Synthesis of chiral 1-[ω(4-chlorophenoxy)alkyl]-4-methylpiperidines and their biological evaluation at σ1, σ2, and sterol δ8-δ7 isomerase sites

Article abstract of DOI:10.1021/jm021014d

Sumitomo's patented σ ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at σ₁, σ₂, and sterol Δ₈-Δ₇ isomerase (SI) sites by in vitro radioligand binding assays, to evaluate the influence of a chiral center in the alkyl chain on the selective σ₁ binding relative to other σ family sites. Generally high σ₁-site affinities were found, so that the chirality introduced by a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain was beneficial to increase σ₁ selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)1-methylethyl]piperidine ((-)-(S)-17) reached the highest σ₁ affinity (K_i = 0.34 nM) and the best selectivity relative to the σ₂ site (547-fold). Compound (-)-(S)-17 displayed also a moderate selectivity (11-fold) relative to the SI site.

Full text of DOI:10.1021/jm021014d

J . Med. Chem. 2003, 46, 2117-2124
2117
Syn th esis of Ch ir a l 1-[ω-(4-Ch lor op h en oxy)a lk yl]-4-m eth ylp ip er id in es a n d Th eir
Biologica l Eva lu a tion a t σ1, σ2, a n d Ster ol ∆8-∆7 Isom er a se Sites
Francesco Berardi,* Fulvio Loiodice, Giuseppe Fracchiolla, Nicola Antonio Colabufo, Roberto Perrone, and
Vincenzo Tortorella
Dipartimento Farmaco-Chimico, Universita` di Bari, via Orabona 4, I-70126 Bari, Italy
Received J uly 30, 2002
Sumitomo’s patented σ ligand 1-[3-(4-chlorophenoxy)propyl]-4-methylpiperidine (15), which has
been claimed as agent for CNS disorders and neuropathies, and its lower homologue 12 were
prepared along with related chiral (4-chlorophenoxy)alkylpiperidines. They were tested at σ1,
σ2, and sterol ∆8-∆7 isomerase (SI) sites by in vitro radioligand binding assays, to evaluate
the influence of a chiral center in the alkyl chain on the selective σ1 binding relative to other
σ family sites. Generally high σ1-site affinities were found, so that the chirality introduced by
a methyl substitution resulted in slight differences. Nevertheless, the shorter oxyethylenic chain
was beneficial to increase σ1 selectivity. However, the (-)-(S)-4-methyl-1-[2-(4-chlorophenoxy)-
1-methylethyl]piperidine ((-)-(S)-17) reached the highest σ1 affinity (Ki ) 0.34 nM) and the
best selectivity relative to the σ2 site (547-fold). Compound (-)-(S)-17 displayed also a moderate
selectivity (11-fold) relative to the SI site.
Ch a r t 1
In tr od u ction
Since the findings that several neuroleptic drugs bind
σ receptors,1,2 a growing interest in σ ligands has been
driven by the need of atypical antipsychotics devoid of
motor side effects that are displayed by the classical
neuroleptics. The hope of employing σ agents in psy-
chosis3,4 has been reinforced by the observation that σ
receptors decreased in postmortem schizophrenic brains.5
At the moment, σ receptors are recognized to be intra-
cellular cytoplasmatic sites, distinguished in at least σ1
and σ2 subtypes.6 Both subtypes are widely distributed
in CNS (central nervous system),7 liver, kidney,8 lung,
and in endocrine, immune, and reproductive tissues,9
and are overexpressed in several tumor cell lines.10,11
Direct functional assays are unknown. Nevertheless,
deduced σ1 receptor functions in CNS include modula-
tory roles on K+ and Ca2+ channels12,13 and on dopam-
