Nitrile analogs of meperidine as high affinity and selective sigma-1 receptor ligands

Article abstract of DOI:10.1016/j.ejmech.2007.09.026

A series of N-substituted-4-cyano-4-phenylpiperidine analogs were synthesized and evaluated for binding affinity at opioid receptors and showed no affinity. The series similarity to previously reported σ ligands prompted analysis at σ receptors to determine the SAR for affinity at σ receptors. Within the N-substituent series the saturated analogs showed increased affinity at both σ receptors. Optimal chain length in the N-arylalkyl series for σ₁ and σ₂ receptors proved to be N-propylphenyl; extension to a four carbon chain dramatically decreased affinity at both receptors. Substituents in the 4-position affect only σ₁ affinity; no change in affinity at σ₂ was shown. The N-isobutyl, N-phenylpropyl, and N-benzyl analogs are worth pursuing due to their good affinity and selectivity at the σ₁ receptor, whereas the N-benzyl analog exhibits the greatest selectivity for σ₁.

Full text of DOI:10.1016/j.ejmech.2007.09.026

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 1304e1308
http://www.elsevier.com/locate/ejmech
Short communication
Nitrile analogs of meperidine as high affinity and selective sigma-1
receptor ligands
Susan L. Mercer a, Jamaluddin Shaikh b, John R. Traynor c,
Rae R. Matsumoto b, Andrew Coop a,
*
a Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
b Department of Pharmacology, University of Mississippi, 303 Faser Hall, University, MS 38677, USA
c Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA
Received 11 June 2007; received in revised form 25 September 2007; accepted 27 September 2007
Available online 6 October 2007
Abstract
A series of N-substituted-4-cyano-4-phenylpiperidine analogs were synthesized and evaluated for binding affinity at opioid receptors and
showed no affinity. The series similarity to previously reported s ligands prompted analysis at s receptors to determine the SAR for affinity
at s receptors. Within the N-substituent series the saturated analogs showed increased affinity at both s receptors. Optimal chain length in
the N-arylalkyl series for s1 and s2 receptors proved to be N-propylphenyl; extension to a four carbon chain dramatically decreased affinity
at both receptors. Substituents in the 4-position affect only s1 affinity; no change in affinity at s2 was shown. The N-isobutyl, N-phenylpropyl,
and N-benzyl analogs are worth pursuing due to their good affinity and selectivity at the s1 receptor, whereas the N-benzyl analog exhibits the
greatest selectivity for s1.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: s Receptor; AC927; UMB24; N-Substituted piperidines
1. Introduction
interacted with numerous other biological systems compli-
cated much of the s receptor literature, and thus there remains
an urgent need for the development of high affinity and selec-
tive ligands for both receptor subtypes to aid in the further elu-
cidation of s receptor mechanism(s).
s Receptors were initially classified as subtypes of the opi-
oid class of receptors by Martin et al. [1], but his classification
is no longer applied since most of the s receptor-mediated
effects are not sensitive to the opioid antagonist, naloxone
[2]. s Receptors are widely distributed throughout the body
[3], with locations in many peripheral organs [4e6], but
they are concentrated in the central nervous system, particu-
larly in brainstem motor regions [7,8]. Further research clari-
fied that s receptors were a unique class of receptors
consisting of two established subtypes, s1 and s2 [9]. Pharma-
cological effects at the s1 receptor include neuroprotection
and motor effects, whereas effects at the s2 receptor include
apoptosis and cell death [10]. Many of the early s ligands
We recently published a series of N-substituted meperidine
analogs [11] during which synthesis, novel and previously
reported N-substituted nitrile piperidine intermediates were
isolated. A representative sample of the nitrile intermediates
were analyzed for binding affinity at the opioid receptors,
and showed no significant affinity at the mu (m), kappa (k),
or delta (d) opioid receptors (Ki > 10,000 nM). Their similar-
ity to previously reported s ligands including AC927 and
UMB24 (Fig. 1) prompted analysis for their binding affinity
at the s receptors. AC927 (N-phenethylpiperidine), a selective
s receptor antagonist, has affinity at both s1 and s2 receptors
[12] and has been used in the development of both s1 [13] and
s2 [14] pharmacophores and regulates cell proliferation
* Corresponding author. Tel.: þ1 410 706 2029; fax: þ1 410 706 5017.
