 receptors. A second
goal was to develop suitable ligands as SPECT or PET
radiotracers for functional imaging studies of these
receptors. Our previous results had shown that the BBP
displayed a high affinity for both σ1 and σ2 receptors,
while the N-(1-benzylpiperidin-4-yl)-2-fluorophenylac-
etamide had the highest selectivity for σ1 receptors in
that series.18 The 4-fluorobenzyl, 3-iodobenzyl, and
4-iodobenzyl are ideal substitutions for the development
of 18F- and 123/125I-labeled radiotracers. Therefore, a
number of analogues were prepared containing either
the 4-fluoro-substituted benzyl group (32, 35, 38, and
41), the 3-iodo-substituted benzyl group (33, 36, 39, and
42), or the 4-iodo-substituted benzyl group (34, 37, 40,
F igu r e 2. Steric and electrostatic contour plots for the final non-crossvalidated CoMFA model overlaid on the parent compound
BP P . (a) Regions color-coded green correspond to areas where increased steric bulk is predicted to lead to greater affinity at the
σ1 receptor, while yellow regions represent areas where increased steric bulk should lead to decreased affinity. (b) Blue regions
correspond to areas where an increase in positive charge should lead to greater affinity at the σ1 receptor, while red regions
correspond to areas where an increase in negative charge should lead to greater affinity.

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4409
F igu r e 3. Plot of actual vs predicted pKi values for σ1 receptor binding data based on final CoMFA model.
the phenylacetamides is the distance to the proposed
hydrogen bonding center, as represented by the distance
from the cationic nitrogen to the carbonyl oxygen of
5.4 Å.
Electrostatic features that strongly influence binding
are shown in Figure 2b. Two areas where increased
positive charge should increase binding affinity were
found near the 4- and 6-position of the phenylacetamide
aromatic ring. A slightly smaller region, with opposite
effects, is found near the 3-position, indicating that in
this area, negative charge should increase binding
affinity. Further, a small area where positive charge
should enhance binding affinity was found near the
benzylic aromatic.
These results appear to be in general agreement with
our earlier conclusions drawn from a Hansch analysis
of more limited data but provide more detail into
interactions in specific areas. For example, the 3-bro-
mophenylacetamide (Ki ) 0.87 nM), the most potent σ1
receptor ligand from both studies, places steric bulk well
within the regions shown in Figure 2a and places
negative charge in the area shown in Figure 2b where
negative charge should lead to enhanced affinity. Con-
versely, 4-methoxyphenylacetamides, which show a
decrease in binding affinity as compared to unsubsti-
tuted BP P , have negative charge near the 4-position
region, a region predicted to show increased affinity with
positive charge. Furthermore, these results provide a
more detailed analysis, particularly for electrostatic
interactions, than that provided by the compounds used
in the CoMFA published by Ablordeppey.33
Figure 2 shows regions, overlaid on the parent
compound BP P , where either steric or electrostatic
features are expected to have a marked influence on
binding affinity to the σ1 receptor. In general, Figure 2
shows that substitutions on the benzylic ring appear to
contribute much less than comparable substitutions on
the phenylacetamide aromatic ring. Examining Figure
2a, the model predicts that steric bulk at either the
3-position or the 4-position on the phenylacetamide
aromatic ring will be well-tolerated and will lead to
increased affinity at the σ1 receptor. However, note that
a region where steric bulk will decrease binding affinity
is predicted further from the 4-position of that same
aromatic moiety. This may indicate a pocket with
limited ability to accommodate larger groups in that
region of the receptor. For example, while the 1-naph-
thylacetamide derivative (7) fits well in this region and
shows affinity comparable to the phenyl derivative
BP P , the 2-naphthyl-acetamide (9) extends past the
sterically allowed region, with a subsequent 14-fold
decrease in binding affinity.
There is a large area of steric bulk tolerance found
near the 1- and 2-position of the phenylacetamide and
behind the viewer’s orientation. This may imply that
larger, nonplanar rings might be tolerated by this
receptor. Two regions near the 5- and 6-positions of the
phenylacetamide ring indicate that steric bulk is not
well-tolerated in these areas. Figure 2a also indicates
that 2-position and in some cases 3-position substitu-
tions on the benzylic aromatic ring will lead to lowered
affinity when the steric bulk of a substituent becomes
too large.
To confirm that these arylacetamide analogues do not
bind to the dopamine D2 class of receptors, in vitro
binding assays were conducted with genetically engi-
neered sf9 cells containing either the rat dopamine
D2-long or the rat D3 receptors.35 The dopamine receptor
binding assays were conducted on analogues 1, 10, and
18 and revealed that the arylacetamide analogues had
no affinity (IC50 > 10 000 nM) for both D2 and D3
receptors.

4410 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Huang et al.
salt) 218-220 °C. NMR (free base; CDCl3/TMS): δ 7.21-7.35
(m, 6H), 7.12 (d, J ) 2.6 Hz, 1H), 6.97 (dd, J ) 1.2, 5 Hz, 1H),
5.29 (d, J ) 8 Hz, 1H), 3.71-3.81 (m, 1H), 3.58 (s, 2H), 3.45
(s, 2H), 2.71 (d, J ) 12 Hz, 2H), 2.09 (dt, J ) 2, 8 Hz, 2H),
1.83 (d, 12 Hz, 2H), 1.36 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd
for C18H22N2OS‚HCl: C, H, N.
In summary, this study investigated a series of N-(1-
benzylpiperidin-4-yl)arylacetamides for their binding
affinities for σ1 and σ2 receptors. A SAR study was
conducted based on structural modifications that were
made in four regions of the template compound BP P .
The σ receptor binding results are qualitatively com-
parable and in agreement with those of our previously
reported series.18 Specifically, (a) replacement of the
phenyl ring of the phenylacetamide moiety with various
aromatic rings maintains a high σ1 receptor affinity
when the aromatic ring is lipophilic and decreases the
σ1 receptor affinity when the aromatic ring is less
lipophilic/more hydrophilic; (b) substitution on the
phenyl ring of the benzyl group maintains a high or
slightly lowered affinity for σ1 receptors when the
substitution is made at the 3- or 4-position and has a
slightly to significantly decreased or no affinity for σ2
receptors as the steric bulk of the substituent increases
at the 2-position; and (c) substitution on both the
phenylacetyl aromatic ring and the benzyl aromatic ring
maintains a high affinity for σ1 receptors with a gener-
ally increased σ2 receptor affinity. Compounds 22, 32,
34, 37, 40, and 43 can be used as PET and SPECT
imaging agents to study the physiological functions of
σ1 receptors.
N-(1-(Ben zyl)p ip er id in -4-yl)-1-n a p h th yla ceta m id e (7).
Recrystallized from ethyl acetate/ethanol; yield, 31%; mp (HCl
salt) 215-217 °C. NMR (free base; CDCl3/TMS): δ 7.82-7.91
(m, 3H), 7.39-7.53 (m, 4H), 7.18-7.26 (m, 5), 5.08 (d, J ) 8
Hz, 1H), 3.81 (s, 2H), 3.72-3.82 (m, 1H), 3.35 (s, 2H), 2.55 (d,
J ) 12 Hz, 2H), 2.00 (dt, J ) 2, 11 Hz, 2H), 1.62 (d, J ) 12
Hz, 2H), 1.10 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd for
C
24H26N2O‚HCl: C, H, N.
N-(1-(Ben zyl)p ip er id in -4-yl)-2-n a p h th yla ceta m id e (9).
Recrystallized from ethyl acetate/hexane; yield, 43%; mp (HCl
salt) 206-208 °C. NMR (free base; CDCl3/TMS): δ 7.81-7.85
(m, 4H), 7.48-7.51 (m, 2H), 7.22-7.37 (m, 6), 5.25 (d, J ) 8
Hz, 1H), 3.73-3.83 (m, 1H), 3.71 (s, 2H), 3.42 (s, 2H), 2.69 (d,
J ) 12 Hz, 2H), 2.05 (dt, J ) 2, 11 Hz, 2H), 1.80 (d, J ) 12
Hz, 2H), 1.30 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd for
C
24H26N2O‚HCl: C, H, N.