inergic,14 NMDA (N-methyl-D-aspartate),7 serotoner-
gic,15 muscarinic16 neurotransmission, and opioid anal-
gesia.17 The σ1 receptor coupling to G-protein18,19 is a
controversial matter, and σ1 receptorial protein has
recently been indicated as a voltage-gated K+ channel
subunit.20 Moreover, the structural homology of mam-
malian cloned σ1 receptor with a yeast sterol-isomerase
(ERG2 protein) has suggested the σ1 receptor interven-
tion in steroid biosynthesis.21 This seems to be con-
firmed by the colocalization on THP1 cells22 of σ1
receptor and sterol ∆8-∆7 isomerase (SI) or EBP (emo-
pamil binding protein), the functional mammalian
counterpart of ERG2-p. The σ2 subtype plays a role in
the regulation of cell proliferation and apoptosis,23
through the control of intracellular Ca2+ storage and
depletion.24 The activity at the σ2 site has also been
thought accountable for EPS (extrapyramidal
symptoms)25-27 that recent findings attribute to the σ1
site too.28 Although a real intrinsic activity cannot be
ascribed to the σ ligands, putative σ1 agonists have been
proposed as antidepressants13,15 and antiamnesics13,29
in learning and memory impairment. Putative antago-
nists are thought to be useful agents for preventing
neurodamage30,31 and treating cocaine abuse,32,33 schizo-
phrenia,34 and other neurological disorders.35 The σ2 site
ligands have been proposed as antineoplastic agents.23
Furthermore, both σ1 and σ2 ligands are required as
cancer diagnostic tools for PET analysis.36
Novel promising agents with selective affinity for σ1
site are shown in Chart 1. (+)-(R)-1-(4-Chlorophenyl)-
3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidi-
none (MS 377)37 was claimed to be clinically active on
schizophrenia, without EPS liability,38 and 4-(4-fluoro-
phenyl)-1-[4-(1,2,4-triazol-1-yl)butyl]-1,2,3,6-tetrahydro-
pyridine (E 5842) exhibited an atypical antipsychotic
profile and did not induce catalepsy, a symptom of
EPS.39 A wide variety of structures are known to bind
σ receptors, among which several arylalkylamines are
included. Structural similarities such as 4-chloro- and
(4-methoxy)phenylalkylamine moieties are shared by
* To whom correspondence should be addressed. Tel.:+39-080-
5442751; fax: +39-080-5442231; e-mail: berardi@farmchim.uniba.it.
10.1021/jm021014d CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/25/2003

2118 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Ta ble 1. Physical Properties
Berardi et al.
c
compd
n
m
R
R′
formulaa
mp, °C
recryst solventb
[R]D
12
0
0
0
0
0
1
1
1
1
1
2
2
1
1
1
2
2
1
1
1
0
0
0
0
H
H
CH3
H
CH3
H
H
CH3
H
CH3
H
H
CH3
H
H
CH3
H
CH3
C
C
C
C
C
C
C
C
C
C
C
C
C
14H20ClNO‚HCl
15H22ClNO‚HCl
15H22ClNO‚HCl
16H24ClNO‚HCl
16H24ClNO‚HCl
15H22ClNO‚HCl
16H24ClNO‚HCl
16H24ClNO‚HCl
15H22ClNO‚HCl
15H22ClNO‚HCl
16H24ClNO‚HCl
16H24ClNO‚HCl
14H17Cl2NO2‚HCl
190-2
162-4
162-4
163-4
163-4
205-6d
145-7
144-6
180-1
180-1
165-7
166-7
165-7
A
B
B
B
B
A
B
B
A
A
A
A
(-)-(R)-13
(+)-(S)-13
(-)-(R)-14
(+)-(S)-14
15
(+)-(R)-16
(-)-(S)-16
(+)-(R)-17
(-)-(S)-17
(-)-(R)-18
(+)-(S)-18
AC 915‚HCl
-34
+36
-8
+10
H
+5
-4
+2.7
-2.7
-2.5
+2.5
CH3
CH3
H
CH3
H
MeOH/Et2O
a
b
Elemental analyses for C, H, and N were within (0.4% of the theoretical values for the formulas given. A: EtOH/AcOEt, B: AcOEt.
c (c ) 1.5, MeOH). Sumitomo’s patented compound (see ref 42: 130-2 °C).