E-mail address: acoop@rx.umaryland.edu (A. Coop).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.09.026

S.L. Mercer et al. / European Journal of Medicinal Chemistry 43 (2008) 1304e1308
1305
N
N
N
AC927
UMB24
N
N
N
N
N
N
2
3
4
5
6
N
N
N
N
N
N
N
N
N
7
8
9
10
N
N
N
N
Fig. 1.
pathways [15]. Preliminary studies also show that AC927
attenuates the locomotor stimulant and neurotoxic effects of
methamphetamine in mice [16,17]. UMB24 (1-(2-phenyl-
ethyl)-4-(2-pyridyl)piperazine) has recently been shown to be
a s2 preferring compound [12,18] which significantly attenu-
ates cocaine-induced convulsions and locomotor activity [18].
Herein we focus on the comparison of the N-substituted
nitrile piperidine analogs (2e10) as well as comparison to
AC927 and UMB24 to determine the StructureeActivity Re-
lationship (SAR) of ligand affinity at the s1 and s2 receptors.
Comparative investigation will determine the relevance of:
(1) unsaturation and branching two carbons away from the
piperidine nitrogen; (2) the distance of a phenyl ring from
the piperidine nitrogen; and (3) influence of substituents in
the 4-position.
3. Pharmacology
The compounds synthesized in this manuscript are similar
to meperidine, a known m opioid analgesic, and other known
s ligands. Therefore, the compounds were evaluated at the
three opioid receptors (m, k, d) as previously described in
Ref. [19] (Table 1) and also at the two established s receptor
subtypes (s1, s2) as previously described in Refs. [18,20]
(Table 1).
4. Results and discussion
A representative sample of test compounds (2, 3, 5, 7, 10)
was evaluated for opioid binding and was found to have no
significant affinity for the opioid receptors (Table 1). Three
test compounds exhibited subnanomolar affinity for the s1 re-
ceptor; compounds 6, 9 and 7 showed Ki values of 0.35, 0.38,
and 0.41 nM, respectively. Compounds 9 and 6 showed the
greatest affinity at the s2 receptor with affinities of 46 and
63 nM, respectively. Compound 7 (N-benzyl) exhibited the
highest selectively for the s1 receptor over the s2 receptor
by a factor of 1600, whereas the N-Me (2) showed weak affin-
ity at both s receptors.
The series of N-alkyl substituted analogs (2e6) all showed
high affinity for s1 receptors, with little if any difference in
affinity with the exception of 2. This indicates that a larger
N-alkyl group leads to good s1 affinity, but the exact nature
of the group (branching, unsaturation) is unimportant. The
highest affinity for the s2 receptor was 63 nM by compound
6, followed by 4, 5, 3, and 2 with affinities of 143, 482,
662, and 2140 nM, respectively. Higher affinities at s2 were
exhibited for saturated compounds 4 and 6 compared to the
corresponding unsaturated compounds 3 and 5. Overall, com-
pound 6 has the highest affinity for both the s1 and s2
2. Chemistry
A range of novel and previously reported N-substituted ni-
trile analogs of meperidine were prepared from nitrile (1) (ob-
tained from SigmaeAldrich, Inc.), via alkylation with alkyl
halides in DMF in the presence of K2CO3 (Scheme 1) to pro-
duce compounds 2e10 (Fig. 1).
R
N
H
N
a
N
N
1
2-10
Scheme 1. Reagents and conditions: (a) RX, K2CO3, DMF.