N -(1-(Be n zyl)p ip e r id in -4-yl)-5-b r om oin d ole -3-a ce t -
a m id e (11). Recrystallized from ethyl acetate/ethanol; yield,
58%; mp (free base) 149-150 °C. NMR (CDCl3/TMS): δ 8.33
(s, 1H), 7.67 (s, 1H), 7.19-7.30 (m, 7H), 7.13 (s, 1H), 5.46 (d,
J ) 8 Hz, 1H), 3.77-3.83 (m, 1H), 3.65 (s, 2H), 3.42 (s, 2H),
2.60 (d, J ) 9 Hz, 2H), 2.03-2.12 (m, 2H), 1.80 (dd, J ) 2, 11
Hz, 2H), 1.26 (dq, J ) 2, 10 Hz, 2H). Anal. Calcd for C23H24N3-
OBr: C, H, N.
Exp er im en ta l Section
N -(1-(Be n zyl)p ip e r id in -4-yl)-5-m e t h oxy-1-in d on e -3-
a ceta m id e (13). Recrystallized from ethyl acetate/hexane;
yield, 20%; mp (HCl salt) 223-226 °C. NMR (free base; DMSO-
d6/TMS): δ 7.66 (d, J ) 8 Hz, 1H), 7.26-7.32 (m, 5H), 6.90-
6.93 (m, 2H), 5.36 (d, J ) 7 Hz, 1H), 3.80-3.85 (m, 6H), 3.50
(s, 2H), 2.78 (d, J ) 7 Hz, 2H), 2.31-2.39 (m, 2H), 2.10-2.16
(m, 1H), 2.08 (t, J ) 15 Hz, 2H), 1.40-1.50 (m, 2H). Anal. Calcd
for C24H28N2O3‚HCl: C, H, N.
N -(1-(Be n zyl)p ip e r id in -4-yl)-(2-p yr im id ylt h io)a ce t -
a m id e (15). Recrystallized from ethyl acetate/hexane; yield,
19%; mp (free base) 138-139 °C. NMR (CDCl3/TMS): δ 8.54
(d, J ) 5 Hz, 2H), 7.20-7.32 (m, 5H), 7.05 (t, J ) 5 Hz, 2H),
6.86 (d, J ) 8 Hz, 1H), 3.74-3.90 (m, 3H), 3.44 (s, 2H), 2.69
(d, J ) 12 Hz, 2H), 2.07 (dt, J ) 2, 11 Hz, 2H), 1.82 (d, J ) 12
Hz, 2H), 1.36 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd for C18H22N4-
OS: C, H, N.
Ch em istr y. Melting points were measured on a Fisher-
J ohns melting point apparatus and are uncorrected. Elemental
analyses were performed at Atlantic Microlabs, Atlanta, GA;
where molecular formulas were indicated, analyses were found
to be within (0.4% of the theoretical values for these elements.
Proton nuclear magnetic resonance (NMR) spectra were
recorded at 300 MHz on a Bruker ASPECT3000 spectrometer.
All proton NMR spectra were obtained in either CDCl3 or
DMSO-d6, and results are recorded as parts per million (ppm)
downfield to tetramethylsilane (TMS). The following abbrevia-
tions are used for multiplicity of NMR signals: s ) singlet, d
) doublet, t ) triplet, q ) quartet, m ) multiplet, dd ) double
doublet, dt ) double triplet, dq ) double quartet, and br )
broad. All starting materials and solvents were purchased from
either Aldrich or Fisher and were used without further
purification.
N-(1-Ben zyl)piper idin -4-yl)-4-iodoph en ylacetam ide (16).
Recrystallized from ethyl acetate/hexane; yield, 87%; mp (free
base) 145-147 °C. NMR (CDCl3/TMS): δ 7.66 (dd, J ) 2, 5
Hz, 2H), 7.22-7.32 (m, 4H), 7.00 (d, J ) 8 Hz, 2H), 5.22 (d, J
) 8 Hz, 1H), 3.60-3.70 (m, 1H), 3.45 (s, 2H), 3.43 (s, 2H), 2.73
(d, J ) 11 Hz, 2H), 2.10 (dt, J ) 2, 11 Hz, 2H), 1.75-1.95 (m,
2H), 1.25-1.45 (m, 2H). Anal. Calcd for C20H23N2OI: C, H, N.
Gen er a l Meth od B. P r ep a r a tion of N-(1-Ben zylp ip er i-
d in -4-yl)im id a zole-4-a ceta m id e (3). To a solution of imi-
dazole-4-acetic acid hydrochloride (1.25 g, 7.7 mmol) in DMSO
(50 mL) and triethylamine (1 mL) were added BOP (3.40 g,
7.7 mmol) and 1-benzyl-4-aminopiperidine (1.46 g, 7.7 mmol)
under stirring. After the solution was stirred at room temper-
ature for 2 h, the mixture was poured into 100 mL of water
and extracted with CH2Cl2 (3 × 20 mL), washed with aqueous
NaHCO3 and saturated aqueous NaCl, and dried over Na2-
SO4. The product was purified on a silica gel column using
CHCl3-EtOH (7:3) as the eluent. Recrystallization from ethyl
acetate/pentane gave 0.83 g of free amine (37%). mp 134-135
°C. NMR (free amine in CDCl3): δ 7.60 (s, 1H), 7.17-7.33 (m,
5H), 6.88 (m, 2H), 3.73-3.84 (m, 1H), 3.52 (s, 2H), 3.47 (s, 2H),
2.73-2.77 (d, 2H), 2.04-2.15 (dt, 2H), 1.84-1.88 (m, 2H),
1.38-1.51 (dq, 2H). Anal. Calcd for C17H22N4O: C, H, N.
N-(1-(Ben zyl)p ip er id in -4-yl)-2-pyr id oa ceta m id e (4). Re-
crystallized from ethyl acetate/hexane; yield, 92%; mp (free
base) 107-108 °C. NMR (CDCl3/TMS): δ 8.69-8.79 (m, 1H),
7.63-7.67 (m, 1H), 7.18-7.33 (m, 7H), 3.75-3.82 (m, 1H), 3.69
(s, 2H), 3.47 (s, 2H), 2.72 (d, J ) 12 Hz, 2H), 2.13 (dt, J ) 2,
Gen er a l Meth od A. P r ep a r a tion of N-(1-Ben zylp ip er i-
d in -4-yl)th iop h en e-2-a ceta m id e (1). To an ice-cold solution
of thiophene-2-acetic acid (1.42 g, 10 mmol) in dry tetrahy-
drofuran (THF) (50 mL) was added DCC (2.06 g, 10 mmol).
After 30 min, 1-benzyl-4-aminopiperidine (1.90 g, 10 mmol)
in THF (20 mL) was added. The reaction was stirred at room
temperature overnight. The solid was removed by filtration,
the solvent was evaporated in vacuo, and the residue was
dissolved in CH2Cl2 (100 mL) and then washed with saturated
aqueous NaCl and dried over Na2SO4. The solvent was
removed in vacuo, and the residue was chromatographed on
a silica gel column using CHCl3 and then CHCl3-EtOH (9.5:
0.5) as the eluents. The product was then recrystallized from
ethyl acetate/hexane to give 0.86 g free amine, mp 122-123
°C. The mother liquid was concentrated and converted into
the HCl salt by treatment with HCl gas in ethyl acetate. After
the solvent was removed, the HCl salt was recrystallized from
ethyl acetate-ethanol to give 1.46 g (69% overall), mp 208-
210 °C. NMR (free amine in CDCl3): δ 7.21-7.32 (m, 6H,
aromatic), 6.97-7.00 (m, 1H, aromatic), 6.92-6.93 (m, 1H,
aromatic), 5.42-5.44 (d, 1H, NH), 3.75 (s, 2H, CH2CO), 3.73-
3.85 (m, 1H, NH-CH), 3.45 (s, 2H, CH2-phenyl), 2.69-2.74
(d, 2H, 2R-Heq of piperidine), 2.05-2.14 (dt, 2H, 2R-Hax of
piperidine), 1.84-1.88 (m, 2H, 2â-Heq of piperidine), 1.29-1.42
(dq, 2H, 2â-Hax of piperidine). Anal. Calcd for C18H23N2OSCl:
C, H, N.