d
Sch em e 1a
highly selective σ1 ligands 2-(1-pyrrolidinyl)ethyl ester
of 3,4-dichlorophenylacetic acid (AC 915)40 and N,N-
dipropyl-2-[4-methoxy-3-(2-phenylethoxyl)phenyl]ethyl-
amine (NE 100)41 (Chart 1). So the potent σ ligand 1-[3-
(4-chlorophenoxy)propyl]-4-methylpiperidine (15, Chart
1) with high selectivity relative to dopamine D2 recep-
tors was patented as an agent for the treatment of CNS
disorders and neuropathies.42 SAFIRs of N-(phenyl-
alkyl)piperidines have been extensively studied,43,44 and
the importance of a tertiary nitrogen atom as a phar-
macophoric element and of the changes in surrounding
structure for the σ1 receptor binding has been recently
pointed out.45 The stereochemistry appears to regulate
mainly σ ligands selectivity. For example, (+)-N-
substituted N-normetazocines preferentially bind σ
receptors whereas their (-)-enantiomers bind opioid
receptors.46,47 (+)-Pentazocine (Chart 1), a classical σ1
receptor ligand of such a class, and related (+)-
(1S,5S,9S)-compounds display higher σ1 receptor affin-
ity and selectivity relative to σ2 receptor subtype than
their corresponding (-)-(1R,5R,9R)-isomers.48,49
a
(a) (R)-CH3CH(OH)COOMe or (S)-CH3CH(OH)COOEt, Ph3P,
DEAD, dry THF; NaOH, THF; (b) 4-methylpiperidine, DCC, dry
CH2Cl2; (c) BMS, dry THF; HCl/Et2O.
Sch em e 2a
Therefore, in pursuing our search for selective σ-sub-
type ligands we prepared the compound 15 and its
homologue 12 along with some chiral related isomers
(compounds 13, 14, 16-18, Table 1), to evaluate the
influence exerted by the presence of a stereogenic center
near the pharmacophoric nitrogen atom on the selective
binding at σ1 site. The chiral center was originated by
inserting a methyl group in any position of the inter-
mediate chain. Affinities and selectivities were evalu-
ated at σ1, σ2, and SI sites by in vitro radioligand binding
assays. In fact, we recently found that some high-affinity
σ1 ligands such as tetralinalkyl-3,3-dimethylpiperidines,
SA 4503, and BD 1008 displayed high affinity also
toward EBP site.50
a
(a) 10% NaOH; (b) MsCl, Et3N, dry CH2Cl2, 0 °C; (c) 4-meth-
ylpiperidine, NaOH, H2O/i-PrOH; HCl/Et2O.
with (S)-ethyl and (R)-methyl lactate, respectively,
followed by alkaline hydrolysis. Homologues (R)-1c and
(S)-1c were obtained by resolution of the racemic acid
as previously reported.52 They all were condensed with
4-methylpiperidine in the presence of dicyclohexylcar-
bodiimide (DCC) to the corresponding amides 2a -c.
These latter were readily reduced to amines 12-14 with
borane-methyl sulfide complex (BMS).
Compounds 15 and 16 were prepared (Scheme 2)
starting from the condensation reaction between 4-
chlorophenol and the appropriate commercially avail-
able 3-halopropanols 3a and (R)- and (S)-3b yielding the
corresponding alcohols 4a ,b which were derivatized to
Ch em istr y
Three different routes were employed to prepare
aryloxyalkylpiperidines 12-18 (Schemes 1-3). Com-
pounds 12-14 were prepared starting from carboxylic
acids 1a -c (Scheme 1). The acid 1a was commercially
available, whereas (R)-1b and (S)-1b were easily pre-
pared by the Mitsunobu reaction51 from 4-chlorophenol

Chiral 1-[ω-(4-Chlorophenoxy)alkyl]-4-methylpiperidines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2119
Sch em e 3a
hydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-
3-benzazocin-8-ol), guinea-pig brain membranes without
cerebellum; (b) σ2 site, [3H]-DTG (1,3-di(2-tolyl)guani-
dine) in the presence of 1 µM (+)-pentazocine to mask
σ1 receptors, rat liver membranes; (c) sterol ∆8-∆7
isomerase site, (()-[3H]-emopamil, guinea-pig liver mem-
branes. The following compounds were used to define
the specific binding, reported in parentheses: (a) (+)-
pentazocine (82-89%), (b) DTG (85-94%), (c) (()-
ifenprodil (72-82%).
Concentrations required to inhibit 50% of radioligand
specific binding (IC50) were determined by using six to
nine different concentrations of the drug studied in two
or three experiments with samples in duplicate. Scat-
chard parameters (Kd and Bmax) and apparent inhibition
constants (Ki) values were calculated using the Graph-
Pad Prism software.57
Resu lts a n d Discu ssion
All tested compounds are good σ1 ligands (Table 2).
Sumitomo’s patented compound 15 showed high affinity
toward σ1 site, but the affinity values for σ2 site and
sterol ∆8-∆7 isomerase site result in low selectivities.