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S.L. Mercer et al. / European Journal of Medicinal Chemistry 43 (2008) 1304e1308
Table 1
Binding affinities of test compounds (2e10), AC927, and UMB24
R
Nitrile
Opioid binding
Ki (nM) ꢀ SEM
m
Sigma binding
Ki (nM) ꢀ SEM
s1
Selectivity
a
b
s2
k
d
s2/s1
CH3
2 [25]
3 [26]
4
>10000
>10000
NT
>10000
>10000
NT
>10000
>10000
NT
113 ꢀ 5.5
2.2 ꢀ 0.33
1.7 ꢀ 0.22
3.7 ꢀ 0.83
0.35 ꢀ 0.01
0.41 ꢀ 0.08
3.3 ꢀ 0.38
0.38 ꢀ 0.04
49 ꢀ 3.2
2142 ꢀ 364
662 ꢀ 78
143 ꢀ 13
482 ꢀ 48
63 ꢀ 2.7
19
300
84
CH2CH]CH2
(CH2)2CH3
CH2C(CH3)]CH2
CH2CH(CH3)2
CH2(C6H5)
(CH2)2(C6H5)
(CH2)3(C6H5)
(CH2)4(C6H5)
AC927
5
>10000
NT
>10000
NT
5000 ꢀ 1300
NT
130
180
1600
36
6 [27]
7 [25]
8
5900 ꢀ 90
NT
NT
>10000
NT
NT
>10000
NT
NT
657 ꢀ 19
118 ꢀ 2.6
46 ꢀ 5.5
9
10 [28]
120
27
9800 ꢀ 680
>10000
>10000
1310 ꢀ 215
138 ꢀ 18
170 ꢀ 5
30 ꢀ 2
5
0.53
UMB24
322 ꢀ 32
Citations refer previously known compounds and/or results; NT ¼ not tested.
a
Displacement of [3H](þ)-pentazocine.
b
Displacement of [3H]DTG in the presence of (þ)-pentazocine.
receptors with a selectivity of 180, while 3 has the highest
selectivity in this series with a selectivity of 300.
1600 fold selectivity for s1 over s2 and no affinity at opioid
receptors appears to be an ideal ligand for study of s1 receptor
function. These s1 selective ligands with no opioid affinity
will further aid in the investigation between the s1 and opioid
receptors [29].
Compounds 9 (N-phenylpropyl) and 7 (N-benzyl) have
similar high affinity for the s1 receptor, with 8 (N-phenethyl)
10-fold lower, and 10 (N-phenylbutyl) 10-fold lower still.
Thus, a nitrogen to phenyl ring chain length of 1e3 carbons
is well tolerated at the s1 receptor with relatively high affinity,
but extension of chain length to 4 carbons decreases affinity.
Compound 9 also exhibits the highest affinity at the s2 recep-
tor (46 nM), with the others in this series somewhat lower.
Overall, compound 9 (N-phenylpropyl) exhibits the best affin-
ity for both the s1 and s2 receptors with a selectivity of 120,
while 7 (N-benzyl) has the highest selectivity in this series
with a selectivity of 1600.
AC927, UMB24 and 8 all contain an N-phenethyl substitu-
ent, but significantly vary in their 4-position substituent, allow-
ing preliminary analysis of the 4-aryl substituent. Compound 8
exhibits the highest affinity for s1 receptors (3.3 nM) followed
by AC927 and UMB24 with affinities of 30 and 322 nM, re-
spectively. The 4-cyano-4-phenyl substituent of 8 is superior
to no 4-substituent (AC927) and a piperazine (UMB24). The
4-position substituent does not appear to significantly influence
affinity at the s2 receptor. Compound 8 has greater selectivity
than AC927 for s1 over s2 receptors by a factor of 36 com-
pared to 5; UMB24 is s2 selective. Overall, substituents in
the piperidine 4-position affect s1 binding affinity but do not
affect s2 binding affinity.