N-(1-(Ben zyl)pip er id in -4-yl)-3-th ioph en ea ceta m ide (2).
Recrystallized from ethyl acetate/ethanol; yield, 64%; mp (HCl

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4411
11 Hz, 2H), 1.85 (d, J ) 12 Hz, 2H), 1.45 (dq, J ) 3, 12 Hz,
2H). Anal. Calcd for C19H23N3O: C, H, N.
with 0.5 N NaOH and water, and dried over Na2SO4. Solvent
was removed, and the residue was purified by a silica gel
column with CHCl3-EtOH (9.5:0.5) as the eluent and recrys-
tallized from ethyl acetate-hexane to give 0.27 g (83%) of free
amine; mp 108-109 °C. NMR (free amine in CDCl3): δ 7.21-
7.37 (m, 7H), 7.97-7.10 (m, 2H), 5.16-5.19 (d, 1H), 3.76-3.79
(m, 1H), 3.55 (s, 2H), 3.52 (s, 2H), 2.70-2.74 (d, 2H), 2.10-
2.18 (dt, 2H), 1.82-1.85 (m, 2H), 1.26-1.37 (dq, 2H). Anal.
Calcd for C20H23N2OF: C, H, N.
N -(1-(3-F lu o r o b e n zy l)p ip e r id in -4-y l)p h e n y la c e t -
a m id e (18). Recrystallized from ethyl acetate/hexane; yield,
58%; mp (free base) 117-118 °C. NMR (CDCl3/TMS): δ 7.20-
7.38 (m, 6H), 6.99-7.03 (m, 2H), 6.88-6.95 (dt, J ) 2, 9 Hz,
1H), 5.20 (d, J ) 8 Hz, 1H), 3.73-3.84 (m, 1H), 3.55 (s, 2H),
3.43 (s, 2H), 2.68 (d, J ) 11 Hz, 2H), 2.10 (dt, J ) 2, 11 Hz,
2H), 1.82 (d, J ) 9 Hz, 2H), 1.32 (dt, J ) 2, 9 Hz, 2H). Anal.
Calcd for C20H23N2OF: C, H, N.
N -(1-(4-F lu o r o b e n zy l)p ip e r id in -4-y l)p h e n y la c e t -
a m id e (19). Recrystallized from ethyl acetate/hexane; yield,
90%; mp (free base) 120-121 °C. NMR (CDCl3/TMS): δ 7.20-
7.35 (m, 7H), 6.94-7.00 (m, 2H), 5.20 (d, J ) 8 Hz, 1H), 3.75-
3.86 (m, 1H), 3.55 (s, 2H), 3.40 (s, 2H), 2.67 (d, J ) 12 Hz,
2H), 2.06 (t, J ) 8 Hz, 2H), 1.82 (d, J ) 8 Hz, 2H), 1.25-1.31
(m, 2H). Anal. Calcd for C20H23N2OF: C, H, N.
N-(1-(Ben zyl)pip er idin -4-yl)-3-pyr id oa ceta m id e (5). Re-
crystallized from ethyl acetate/hexane; yield, 44%; mp (free
base) 111-112 °C. NMR (CDCl3/TMS): δ 8.54 (dd, J ) 1.5, 5
Hz, 1H), 8.50 (d, J ) 2 Hz, 1H), 7.63-7.67 (m, 1H), 7.21-7.34
(m, 5H), 5.29 (d, J ) 7 Hz, 1H), 3.70-3.86 (m, 1H), 3.52 (s,
2H), 3.46 (s, 2H), 2.76 (d, J ) 12 Hz, 2H), 2.08 (dt, J ) 2, 11
Hz, 2H), 1.86 (d, J ) 12 Hz, 2H), 1.40 (dq, J ) 3, 12 Hz, 2H).
Anal. Calcd for C19H23N3O: C, H, N.
N-(1-(Ben zyl)pip er id in -4-yl)-4-pyr id oa ceta m id e (6). Re-
crystallized from ethyl acetate/ethanol; yield, 49%; mp (free
base) 224-226 °C. NMR (DMSO-d6/TMS): δ 8.48 (d, J ) 4
Hz, 2H), 8.30 (d, J ) 6 Hz, 1H), 7.49 (s, 5H), 7.27 (d, J ) 5 Hz,
2H), 4.26 (s, 1H), 3.03-3.61 (m, 8H), 1.94 (d, J ) 12 Hz, 2H),
1.59-1.62 (m, 2H). Anal. Calcd for C19H23N3O: C, H, N.
N-(1-(Ben zyl)p ip er id in -4-yl)in d ole-3-a cet a m id e (10).
Recrystallized from ethyl acetate/ethanol; yield, 58%; mp (free
base) 139-140 °C. NMR (CDCl3/TMS): δ 8.40 (s, 1H), 7.53
(d, J ) 8 Hz, 1H), 7.40 (d, J ) 8 Hz, 1H), 7.22-7.27 (m, 6H),
7.11-7.16 (m, 2H), 5.56 (d, J ) 8 Hz, 1H), 3.75-3.85 (m, 1H),
3.72 (s, 2H), 3.40 (s, 2H), 2.65 (d, J ) 9 Hz, 2H), 1.76-2.09
(m, 4H), 1.21 (dq, J ) 2, 10 Hz, 2H). Anal. Calcd for
C
23H25N3O: C, H, N.
N-(1-(2-Iodoben zyl)piper idin -4-yl)ph en ylacetam ide (20).
Recrystallized from ethyl acetate/hexane; yield, 74%; mp (free
base) 135-136 °C. NMR (CDCl3/TMS): δ 7.80 (d, J ) 8 Hz,
1H), 7.23-7.38 (m, 7H), 6.93 (dt, J ) 2, 8 Hz, 1H), 5.20 (d, J
) 8 Hz, 1H), 3.77-3.94 (m, 1H), 3.56 (s, 2H), 3.45 (s, 2H), 2.72
(d, J ) 11 Hz, 2H), 2.20 (dt, J ) 2, 11 Hz, 2H), 1.85 (d, J ) 9
Hz, 2H), 1.35 (dt, J ) 2, 9 Hz, 2H). Anal. Calcd for C20H23N2-
OI: C, H, N.
N-(1-(Ben zyl)p ip er id in -4-yl)-5-m et h oxyin d ole-3-a cet -
a m id e (12). Recrystallized from ethyl acetate/ethanol; yield,
36%; mp (HCl salt) 177-178 °C. NMR (free base; CDCl3/
TMS): δ 8.15 (s, 1H), 7.19-7.30 (m, 6H), 7.09 (d, J ) 2.4 Hz,
1H), 6.87-6.94 (m, 2H), 5.57 (d, J ) 8 Hz, 1H), 3.79-3.86 (m,
4H), 3.68 (s, 2H), 3.40 (s, 2H), 2.64 (d, J ) 11.4 Hz, 2H), 2.05
(dt, J ) 2.3, 12 Hz, 2H), 1.76 (m, 2H), 1.20-1.30 (m, 2H). Anal.
Calcd for C23H27N2O2‚HCl: C, H, N.
N-(1-(3-Iodoben zyl)piper idin -4-yl)ph en ylacetam ide (21).
Recrystallized from ethyl acetate/hexane; yield, 85%; mp (free
base) 133-134 °C. NMR (CDCl3/TMS): δ 7.64 (s, 1H), 7.56
(d, J ) 8 Hz, 1H), 7.17-7.38 (m, 6H), 7.02 (t, J ) 8 Hz, 1H),
5.19 (d, J ) 8 Hz, 1H), 3.74-3.84 (m, 1H), 3.40 (s, 2H), 3.37
(s, 2H), 2.67 (d, J ) 11 Hz, 2H), 2.07 (dt, J ) 2, 11 Hz, 2H),
1.83 (d, J ) 9 Hz, 2H), 1.30 (dt, J ) 2, 9 Hz, 2H). Anal. Calcd
for C20H23N2OI: C, H, N.