However, all chiral phenoxypropyl analogues with a
methyl group on the intermediate chain (compounds 14,
16, and 18) displayed the same behavior. Therefore
neither the methyl position nor the configuration of the
chiral carbon atom influenced considerably the affinity
and selectivity, in the oxypropyl chain series. The
intermediate chain shortening from compound 15 to
compound 12 resulted in a slight improvement of the
σ1 site affinity (Ki ) 0.86 nM) and in a appreciable rise
in selectivity relative to σ2 site (278-fold).
Considering the phenoxyethyl derivatives with the
methyl group in R-position to the nitrogen atom, the
compound (-)-(S)-17 demonstrated an improvement in
σ1 site affinity (Ki ) 0.34 nM) and selectivity (547-fold)
compared to its upper homologous compound (+)-(S)-
18 (Ki ) 2.69 nM) and to its enantiomer (+)-(R)-17 (Ki
) 1.18 nM). On the contrary, the selectivity relative to
SI worsened for compound (-)-(S)-17 compared to the
same above compounds. When the methyl group was
placed in â-position to the nitrogen atom, the affinity
decreased from compound (+)-(R)-16 to compound with
the same configuration (-)-(R)-13 whereas it remained
comparable proceeding from compound (-)-(S)-16 to
compound (+)-(S)-13. As regards the isomers with the
methyl group in R-position to the oxygen atom, higher
affinities were observed for compound (-)-(R)-14 com-
pared to its homologue with the same configuration (-)-
(R)-13, whereas the main difference between their
respective enantiomers (+)-(S)-14 and (+)-(S)-13 was a
decrease in the σ2 site affinity (Ki ) 318 nM) for this
latter.
a
(a) Phthalic anhydride, Et3N, toluene; (b) see ref 54; (c)
4-chlorophenol, Ph3P, DEAD (or DIAD), dry THF; (d) 55% N2H4,
AcOH/CH3OH; (e) 3-methylglutaric anhydride, dry THF; AcCl; (f)
BMS, dry THF; HCl/Et2O.
the methylsulfonates 5a ,b and finally reacted with
4-methylpiperidine to give the desired amines.
For the preparation of aryloxyalkylpiperidines 17 and
18, a different synthetic approach was followed (Scheme
3). The key step of this pathway was the preparation of
the phthalimido alcohol intermediates 8a ,b from the
commercially available enantiomers of alaninol (6) and
1,3-butanediol (7), respectively. However, phthalimides
(R)- and (S)-8a were obtained by simply reacting (R)-
or (S)-6 with phthalic anhydride,53 whereas (R)- and (S)-
8b were prepared starting from (S)- and (R)-7, respec-
tively, by a previously reported three-step procedure54
in which, also, a complete inversion of configuration
occurred. Intermediates 8a ,b were reacted with 4-
chlorophenol, under Mitsunobu conditions, to give com-
pounds 9a ,b. Hydrazinolysis of these latter easily
yielded the aryloxyalkylamines 10a ,b. A treatment with
3-methylglutaric anhydride, prepared in situ, and acetyl
chloride55 provided the piperidindione derivatives 11a ,b
which were readily reduced with borane-methyl sulfide
to give the desired amines 17 and 18.
All of the final optically active aryloxyalkylpiperidines
had enantiomeric excesses >95% as determined by H
NMR spectroscopy of the diastereomeric salts obtained
using S-2-(4-chlorophenoxy)phenylacetic acid56 as chiral
solvating agent. The compound AC 915 was synthesized
according to the literature40 and identified by GC/MS
1
1
and 300 MHz H NMR analyses. Since the preparation
of its oxalic acid salt failed, it was converted in the
hydrochloride salt, whose purity was proved by elemen-
tal microanalysis.
Recep tor Bin d in g Stu d ies. The target compounds
12-18 and the reference compound AC 915, as hydro-
chloride salts, were evaluated for in vitro affinity at σ1
and σ2 receptors and at sterol ∆8-∆7 isomerase site by
radioreceptor binding assays. The specific radioligands
and tissue sources were respectively: (a) σ1 site, (+)-
[3H]-pentazocine ((+)-[2S-2R,6R,11R)]-1,2,3,4,5,6-hexa-
For each pair of enantiomers examined, little differ-
ences in the affinities were observed, except for com-
pound (-)-(S)-17 compared to its enantiomer (+)-(R)-
17, as already seen. Therefore, the stereochemistry of
the chiral center inserted in the intermediate chain did
not influence the selectivity, unless the chiral center is
adjacent to the nitrogen atom and the intermediate
chain is shortened. The best selectivity values were
substantially reached on account of moderate affinities
toward the σ2 site. These results confirm that more

2120 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Ta ble 2. Binding Affinities and Selectivities
Berardi et al.