6. Experimental protocols
6.1. Chemistry
All reactions were performed under an atmosphere of nitro-
gen, and all solvents were removed on a rotary evaporator un-
der reduced pressure. TLC was performed on plates coated
with silica gel GHLF-0.25 mm plates (60 F254) (Analtech).
Mass spectra were obtained on a ThermoFinnigan LCQ
Classic. 1H NMR spectra were obtained in CDCl3 on a Varian
Inova 500 MHz instrument in d units using TMS as an internal
standard. Melting points were determined on a Mel-Temp
(Laboratory Devices) apparatus and are uncorrected. Elemen-
tal analyses were conducted by Atlantic Microlabs (Norcross,
Georgia USA) and were within ꢀ0.4% of the theoretical
values.
6.1.1. General procedure for the synthesis of N-substituted
nitrile meperidine analogs (2, 3, 5, 7e10)
The appropriate halogenated compound (1 eq.) and K2CO3
(10 eq.) were added to a solution of freebased 4-cyano-4-
phenylpiperidine (SigmaeAldrich) (1 eq.) in DMF (20 mL/
g). After stirring overnight at room temperature, H2O
(3 ꢁ amount of DMF) was added. The reaction mixture was
extracted into Et2O, washed with brine, and dried (Na2SO4).
Removal of the solvent under reduced pressure gave the crude
compound. All compounds were converted to salts by either
recrystallization or lyophilization.
5. Conclusion
Analysis of the N-substituted nitrile piperidine analogs at s
receptors led to selective s1 ligands. Compounds 6, 7, and 9
are worth pursuing as high affinity selective ligands due to
their subnanomolar affinity at the s1 receptor. The high affin-
ity of the N-benzyl substituent is consistent with previously
reported compounds [21]. Compounds 6 and 9 also have
good affinity at the s2 receptor, whereas compound 7 with
6.1.1.1. 1-Methyl-4-phenylpiperidine-4-carbonitrile hydrochlo-
ride (2). RX ¼ methyl iodide (SigmaeAldrich); purified by

S.L. Mercer et al. / European Journal of Medicinal Chemistry 43 (2008) 1304e1308
1307
1
flash chromatography (SiO2/1:20 MeOHeCHCl3); lyophilized
with 1 M HCl to produce salt; yield 54%; mp 206e211 ꢂC; 1H
NMR (CDCl3) d 7.54 (d, 7.80 Hz, 2H), 7.43 (t, 7.37 Hz, 2H),
7.36 (t, 6.50 Hz, 1H), 2.99 (d, 12.14 Hz, 2H), 2.52 (t,
11.70 Hz, 2H), 2.42 (s, 3H), 2.15 (t, 11.70 Hz, 4H); MS (ESI)
m/z ¼ 201.28 (M þ Hþ). Anal. (C13H17ClN2$0.25H2O) C, H, N.
salt; yield 34%; mp 210e211 ꢂC; H NMR (CDCl3) d 7.51
(d, 7.11 Hz, 4H), 7.41 (t, 7.44 Hz, 4H), 7.33 (t, 7.28 Hz,
2H), 3.18 (m, 4H), 2.10 (d, 12.61 Hz, 2H), 2.00 (m, 2H),
1.56 (m, 8H); MS (ESI) m/z ¼ 319.21 (M þ Hþ).
6.1.2. General hydrogenation procedure (4, 6) derived from
Maeda et al [23]
6.1.1.2. 1-Allyl-4-phenylpiperidine-4-carbonitrile hydrochlo-
ride (3). RX ¼ allyl bromide (SigmaeAldrich); purified by
flash chromatography (SiO2/1:20 MeOHeCHCl3); lyophilized
with 1 M HCl to produce salt; yield 59%; mp 237e240 ꢂC; 1H
NMR (CDCl3) d 7.51 (d, 7.35 Hz, 2H), 7.40 (t, 7.12 Hz, 2H),
7.33 (t, 7.35 Hz, 1H), 5.88 (m, 1H), 5.25 (s, 2H), 5.20 (t,
9.64 Hz, 2H), 3.11 (d, 5.51 Hz, 2H), 3.05 (d, 11.31 Hz, 2H),
2.49 (t, 11.00 Hz, 2H), 2.12 (s, 2H); MS (ESI) m/z ¼ 227.15
(M þ Hþ). Anal. (C15H19ClN2) C, H, N.