N -(1-(Be n zyl)p ip e r id in -4-yl)-7-h yd r oxycou m a r in -4-
a ceta m id e (14). Recrystallized from ethyl acetate/ethanol;
yield, 100%; mp (HCl salt) 189-192 °C. NMR (free base;
DMSO-d6/TMS): δ 10.58 (s, 1H), 8.38 (d, J ) 7 Hz, 1H), 6.80-
7.59 (m, 5H), 6.72-6.76 (m, 2H), 5.72 (s, 1H), 4.00-4.04 (m,
3H), 3.63-3.75 (m, 1H), 3.47-3.59 (m, 2H), 3.35-3.46 (m, 2H),
3.04-3.11 (m, 2H), 1.90-2.01 (m, 2H), 1.20-1.57 (m, 2H).
Anal. Calcd for C24H28N2O4‚HCl: C, H, N.
N-(1-(4-Iodoben zyl)piper idin -4-yl)ph en ylacetam ide (22).
Recrystallized from ethyl acetate/hexane; yield, 41%; mp (free
base) 136-138 °C. NMR (CDCl3/TMS): δ 7.62 (d, J ) 8 Hz,
2H), 7.17-7.38 (m, 5H), 7.01 (d, J ) 8 Hz, 2H), 5.20 (d, J ) 7
Hz, 1H), 3.74-3.84 (m, 1H), 3.55 (s, 2H), 3.37 (s, 2H), 2.66 (d,
J ) 12 Hz, 2H), 2.06 (dt, J ) 2, 11 Hz, 2H), 1.82-1.90 (d, J )
8 Hz, 2H), 1.30 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd for C20H23N2-
OI: C, H, N.
N-(1-(2-Tr iflu or om eth ylben zyl)p ip er id in -4-yl)p h en yl-
a ceta m id e (23). Recrystallized from ethyl acetate; yield, 85%;
mp (free base) 133-134 °C. NMR (CDCl3/TMS): δ 7.70 (d, J
) 8 Hz, 1H), 7.60 (d, J ) 8 Hz, 1H), 7.47 (t, J ) 8 Hz, 1H),
7.23-7.39 (m, 6H), 5.23 (d, J ) 8 Hz, 1H), 3.72-3.92 (m, 1H),
3.59 (s, 2H), 3.56 (s, 2H), 2.68 (d, J ) 11 Hz, 2H), 2.18 (dt, J
) 2, 11 Hz, 2H), 1.85 (d, J ) 9 Hz, 2H), 1.32 (dt, J ) 2, 9 Hz,
2H). Anal. Calcd for C21H23N2OF3: C, H, N.
N-(1-(3-Tr iflu or om eth ylben zyl)p ip er id in -4-yl)p h en yl-
a ceta m id e (24). Recrystallized from ethyl acetate; yield, 56%;
mp (free base) 141-142 °C. NMR (CDCl3/TMS): δ 7.23-7.55
(m, 9H), 5.22 (d, J ) 8 Hz, 1H), 3.72-3.92 (m, 1H), 3.55 (s,
2H), 3.48 (s, 2H), 2.68 (d, J ) 11 Hz, 2H), 2.10 (dt, J ) 2, 11
Hz, 2H), 1.82 (d, J ) 9 Hz, 2H), 1.30 (dt, J ) 2, 9 Hz, 2H).
Anal. Calcd for C21H23N2OF3: C, H, N.
N-(1-(4-Tr iflu or om eth ylben zyl)p ip er id in -4-yl)p h en yl-
a ceta m id e (25). Recrystallized from ethyl acetate; yield, 66%;
mp (free base) 128-129 °C. NMR (CDCl3/TMS): δ 7.54 (d, J
) 8 Hz, 2H), 7.23-7.41 (m, 7H), 5.22 (d, J ) 8 Hz, 1H), 3.72-
3.92 (m, 1H), 3.56 (s, 2H), 3.49 (s, 2H), 2.68 (d, J ) 11 Hz,
2H), 2.10 (dt, J ) 2, 11 Hz, 2H), 1.85 (d, J ) 9 Hz, 2H), 1.30
(dt, J ) 2, 9 Hz, 2H). Anal. Calcd for C21H23N2OF3: C, H, N.
N-(1-(4-Nit r ob en zyl)p ip er id in -4-yl)p h en yla cet a m id e
(26). Recrystallized from ethyl acetate/ethanol; yield, 74%; mp
(free base) 140-142 °C. NMR (CDCl3/TMS): δ 8.15 (d, J ) 9
Hz, 2H), 7.46 (d, J ) 9 Hz, 2H), 7.23-7.39 (m, 5H), 5.20 (d, J
Meth od C. P r ep a r a tion of 1-(1-Na p h th yl)-3-(1-ben zyl-
p ip er id in -4-yl)u r ea (8). A mixture of 1-naphthylisocyanate
(1.69 g, 10 mmol), 1-benzyl-4-aminopiperidine (1.90 g, 10
mmol), and dibutyltin diacetate (3 drops) in 40 mL of CH2Cl2
was stirred at room temperature for 2 h. The mixture was
poured into ice-cold water, extracted with CH2Cl2 (3 × 20 mL),
washed with saturated aqueous NaCl, and dried over Na2SO4.
It was concentrated in vacuo and purified by a silica gel column
using CHCl3-EtOH (9.5:0.5) as the eluent. The product was
recrystallized from ethanol/ethyl acetate to give 3.42 g (100%)
of free amine, mp 183-185 °C. A small amount was converted
into HCl salt using ethanol-HCl and recrystallized from
ethanol-water to yield the salt for biological assay, mp 247-
250 °C. NMR (free amine in CDCl3 + DMSO-d6): δ 8.33 (s,
1H), 8.02-8.09 (m, 2H), 7.79-7.85 (m, 1H), 7.23-7.50 (m, 9H),
6.40-6.43 (d, 1H), 3.64-3.67 (m, 1H), 3.50 (s, 2H), 2.78-2.82
(d, 2H), 2.12-2.19 (dt, 2H), 1.93-1.97 (dd, 2H), 1.43-1.56 (dq,
2H). Anal. Calcd for C23H26N3OCl: C, H, N.
Gen er a l Met h od D. P r ep a r a t ion of N-(1-(2-F lu or o-
ben zyl)p ip er id in -4-yl)p h en yla ceta m id e (17). BP P (4.0 g,
13 mmol) was dissolved in 100 mL of methanol containing 20
mg of palladium hydroxide on carbon and hydrogenated under
50 psi for 12 h. The catalyst was filtered, and the solution was
evaporated under reduced pressure to give a residue that was
recrystallized from ethyl acetate-hexane to give 2.57 g (90%)
1
of 4-phenylacetamidopiperidine; mp 127-129. H NMR (free
amine in CDCl3): δ 7.23-7.39 (m, 4H), 5.22-5.28 (d, 1H),
3.79-3.92 (m, 1H), 3.56 (s, 2H), 2.94-3.01 (dt, 2H), 2.60-2.69
(dt, 2H), 1.82-1.87 (m, 2H), 1.01-1.24 (dq, 2H).
A mixture of 4-phenylacetamidopiperidine (0.22 g, 1 mmol),
2-fluorobenzyl bromide (0.19 g, 1 mmol), and 0.5 mL triethy-
lamine in 50 mL dichloromethane was stirred at room tem-
perature overnight. The solvent was removed in vacuo, and
the residue was dissolved in 50 mL of ethyl acetate, washed

4412 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Huang et al.