Ki ( SEM (nM)
σ2
Ki ratio
compound
σ1
sterol ∆8-∆7 isomerase (SI)
σ2/ σ1
SI/σ1
12
0.86 ( 0.11
12.6 ( 1.90
1.81 ( 0.28
1.83 ( 0.36
1.40 ( 0.28
1.78 ( 0.34
1.09 ( 0.09
1.70 ( 0.43
1.18 ( 0.05
0.34 ( 0.11
2.21 ( 0.79
2.69 ( 0.43
2.51 ( 0.68
2.70 ( 0.25
239 ( 15
3.70 ( 0.20
35.1 ( 10.6
3.38 ( 1.67
12.0 ( 0.2
30.1 ( 6.3
9.65 ( 0.35
14.5 ( 3.4
18.7 ( 5.6
27.5 ( 7.1
3.73 ( 0.98
7.79 ( 2.38
37.0 ( 1.3
>104
278
26
176
36
10
22
37
36
44
547
7
4.3
2.8
1.9
6.6
22
5.4
13
11
23
11
3.5
14
(-)-(R)-13
(+)-(S)-13
(-)-(R)-14
(+)-(S)-14
15
(+)-(R)-16
(-)-(S)-16
(+)-(R)-17
(-)-(S)-17
(-)-(R)-18
(+)-(S)-18
AC 915‚HCl
(+)-pentazocine
DTG
332 ( 16
318 ( 76
65.9 ( 14.3
13.9 ( 2.1
38.6 ( 7.6
40.8 ( 3.8
62.0 ( 2.2
52.3 ( 10.5
186 ( 12
15.1 ( 3.6
31.6 ( 1.1
12
>104
31.2 ( 2.10
(()-ifenprodil
2.71 ( 0.04
Ch a r t 2
1-[2-(4-chlorophenoxy)-1-methyl]ethylpiperidine ((-)-
(S)-17)) reached the highest σ1 affinity (Ki ) 0.34 nM)
and the best selectivity relative to σ2 site (547-fold).
Compound (-)-(S)-17 displayed also a moderate selec-
tivity (11-fold) relative to the SI site.
Exp er im en ta l Section
Ch em ica l Meth od s. Column chromatography was per-
formed on ICN silica gel 60 Å (63-200 µm) as the stationary
phase. Melting points were determined in open capillaries on
a Gallenkamp electrothermal apparatus and are uncorrected.
Mass spectra were recorded with a HP GC/MS 6890-5973
MSD spectrometer, electron impact 70 eV, equipped with HP
stringent structural requirements are needed for σ2 in
comparison to σ1 receptor binding, suggesting that a
shorter chain with less conformational freedom coupled
with the eutomeric (S)-configuration leads to a reduced
flexibility of the ligand. Therefore, an oxyethylenic chain
between the phenyl ring and the piperidine nitrogen
atom strengthens the configurational requirement so as
to improve the σ1 site binding and reduce σ2 site binding
at once. In confirmation of that, one can suppose that
(-)-(S)-17 could likely assume a conformation similar
to the stereochemistry of the already reported compound
19 (Chart 2, σ1, Ki) 0.86 nM and σ2 , Ki ) 554 nM).45
Moreover, although the 4-methylpiperidine derivative
20 emerged therein as the most active σ1 ligand, the
best selectivity relative to the σ2 site was reached by
compound 19, probably due to its partially constrained
alkyl chain.
Finally, no compound displayed a SI affinity greater
than the σ1 site affinity, even if the respective Ki values
ran rather parallel. Indeed, the most selective σ1 ligands
12, (+)-(S)-13 and (-)-(S)-17 are also the best SI ligands.
Similarly, in this series the compound (-)-(R)-13 dem-
onstrated the lowest affinities toward the sites tested.
Only the compound (+)-(R)-17 resulted moderately
selective relative to both the σ2 and SI sites.