A suspension of 10% Pd/C in EtOH (1 mL) was added to
a solution of alkene (1 eq.) and NH4HCO2 (10 eq.) in EtOH
(20 mL/g). After refluxing overnight and cooling, the solution
was filtered through Celite and the solvent removed under re-
duced pressure. The resulting residue was redissolved in
EtOAc, washed with brine, and dried (Na2SO4). Removal of
the solvent under reduced pressure yielded the crude com-
pound. Compounds were purified using flash chromatography
(SiO/1:20 MeOHeCHCl3) and converted to salts.
6.1.1.3.
1-(2-Methylallyl)-4-phenylpiperidine-4-carbonitrile
6.1.2.1. 1-Propyl-4-phenylpiperidine-4-carbonitrile oxalate
(4). Recrystallized from acetone and oxalic acid to produce
oxalate salt; yield 27%; mp 170 ꢂC; 1H NMR (CDCl3)
d 7.59 (d, 7.75 Hz, 2H), 7.45 (m, 3H), 4.12 (q, 6.97 Hz, 2H),
3.80 (d, 13.75 Hz, 1H), 3.65 (m, 1H), 3.49 (s, 1H), 3.13 (d,
9.71 Hz, 1H), 2.98 (t, 7.77 Hz, 1H), 2.22 (d, 10.68 Hz, 1H),
2.05 (s, 2H), 1.26 (t, 7.21 Hz, 3H), 1.06 (t, 7.31 Hz, 1H),
0.91 (m, 1H); MS (ESI) m/z ¼ 229.40 (M þ Hþ). Anal.
(C17H22N2O4$H2O) C, H, N.
hydrochloride (5). RX ¼ 3-bromo-2-methyl-propene (Sig-
maeAldrich); purified by flash chromatography (SiO2/1:20
MeOHeCHCl3); lyophilized with 1 M HCl to produce salt;
yield 33%; mp 243e245 ꢂC; H NMR (CDCl3) d 7.51 (d,
7.58 Hz, 2H), 7.40 (t, 7.58 Hz, 2H), 7.33 (t, 7.18 Hz, 1H),
4.91 (s, 1H), 4.88 (s, 1H), 2.97 (m, 4H), 2.42 (m, 2H), 2.10
(m, 4H), 1.76 (s, 3H); MS (ESI) m/z ¼ 241.17 (M þ Hþ).
Anal. (C16H21ClN2$0.1H2O) C, H, N.
1
6.1.1.4. 1-Benzyl-4-phenylpiperidine-4-carbonitrile oxalate
(7). RX ¼ benzyl bromide (SigmaeAldrich); purified from
MeOH and oxalic acid to produce oxalate salt; yield 65%;
mp 244e245 ꢂC; NMR consistent with previously reported
spectra [22]; MS (ESI) m/z ¼ 277.17 (M þ Hþ). Anal.
(C21H22N2O4) C, H, N.
6.1.2.2. 1-Isobutyl-4-phenylpiperidine-4-carbonitrile trifluor-
oacetate (6). Lyophilized with 1 M TFA to produce salt; yield
21%; mp 144e147 ꢂC; 1H NMR (CDCl3) d 7.45 (m, 4H), 7.37
(t, 6.94 Hz, 1H), 4.64 (m, 1H), 4.22 (m, 1H), 3.80 (m, 1H),
3.62 (m, 1H), 3.12 (m, 1H), 2.20 (m, 4H), 1.97 (m, 2H),
1.62 (m, 3H), 0.92 (m, 2H); MS (ESI) m/z ¼ 243.18
(M þ Hþ). Anal. (C18H23F3N2O2) C, H, N.