) 8 Hz, 1H), 3.72-3.92 (m, 1H), 3.56 (s, 2H), 3.53 (s, 2H), 2.70
(d, J ) 11 Hz, 2H), 2.15 (dt, J ) 2, 11 Hz, 2H), 1.88 (d, J ) 9
Hz, 2H), 1.38 (dt, J ) 2, 9 Hz, 2H). Anal. Calcd for
A mixture of 2-fluorophenylacetic acid (1.54 g, 10 mmol) and
DCC (2.06 g, 10 mmol) in 50 mL of dichloromethane was
stirred for 5 min, 4-amino-1-(tert-butoxycarbonyl)piperidine
(2.0 g, 10 mmol) was added, and the solution was stirred at
room temperature overnight. The solid was removed by
filtration, and the solution was concentrated in vacuo to afford
a residue that was then reacted with CF3COOH to remove the
tert-butoxycarbonyl group to afford 0.80 g (34%) of 4-(2-
fluorophenyl)acetamidopiperidine; mp 126-128 °C. NMR (free
amine in CDCl3): δ 7.25-7.35 (m, 2H), 7.05-7.15 (m, 2H),
5.51-5.54 (d, 1H), 3.88-3.96 (m, 1H), 3.56 (s, 2H), 3.42-3.52
(m, 1H), 2.69-2.78 (dt, 2H), 1.91-1.96 (d, 2H), 1.36-1.46 (m,
2H), 1.03-1.20 (m, 2H).
4-(2-Fluorophenyl)acetamidopiperidine (0.118 g, 0.5 mmol)
in 40 mL of dichloromethane was added with 4-fluorobenzyl
bromide (0.095 g, 0.5 mmol) and triethylamine (0.5 mL). After
the solution was stirred at room temperature overnight, the
solvent was removed in vacuo. The residue was dissolved in
50 mL of ethyl acetate and washed with 0.5 N NaOH and
water and dried over Na2SO4. The solvent was removed in
vacuo, and the product was purified by silica gel column
chromatography using CHCl3-EtOH (9.5:0.5) as the eluent.
The product was recrystallized from ethyl acetate-hexane to
give 0.10 g (59%) of N-(1-(4-fluorobenzyl)piperidin-4-yl)-2-
fluorophenylacetamide; mp 129-131 °C. NMR (free amine in
CDCl3): δ 7.20-7.32 (m, 4H), 6.93-7.15 (m, 4H), 5.32-5.34
(d, 1H), 3.73-3.84 (m, 1H), 3.55 (s, 2H), 3.41 (s, 2H), 2.68-
2.72 (d, 2H), 2.03-2.11 (dt, 2H), 1.83-1.88 (m, 2H), 1.28-1.41
(dq, 2H). Anal. Calcd for C20H22N2OF2: C, H, N.
N -(1-(3-Iod ob e n zyl)p ip e r id in -4-yl)-2-flu or op h e n yl-
a ceta m id e (33). Recrystallized from ethyl acetate/hexane;
yield, 83%; mp (free base) 135-136 °C. NMR (CDCl3/TMS): δ
7.65 (s, 1H), 7.57 (d, J ) 8 Hz, 1H), 7.22-7.32 (m, 3H), 6.99-
7.15 (m, 3H), 5.35 (d, J ) 8 Hz, 1H), 3.73-3.84 (m, 1H), 3.55
(s, 2H), 3.39 (s, 2H), 2.70 (d, J ) 12 Hz, 2H), 2.08 (dt, J ) 2,
12 Hz, 2H), 1.86 (d, J ) 10 Hz, 2H), 1.32 (dq, J ) 4, 12 Hz,
2H). Anal. Calcd for C20H22N2OFI: C, H, N.
N -(1-(4-Iod ob e n zyl)p ip e r id in -4-yl)-3-flu or op h e n yl-
a ceta m id e (34). Recrystallized from ethyl acetate/hexane;
yield, 57%; mp (free base) 144-145 °C. NMR (CDCl3/TMS): δ
7.26-7.30 (m, 6H), 7.00-7.20 (m, 2H), 5.35 (d, J ) 7 Hz, 1H),
3.72-3.90 (m, 1H), 3.55 (s, 2H), 3.46 (s, 2H), 2.60 (d, J ) 12
Hz, 2H), 2.10 (dt, J ) 2, 11 Hz, 2H), 1.75-1.95 (m, 2H), 1.30-
1.45 (m, 2H). Anal. Calcd for C20H22N2OFI: C, H, N.
N-(1-(4-F lu or ob en zyl)p ip er id in -4-yl)-3-flu or op h en yl-
a ceta m id e (35). Recrystallized from ethyl acetate/hexane;
yield, 58%; mp (free base) 115-117 °C. NMR (CDCl3/TMS): δ
7.15-7.40 (m, 4H), 6.90-7.10 (m, 4H), 5.70 (d, J ) 8 Hz, 1H),
3.75-3.82 (m, 1H), 3.53 (s, 2H), 3.41 (s, 2H), 2.70 (d, J ) 12
Hz, 2H), 2.00-2.10 (m, 2H), 1.60-1.70 (m, 2H), 1.05-1.15 (m,
2H). Anal. Calcd for C20H22N2OF2: C, H, N.
N -(1-(3-Iod ob e n zyl)p ip e r id in -4-yl)-3-flu or op h e n yl-
a ceta m id e (36). Recrystallized from ethyl acetate/hexane;
yield, 74%; mp (free base) 111-112 °C. NMR (CDCl3/TMS): δ
7.66 (s, 1H), 7.57 (d, J ) 8 Hz, 1H), 7.23-7.38 (m, 2H), 6.96-
7.05 (m, 4H), 5.26 (d, J ) 8 Hz, 1H), 3.75-3.82 (m, 1H), 3.53
(s, 2H), 3.40 (s, 2H), 2.72 (d, J ) 12 Hz, 2H), 2.09 (dt, J ) 2,
12 Hz, 2H), 1.86 (d, J ) 12 Hz, 2H), 1.35 (dq, J ) 4, 12 Hz,
2H). Anal. Calcd for C20H22N2OFI: C, H, N.
N -(1-(4-Iod ob e n zyl)p ip e r id in -4-yl)-3-flu or op h e n yl-
a ceta m id e (37). Recrystallized from ethyl acetate/hexane;
yield, 57%; mp (free base) 135-136 °C. NMR (CDCl3/TMS): δ
7.26-7.30 (m, 6H), 6.90-7.05 (m, 2H), 5.25 (d, J ) 7 Hz, 1H),
3.72-3.82 (m, 1H), 3.55 (s, 2H), 3.40 (s, 2H), 2.75 (d, J ) 12
Hz, 2H), 2.10 (dt, J ) 2, 11 Hz, 2H), 1.80-1.92 (m, 2H), 1.35
(dq, J ) 3, 12 Hz, 2H). Anal. Calcd for C20H22N2OFI: C, H, N.
N-(1-(4-F lu or oben zyl)p ip er id in -4-yl)-3-ch lor op h en yl-
a ceta m id e (38). Recrystallized from ethyl acetate/hexane;
yield, 67%; mp (free base) 101-102 °C. NMR (CDCl3/TMS): δ
7.25-7.28 (m, 6H), 7.00 (t, J ) 9 Hz, 2H), 5.20 (d, J ) 8 Hz,
1H), 3.75-3.85 (m, 1H), 3.51 (s, 2H), 3.43 (s, 2H), 2.70 (d, J )
12 Hz, 2H), 2.08 (dt, J ) 2, 11 Hz, 2H), 1.85 (d, J ) 12 Hz,
2H), 1.32 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd for C20H22N2-
OFCl: C, H, N.
C
20H23N3O3: C, H, N.
N-(1-(3,4-Dich lor ob en zyl)p ip er id in -4-yl)p h en yla cet -
a m id e (27). Recrystallized from ethyl acetate/ethanol; yield,
80%; mp (free base) 157-158 °C. NMR (CDCl3/TMS): δ 7.22-
7.38 (m, 7H), 7.09 (dd, J ) 1.5, 8 Hz, 1H), 5.20 (d, J ) 8 Hz,
1H), 3.72-3.92 (m, 1H), 3.55 (s, 2H), 3.37 (s, 2H), 2.65 (d, J )
11 Hz, 2H), 2.08 (dt, J ) 2, 11 Hz, 2H), 1.82 (d, J ) 9 Hz, 2H),
1.30 (dt, J ) 2, 9 Hz, 2H). Anal. Calcd for C21H22N2OCl2: C,
H, N.