1
chemstation. H NMR spectra were recorded in CDCl3 either
on a Varian EM-390 (when 90 MHz is indicated), using
tetramethylsilane as internal standard, or on a Bruker AM
300 WB (300 MHz) spectrometer. For optical isomers, NMR
spectra are identical and reported only for one of the two
enantiomers. Chemical shifts are expressed as parts per
million (δ). Infrared spectra were registered on a Perkin-Elmer
FT-IR spectrophotometer (Spectrum one). Microanalyses of
solid compounds were carried out with a Carlo Erba mod. 1106
analyzer; the analytical results are within (0.4% of the
theoretical values. Optical rotations were measured with a
Perkin-Elmer 341 polarimeter at room temperature (20 °C):
concentrations are expressed as g/100 mL. Chemicals were
from Aldrich and were used without any further purification.
(+)-(R)- a n d (-)-(S)-2-(4-Ch lor op h en oxy)p r op a n oic Ac-
id s [(+)-(R)-1b, (-)-(S)-1b]. A solution of diethyl azodicar-
boxylate (DEAD, 11 mmol) in dry THF (45 mL) was added
dropwise to a mixture of (S)-ethyl or (R)-methyl lactate (10
mmol), 4-chlorophenol (10 mmol), and triphenylphosphine (10
mmol) in dry THF (85 mL). The reaction mixture was stirred
at room-temperature overnight, under N2 atmosphere. The
solvent was evaporated, and a mixture of Et2O and hexane
(1:1) was added in order to precipitate the formed triph-
enylphosphine oxide, which was filtered off. This procedure
was repeated several times. The filtrate was evaporated to
dryness, and the crude product was dissolved in THF (125 mL)
and added of 1 N NaOH (125 mL). The mixture was stirred at
room-temperature overnight after which the organic solvent
was evaporated, and the remaining aqueous phase was washed
twice with CHCl3, acidified with 2 N HCl and extracted with
CHCl3. The organic layer was dried over Na2SO4, and the
solvent was removed under reduced pressure affording a solid
which was crystallized from hexane. Yield: 80-85%. Spectro-
scopic properties and optical rotation values were identical to
the data reported in the literature.58
Con clu sion s
The slight differences found in the high affinities
toward the σ1 site demonstrate that the chirality in the
intermediate chain of the phenoxypropylpiperidines 14,
16, and 18 generally does not exert an important
influence on the σ1 site binding. Nevertheless, a shorter
oxyethylenic chain was beneficial to increase σ1 relative
to σ2 site selectivity. Moreover, when in such a chain
the methyl substituent is adjacent to the piperidine
nitrogen atom, the chiral center appears to be more
determinant, possibly due to the more constrained
compounds generated. Therefore, the (-)-(S)-4-methyl-
P r ep a r a tion of Ar yloxya lk a n oylp ip er id in es (2a -c).
Gen er a l P r oced u r e. To a stirred solution of the appropriate
4-chlorophenoxyalkanoic acid 1 (5 mmol) in anhydrous CH2-
Cl2 (25 mL) were added N,N′-dicyclohexylcarbodiimide (DCC,
5.2 mmol) and 4-methylpiperidine (5.2 mmol). The resulting

Chiral 1-[ω-(4-Chlorophenoxy)alkyl]-4-methylpiperidines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2121
mixture was stirred overnight at room temperature. Then it
was diluted with CH2Cl2 (80 mL), and the precipitate was
filtered off. The organic layer was washed with 2 N HCl (2 ×
75 mL), followed by brine (1 × 75 mL), NaHCO3 saturated
solution (2 × 75 mL), and brine (1 × 75 mL); then it was dried
over Na2SO4 and filtered. The solvent was evaporated in vacuo
to afford a white solid which was chromatographed on silica
gel column (petroleum ether/ethyl acetate 7:3 as eluent).
Compounds 2a -c were obtained as pale yellow oils in 52-
70% yields.
NCH and 1 of CH2N), 3.17-3.54 and 3.65-3.80 (m, 3H, 2
piperidine NCH and 1 of CH2N), 5.34-5.39 (m, 1H, OCH),
6.90-7.24 (m, 4H, aromatic), 12.41 (br s, 1H, NH+, D2O
exchanged); GC/MS m/z (free amine) 267 (M+, 2), 112 (100).