6.1.1.5. 1-Phenylethyl-4-phenylpiperidine-4-carbonitrile tri-
fluoroacetate (8). RX ¼ 2-bromoethyl benzene (Sigmae
Aldrich); purified by flash chromatography (SiO2/1:20
MeOHeCHCl3); lyophilized with 1 M TFA to produce salt;
6.2. Sigma pharmacology
Competition binding assays were performed in homoge-
nates from rat brain minus cerebellum (450e500 mg protein/
tube) using procedures previously described in detail
[18,20,24]. The assays were conducted in 50 mM TriseHCl,
pH 8.0 using a total volume of 500 mL/tube. s1 Receptors
were labeled using 5 nM [3H](þ)-pentazocine; s2 receptors
were labeled with 3 nM [3H]di-o-tolylguanidine in the pres-
ence of 300 nM (þ)-pentazocine to mask s1 receptors. Non-
specific binding was determined in the presence of 10 mM
haloperidol. Twelve concentrations of test ligand were used
in each assay. After incubation for 120 min at 25 ꢂC, the assays
were terminated with the addition of ice-cold 10 mM Trise
HCl, pH 8.0 and vacuum filtration through glass fiber filters.
Ki values were calculated from the data using Graph Pad Prism
and previously determined Kd values.
1
yield 30%; mp 182e187 ꢂC; H NMR (CDCl3) d 7.60 (d,
7.27 Hz, 4H), 7.48 (m, 4H), 7.38 (m, 2H), 3.19 (d, 11.55 Hz,
2H), 3.05 (t, 7.49 Hz, 2H), 2.93 (t, 7.70 Hz, 2H), 2.81 (t,
7.49 Hz, 2H), 2.67 (t, 11.33 Hz, 2H), 2.22 (m, 2H); MS
(ESI) m/z ¼ 291.18 (M þ Hþ). Anal. (C22H23F3N2O2) C, H, N.
6.1.1.6. 1-Phenylpropyl-4-phenylpiperidine-4-carbonitrile tri-
fluoroacetate (9). RX ¼ 1-bromo-3-phenylpropane (Sigmae
Aldrich); purified by flash chromatography (SiO/1:20
MeOHeCHCl3); lyophilized with 1 M TFA to produce salt;
1
yield 35%; mp 140e145 ꢂC; H NMR (CDCl3) d 7.50e7.19
(m, 10H), 3.03 (d, 11.93 Hz, 2 H), 2.71 (t, 7.33 Hz, 2H),
2.66 (t, 7.46 Hz, 2H), 2.48 (t, 6.71 Hz, 2H), 2.11 (s, 2H),
2.00 (t, 7.33 Hz, 2H), 1.86 (t, 7.21 Hz, 2H); MS (ESI) m/
z ¼ 305.20 (M þ Hþ). Anal. (C21H24N2$0.8C2HF3O2) C, H, N.
Acknowledgments
6.1.1.7. 1-Phenylbutyl-4-phenylpiperidine-4-carbonitrile oxa-
late (10). RX ¼ 1-chloro-4-phenylbutane (SigmaeAldrich);
purified from acetone and oxalic acid to produce oxalate
The authors thank Drs. Kellie Hom and Julie Ray for their
excellent technical assistance. These studies were supported in

1308
S.L. Mercer et al. / European Journal of Medicinal Chemistry 43 (2008) 1304e1308
[12] D.Y. Maeda, W. Williams, W.E. Kim, L.N. Thatcher, W.D. Bowen,
A. Coop, Bioorg. Med. Chem. Lett. 12 (2002) 497e500.
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part by the National Institute on Drug Abuse, National Insti-
tutes of Health (NIDA, NIH) (DA013583, DA013978, and
DA000254) and also the University of Maryland, School of
Pharmacy. SLM is supported by a Fellowship from the Univer-
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Independent Scientist Award (K02 DA019634).
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