N-(1-(3,4-Diflu or ob en zyl)p ip er id in -4-yl)p h en yla cet -
a m id e (28). Recrystallized from ethyl acetate/hexane; yield,
55%; mp (free base) 110-111 °C. NMR (CDCl3/TMS): δ 7.23-
7.38 (m, 5H), 6.96-7.15 (m, 3H), 5.20 (d, J ) 8 Hz, 1H), 3.74-
3.94 (m, 1H), 3.55 (s, 2H), 3.37 (s, 2H), 2.68 (d, J ) 11 Hz,
2H), 2.08 (dt, J ) 2, 11 Hz, 2H), 1.85 (d, J ) 9 Hz, 2H), 1.30
(dt, J ) 2, 9 Hz, 2H). Anal. Calcd for C21H22N2OF2: C, H, N.
N-(1-(3,4-Meth ylen edioxyben zyl)piper idin -4-yl)ph en yl-
a ceta m id e (29). Recrystallized from ethyl acetate/ethanol;
yield, 68%; mp (free base) 110-111 °C. NMR (CDCl3/TMS): δ
7.22-7.38 (m, 5H), 6.67-6.79 (m, 3H), 5.90 (s, 2H), 5.18 (d, J
) 8 Hz, 1H), 3.73-3.88 (m, 1H), 3.55 (s, 2H), 3.34 (s, 2H), 2.68
(d, J ) 11 Hz, 2H), 2.05 (dt, J ) 2, 11 Hz, 2H), 1.82 (d, J ) 9
Hz, 2H), 1.38 (dt, J ) 2, 9 Hz, 2H). Anal. Calcd for
C
21H24N2O3: C, H, N.
N -(2-N a p h t h y lm e t h y l)p ip e r id in -4-y l)p h e n y la c e t -
a m id e (30). Recrystallized from ethyl acetate/ethanol; yield,
56%; mp (free base) 145-146 °C. NMR (CDCl3/TMS): δ 7.76-
7.80 (m, 3H), 7.68 (s, 1H), 7.43-7.45 (m, 3H), 7.22-7.34 (m,
5H), 5.20 (d, J ) 8 Hz, 1H), 3.76-3.86 (m, 1H), 3.60 (s, 2H),
3.54 (s, 2H), 2.75 (d, J ) 11 Hz, 2H), 2.10 (t, J ) 9 Hz, 2H),
1.83 (d, J ) 9 Hz, 2H), 1.35 (dq, J ) 4, 10 Hz, 2H). Anal. Calcd
for C24H26N2O: C, H, N.
N-(2-P h en yleth yl)piper idin -4-yl)ph en ylacetam ide (31).
Recrystallized from ethyl acetate/hexane; yield, 16%; mp (free
base) 131-133 °C. NMR (CDCl3/TMS): δ 7.16-7.38 (m, 10H),
5.20 (d, J ) 8 Hz, 1H), 3.79-3.89 (m, 1H), 3.56 (s, 2H), 2.73-
2.85 (m, 4H), 2.53-2.58 (m, 2H), 2.15 (t, J ) 12 Hz, 2H), 1.88
(br d, J ) 12 Hz, 2H), 1.34 (dq, J ) 4, 10 Hz, 2H). Anal. Calcd
for C21H26N2O‚1/4H2O: C, H, N.
Gen er a l Met h od E . P r ep a r a t ion of N-(1-(4-F lu or o-
ben zyl)p ip er id in -4-yl)-2-flu or op h en yla ceta m id e (32). To
a solution of 4-amino-1-benzylpiperidine (9.5 g, 50 mmol) in
200 mL of dry dicholoromethane were added trifluoroacetic
anhydride (12.6 g, 60 mmol) and 5 mL triethylamine under
ice and stirring. After the solution was stirred at room
temperature for 12 h, the solvent was removed under vacuo,
the residue was dissolved in ethyl acetate and washed with
aqueous NaHCO3 and water and dried over Na2SO4. The
solvent was removed, and the product was recrystallized from
ethyl acetate to give 13.5 g (94%) of 1-benzyl-4-trifluoroacet-
amidopiperidine. NMR (free amine in CDCl3): δ 7.29-7.38 (m,
5H), 6.55-6.62 (d, 1H), 3.87-3.96 (m, 1H), 3.69 (s, 2H), 3.02-
3.06 (d, 2H), 2.27-2.36 (dt, 2H), 1.98-2.01 (m, 2H), 1.67-1.81
(dq, 2H).
The above product was dissolved in 150 mL of methanol
containing 50 mg of palladium hydroxide on carbon and
hydrogenated at 50 psi for 12 h. The catalyst was removed by
filtration, and the solution was concentrated in vacuo to give
an oil that was reacted with di-tert-butyl-di-carbonate (11.0
g, 50 mmol) in 200 mL of dicholoromethane for 6 h. The
reaction mixture was transferred into a separatory funnel and
washed with aqueous NaHCO3 and water and dried over
Na2SO4. After the solvent was removed, the residue was
dissolved in 100 mL of methanol and 50 mL of 30% ammonium
hydroxide and refluxed for 6 h. The solvent was removed, and
the residue was dissolved in 100 mL of dichloromethane,
washed with 1 N NaOH and water, and dried over Na2SO4.
The solvent was removed, and the product was recrystallized
from ethyl acetate-hexane to give 5.75 g (58%) of 4-amino-1-
(tert-butoxycarbonyl)piperidine. NMR (free amine in CDCl3):
δ 3.90-4.20 (m, 2H), 2.65-2.95 (m, 2H), 1.15-2.00 (m, 14H).

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4413
N -(1-(4-Iod ob e n zyl)p ip e r id in -4-yl)-3-ch lor op h e n yl-
a ceta m id e (39). Recrystallized from ethyl acetate/hexane;
yield, 87%; mp (free base) 119-120 °C. NMR (CDCl3/TMS): δ
7.20-7.35 (m, 7H), 7.10-7.15 (m, 1H), 5.20 (d, J ) 7 Hz, 1H),
3.70-3.90 (m, 1H), 3.50 (s, 2H), 3.45 (s, 2H), 2.75 (d, J ) 12
Hz, 2H), 2.10 (dt, J ) 2, 11 Hz, 2H), 1.80-1.90 (m, 2H), 1.55
(dq, J ) 3, 12 Hz, 2H). Anal. Calcd for C20H22N2OClI: C, H,
N.
N -(1-(4-Iod ob e n zyl)p ip e r id in -4-yl)-3-ch lor op h e n yl-
a ceta m id e (40). Recrystallized from ethyl acetate/hexane;
yield, 60%; mp (free base) 134-135 °C. NMR (CDCl3/TMS): δ
7.62 (d, J ) 8 Hz, 2H), 7.25-7.28 (m, 3H), 7.12-7.16 (m, 1),
7.03 (d, J ) 8 Hz, 2H), 5.32 (d, J ) 8 Hz, 1H), 3.72-3.85 (m,
1H), 3.57 (s, 2H), 3.39 (s, 2H), 2.70 (d, J ) 12 Hz, 2H), 2.08
(dt, J ) 2, 11 Hz, 2H), 1.85 (d, J ) 12 Hz, 2H), 1.37 (dq, J )
3, 12 Hz, 2H). Anal. Calcd for C20H22N2OClI: C, H, N.
N-(1-(4-F lu or oben zyl)p ip er id in -4-yl)-3-br om op h en yl-
a ceta m id e (41). Recrystallized from ethyl acetate/hexane;
yield, 69%; mp (free base) 109-110 °C. NMR (CDCl3/TMS): δ
7.42-7.44 (m, 2H), 7.20-7.55 (m, 4H), 6.98 (t, J ) 9 Hz, 2H)
5.70 (d, J ) 8 Hz, 1H), 3.72-3.82 (m, 1H), 3.50 (s, 2H), 3.42
(s, 2H), 2.72 (d, J ) 12 Hz, 2H), 2.10 (dt, J ) 2, 11 Hz, 2H),
1.80-2.00 (m, 2H), 1.45 (dq, J ) 3, 12 Hz, 2H). Anal. Calcd
for C20H22N2OFBr: C, H, N.
N -(1-(3-Iod ob e n zyl)p ip e r id in -4-yl)-3-b r om op h e n yl-
a ceta m id e (42). Recrystallized from ethyl acetate/hexane;
yield, 85%; mp (free base) 136-137 °C. NMR (CDCl3/TMS): δ
7.66 (s, 1H), 7.58 (d, J ) 8 Hz, 1H), 7.41-7.44 (m, 2H), 7.22-
7.26 (m, 3H), 7.02 (t, J ) 8 Hz, 1H), 5.76 (d, J ) 8 Hz, 1H),
3.74-3.84 (m, 1H), 3.50 (s, 2H), 3.39 (s, 2H), 2.72 (d, J ) 12
Hz, 2H), 2.09 (dt, J ) 2, 12 Hz, 2H), 1.86 (d, J ) 10 Hz, 2H),
1.45 (dq, J ) 4, 12 Hz, 2H). Anal. Calcd for C20H22N2OBrI: C,
H, N.
N -(1-(4-Iod ob e n zyl)p ip e r id in -4-yl)-3-b r om op h e n yl-
a ceta m id e (43). Recrystallized from ethyl acetate/hexane;
yield, 66%; mp (free base) 140-141 °C. NMR (CDCl3/TMS): δ
7.62 (d, J ) 8 Hz, 2H), 7.41-7.44 (m, 2H), 7.17-7.26 (m, 2H),
7.03 (d, J ) 8 Hz, 2H), 5.23 (d, J ) 7 Hz, 1H), 3.72-3.82 (m,
1H), 3.49 (s, 2H), 3.39 (s, 2H), 2.70 (d, J ) 12 Hz, 2H), 2.08 (t,
J ) 11 Hz, 2H), 1.84 (d, J ) 9 Hz, 2H), 1.35 (dq, J ) 3, 12 Hz,
2H). Anal. Calcd for C20H22N2OBrI: C, H, N.
P r ep a r a tion of 4-Iod oben zyl Ch lor id e. A solution of 2.0
M n-BuLi (44 mL, 0.088 mol) was added dropwise under argon
to a cooled (-78 °C) stirring solution of 4-bromobenzyl alcohol
(7.48 g, 0.04 mol) in dry THF (150 mL). The resulting mixture
was stirred at -78 °C for 90 min, and then, a solution of n-Bu3-
SnCl (28.86 g, 0.088 mol) in dry THF (50 mL) was added
dropwise. The reaction was continued at room temperature
overnight. The solvent was removed in vacuo, and the residue
was dissolved in CH2Cl2 (150 mL), washed with water, and
dried over Na2SO4. The solvent was removed, and the product
was purified by a silica gel column chromatography using
hexane/acetone (9:1) as the eluent to give 4-tributyltinbenzyl
alcohol, an oil (9.05 g, 57%). NMR (free amine in CDCl3): δ
7.45-7.48 (d, 2H), 7.31-7.34 (d, 2 H), 4.65-4.68 (d, 2 H), 1.48-
1.58 (m, 6H), 1.26-1.38 (m, 6H), 1.02-1.08 (m, 6H), 0.85-
0.91 (t, 9H).
The above 4-tributyltinbenzyl alcohol (3.97 g, 0.01 mol) was
added into a triphenylphosphine solution in carbon tetrachlo-
ride (30 mL). The mixture was stirred under reflux overnight.
The solid was filtered off, and the filtrate was added into CH2-
Cl2 (60 mL), washed with water, and dried over Na2SO4. The
solvent was removed, and the product was purified by a silica
gel column chromatography using hexane/ethyl acetate (9.5:
0.5) as the eluent to give 4-tributyltinbenzyl chloride (4.11 g,
99%). NMR (free amine in CDCl3): δ 7.45-7.48 (d, 2H), 7.32-
7.35 (d, 2 H), 4.54 (s, 2 H), 1.47-1.57 (m, 6H), 1.23-1.36 (m,
6H), 1.02-1.09 (m, 6H), 0.85-0.92 (t, 9H).
removed, and the product was purified by a silica gel column
chromatography using hexane as the eluent and recrystallized
from pentane to give 4-iodobenzyl chloride (2.46 g, 97%). NMR
(free amine in CDCl3): δ 7.67-7.72 (d, 2H), 7.11-7.15 (d, 2
H), 4.52 (s, 2 H). Anal. Calcd for C7H6ClI‚1/4H2O: C, H.
P h a r m a cology. Tissu e Sou r ce a n d Ra d ioliga n d s. σ1
binding sites were labeled with the σ1-selective radioligand,
[3H](+)-pentazocine (DuPont-NEN, Bilerica, MA) in guinea pig
brain membranes (Rockland Biological, Gilbertsville, PA)
according to published procedures.1,36 σ2 sites were assayed
in rat liver membranes with [3H]DTG (DuPont-NEN, Bilerica,
MA) in the presence of (+)-pentazocine (100 nM) to mask σ1
sites.1,36
Mem br a n e P r ep a r a tion . Crude synaptosomal (P2) mem-
brane homogenates were prepared from frozen guinea pig
brains without cerebellum.36,37 Brains were allowed to thaw
slowly on ice before homogenization. Crude P2 membranes
were also prepared from the livers of male Sprague-Dawley
rats (300-350 g). Animals were sacrificed by decapitation, and
the livers were removed and minced before homogenization.
Tissue homogenization was carried out at 4 °C in 10 mL/g
tissue weight of 10 mM Tris-HCl/0.32 M sucrose, pH 7.4, using
a Potter-Elvehjem tissue grinder. The crude homogenate was
centrifuged for 10 min at 1000g, and the supernatant was
saved on ice. The pellet was resuspended in 2 mL/g tissue
weight of ice-cold 10 mM Tris-HCl/0.32 M sucrose, pH 7.4, by
vortexing. After the pellet was centrifuged at 1000g for 10 min,
the pellet was discarded and the supernatants were combined
and centrifuged at 31 000g for 15 min. The pellet was
resuspended in 3 mL/g 10 mM Tris-HCl, pH 7.4, by vortexing,
and the suspension was allowed to incubate at 25 °C for 15
min. Following centrifugation at 31 000g for 15 min, the
aliquots were stored at -80 °C until used. The protein
concentration of the suspension was determined by the method
of Bradford38 and generally ranged from 6 to 11 mg protein/
mL.
σ1 Bin d in g Assa y. Guinea pig brain membrane homoge-
nates (100 µg protein) were incubated with 3 nM [3H](+)-
pentazocine (31.6 Ci/mmol) in 50 mM Tris-HCl (pH 8.0) at 25
°C for either 120 or 240 min. Test compounds were dissolved
in ethanol and then diluted in buffer for a total incubation
volume of 0.5 mL. Test compounds were added in concentra-
tions ranging from 0.005 to 1000 nM. Assays were terminated
by the addition of ice-cold 10 mM Tris-HCl (pH 8.0) followed
by rapid filtration through Whatman GF/B glass fiber filters
(presoaked in 0.5% polyethylenimine) using a Brandel cell
harvester (Gaithersburg, MD). Filters were washed twice with
5 mL of ice-cold buffer. Nonspecific binding was determined
in the presence of 10 µM (+)-pentazocine. Liquid scintillation
counting was carried out in EcoLite(+) (ICN Radiochemicals,
Costa Mesa, CA) using a Beckman LS 6000IC spectrometer
with a counting efficiency of 50%.
σ2 Bin d in g Assa y. Rat liver membrane homogenates (35
µg of protein) were incubated with 3 nM [3H]DTG (38.3 Ci/
mmol) in the presence of 100 nM (+)-pentazocine to block σ1
sites. Incubations were carried out in 50 mM Tris-HCl (pH
8.0) for 120 min at 25 °C in a total incubation volume of 0.5
mL. Test compounds were added in concentrations ranging
from 0.005 to 1000 nM. Assays were terminated by the
addition of ice-cold 10 mM Tris-HCl (pH 8.0) followed by rapid
filtration through Whatman GF/B glass fiber filters (presoaked
in 0.5% polyethylenimine) using a Brandel cell harvester
(Gaithersburg, MD). Filters were washed twice with 5 mL of
ice-cold buffer. Nonspecific binding was determined in the
presence of 5 µM DTG. Liquid scintillation counting was
carried out in EcoLite(+) (ICN Radiochemicals, Costa Mesa,
CA) using a Beckman LS 6000IC spectrometer with a counting
efficiency of 50%.
To a solution of 4-tributyltinbenzyl chloride (4.15 g, 0.01
mol) in CH2Cl2 (30 mL) was added iodine (4.0 g, 0.016 mol).
The mixture was stirred at room temperature overnight. A
Na2S2O5 aqueous solution (10%, 30 mL) was added to consume
excess I2. The solution was extracted with CH2Cl2 (60 mL),
washed with water, and dried over Na2SO4. The solvent was
Da ta An a lysis. The IC50 values at σ sites were generally
determined in triplicate from nonlinear regression of binding
data as analyzed by J MP (SAS Institute, Cary, NC), using
eight concentrations of each compound. Ki values were calcu-
lated using the method of Cheng-Prusoff39 and represent
mean values ( standard error of the mean (SEM). The Kd

4414 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Huang et al.
value used for [3H]DTG in rat liver was 17.9 nM and was 4.8
be oriented to place the substituents either above or
below the plane of the piperidine ring, conformations
were chosen in which substituents were oriented below
the plane of the piperidine ring (as indicated by arrows
in Figure 1) and placed in an orientation similar to other
nonsymmetrical substituents. Energy differences are
typically small (less than 0.2 kcal) for these various
conformational changes.
nM for [3H](+)-pentazocine in guinea pig brain.1,36
Molecu la r Mod elin g
Molecular modeling studies were performed using
Sybyl.22 Calculations were carried out on a Silicon
Graphics Indigo workstation. For all compounds, initial
molecular models were based on BP P , the parent
compound for the acetamide series. Structures were
modified as needed with fragments or atoms added from
the Sybyl structural library, using standard bond lengths
and angles. Charges, except as noted, were calculated
using the Gasteiger-Hu¨ckel23 or AM124 method. Struc-
tures were minimized using the Tripos force field to
gradient convergence using both steric and electrostatic
components (criteria: gradient energy change, 0.01 kcal/
mol; rms displacement, 0.001 Å; nonbonded cutoff, 8.000
Å; dielectric function as distance dependent; dielectric
constant, 1.000). To identify low energy conformations
as starting points for CoMFA,25 systematic search
procedures (as implemented in Sybyl) and random26
conformational analyses were used to explore the con-
formational flexibility of BP P .
Rotatable bonds were defined as shown in Figure 1.
For the systematic conformational search, rotatable
bonds 1, 2, and 4 were examined using 5° increments
with no charges on the molecule. An energy window of
5 kcal/mol greater than that of the starting conformation
was used to limit the number of final conformations.
For random searches, all four rotatable bonds were
examined and calculations were carried out with
Gasteiger-Hu¨ckel charges and a 10 kcal/mol energy
window (only conformations with energies no more than
10 kcal/mol greater than the original conformation were
retained). Conformations identified by the random
search procedure were retained only when certain
difference criteria were met (rms threshold, 0.20; data
convergence, 0.005).
On the basis of these conformational analyses, a
conformation for BP P was selected that showed a
reasonable overlap with the crystal structure of the rigid
σ1 selective compound pentazocine.27 τ1 ) -78° (C-C-
NH-C(O)); τ2 ) -180° (C-NH-C(O)-C); τ3 ) 49°
(NH-C(O)-C-C(ar)); and τ4 ) 55° (C(O)-C-C(ar)-
C(ar)). This conformation was approximately 0.5 kcal/
mol higher in energy than the global minimum confor-
mation identified by the random search method. The
benzylic group pendant to the piperidine nitrogen was
also examined for low-energy conformations. Three low-
energy conformational regions (with similar minima)
were identified. The conformation most closely aligning
to pentazocine was chosen for use in the modeling
studies for all other compounds. Conformations of other
compounds were prepared following modification of
BP P . In some cases, where large divergence was
observed from the beginning conformation on full mini-
mization, a limited number of iterations were applied
(200) to allow reduction of the most serious steric and
electrostatic interactions. For a few compounds where
large changes in conformation occurred with any degree
of minimization, torsional constraints were introduced
to maintain a similar structure to that of BP P . In cases
where ortho and meta substituents on the aromatic
rings could take on several orientations (for example,
the OCH3 group) and where the rings themselves could
CoMF A. Compounds chosen for inclusion in the
analysis set were acetamides from this study and from
our previous work.18 Out of 81 possible acetamides, 79
were included in the initial compound set for analysis.
Prior to CoMFA, conformations were aligned using a
least squares fit (where bond lengths, bond angles, etc.
were held fixed and all alignment points were given
equal weight) to all heavy atoms of the piperidine ring
and the amide nitrogen of BP P . Following alignment,
conformations for each compound were placed in a grid
of C-sp3 probe atoms (+1 charges) spaced at 2 Å
intervals and extending 4 Å from the overall molecular
area. Regions were automatically defined, and steric and
electrostatic interactions for each grid point were then
evaluated for all atoms in each molecule and added to
the table as a CoMFA field. Default values of (30 kcal/
mol were used to truncate the fields. Electrostatic
energies within common steric regions28 were not dropped
in these calculations. Initially, crossvalidated (leave-one-
out) partial least squares analyses29 were performed
with the number of groups equal to the number of
molecules. Up to 10 components were allowed in these
initial analyses, with the results used to identify the
optimum number of components to use in the final non-
crossvalidated analysis. Final analyses were carried out
with CoMFA standard scaling. Crossvalidated q2 (rcv2),
conventional (non-crossvalidated) r2, F statistic, stan-
dard error of the estimate, probability of r2 ) 0, steric
and electrostatic field coefficients (normalized), and
fraction of contribution values were calculated and are
presented in the text or tables.
For CoMFA analyses, steric and electrostatic interac-
tions that result in marked changes in activity are
typically represented as three-dimensional coefficient
contour diagrams. Points are mapped as polyhedra with
the polyhedra outer surfaces drawn when the product
of a specific term coefficient (steric or electrostatic) and
the standard deviation of the associated column is
greater than or less than a standard cutoff value,
indicating a strong influence of change in that term in
that region of space for one or more analogues. By color-
coding these regions of space, information may be
conveyed on the effects of increases or decreases in steric
bulk or electrostatic charge in a given area. Steric
CoMFA contributions were set at the 80 and 25% levels,
with green areas as those where steric bulk increases
binding and areas where steric bulk decreases binding
color-coded yellow. Electrostatic CoMFA contributions
were set at the 85 and 15% level, with areas where
increasing negative charge correlates with an increase
in binding color-coded red and areas where an increase
in positive charge leads to an increase in binding color-
coded blue.
CoMF A An a lysis. All crossvalidated analyses were
carried out with CoMFA standard scaling and a 2.0 kcal
filter. Final non-crossvalidated analyses were carried

N-(1-Benzylpiperidin-4-yl)arylacetamide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25 4415
(20) Ye, Y.; Huang, Y.; Wang, Z.; Chen, S.; Tian, Y. Synthesis of new
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(22) Sybyl, Version 6.6, and MOPAC, Version 6.00, Tripos Associates
Inc., 1699 S. Hanely Rd., Suite 303, St. Louis, MO, 63144-2913.
(23) Gasteiger-Hu¨ckel charges were calculated using a method
derived from two other charge calculation methods as imple-
mented in Sybyl. These are a combination of the Gasteiger-
Marsili (σ-component) and Hu¨ckel (π-component) methods.
(24) Dewar, M. J . S.; Zoebish, E. G.; Healy, E. F.; Stewart, J . J . P.
AM1: A New General Purpose Quantum Mechanical Molecular
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out with CoMFA standard scaling and no filter. Elec-
trostatic and steric components of the CoMFA analyses
were calculated using default values.
Ack n ow led gm en t. This research was funded by
Grants CA81825 and DA12647 awarded by the National
Institutes of Health.
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