(-)-(R)- a n d (+)-(S)-4-Meth yl-1-[3-(4-ch lor op h en oxy)-
bu tyl]p ip er id in e h yd r och lor id es [(-)-(R)-14, (+)-(S)-14]:
1H NMR: δ 1.01 (d, 3H, piperidine CH3), 1.28 (d, 3H, CH3),
1.45-1.70 (m, 1H, piperidine CH), 1.72-1.88 (m, 2H, 2
piperidine NCH2CH), 1.90-2.10 (m, 2H, 2 piperidine NCH2CH),
2.13-2.25 (m, 1H, 1 of OCHCH2), 2.26-2.47 (m, 1H, 1 of
OCHCH2), 2.52-2.70 and 2.90-3.15 (m, 4H, 2 piperidine NCH
and CH2N), 3.15-3.65 (m, 2H, 2 piperidine NCH), 4.35-4.53
(m, 1H, OCH), 6.73-7.24 (m, 4H, aromatic), 12.14 (br s, 1H,
NH+, D2O exchanged); GC/MS m/z (free amine) 281 (M+, 3),
112 (100).
4-Me t h yl-1-[2-(4-ch lor op h e n oxy)-1-oxoe t h yl]p ip e r i-
1
d in e (2a ): 56% yield; H NMR: δ 0.92 (d, 3H, CH3), 1.02-
1.19 (m, 2H, NCH2CH2), 1.50-1.90 (m, 3H, CH and NCH2CH2),
2.59, 3.01, 3.87 and 4.48 (4m, 4H, 2 NCH2), 4.63 (s, 2H, OCH2),
6.83-7.24 (m, 4H, aromatic); GC/MS m/z 269 (M+ + 2, 31),
267 (M+, 85), 140 (100); FT-IR 1651 cm-1 (CdO).
P r ep a r a tion of Ar yloxya lk yl Alcoh ols (4a ,b). Gen er a l
P r oced u r e. Compound 3a (or 3b) (12 mmol) was added to a
stirred solution of 4-chlorophenol (15 mmol) in 10% NaOH (10
mL). The resulting mixture was refluxed with stirring for 45
min and then was allowed to cool to room temperature and
extracted with Et2O (3 × 20 mL). The combined organic
extracts were washed with 10% NaOH (2 × 10 mL) followed
by brine (2 × 10 mL); then they were dried over Na2SO4 and
filtered. The solvent was evaporated in vacuo to afford 4a (or
4b); colorless oils in 30-45% yields.
(-)-(R)-4-Meth yl-1-[2-(4-ch lor op h en oxy)-1-oxop r op yl]-
p ip er id in e [(-)-(R)-2b]: 58% yield; [R]D ) -10 (c ) 1.5,
MeOH); 1H NMR: δ 0.75-1.00 (dd, 3H, piperidine CH3), 1.01-
1.18 (m, 2H, NCH2CH2), 1.50-1.93 (m, 6H, CH3, piperidine
CH and NCH2CH2), 2.54 (q, 1H, 1 of N(CH2)2), 2.93 (m, 1H, 1
of N(CH2)2), 4.05-4.25 (m, 1H, 1 of N(CH2)2), 4.47 (d, 1H, 1 of
N(CH2)2), 4.88 (q, 1H, OCH), 6.77-7.24 (m, 4H, aromatic); GC/
MS m/z 283 (M+ + 2, 9), 281 (M+, 27), 126 (100); FT-IR 1658
cm-1 (CdO).
3-(4-Ch lor op h en oxy)-1-p r op a n ol (4a ): 45% yield; 1H
NMR (90 MHz): δ 1.85-2.20 (m, 3H, CH2CH2CH2 and OH,
D2O exchanged), 3.85 (t, 2H, CH2OH), 4.10 (t, 2H, ArOCH2),
6.70-7.40 (m, 4H, aromatic); GC/MS m/z 188 (M+ + 2, 11),
186 (M+, 32), 128 (100).
(+)-(S)-4-Meth yl-1-[2-(4-ch lor op h en oxy)-1-oxop r op yl]-
p ip er id in e [(+)-(S)-2b]: 70% yield; [R]D ) +9 (c ) 1.5,
MeOH).
(+)-(R)-4-Meth yl-1-[3-(4-ch lor op h en oxy)-1-oxobu tyl]p i-
p er id in e [(+)-(R)-2c]: 52% yield; [R]D ) +19 (c ) 1.5, MeOH);
1H NMR: δ 0.91 (d, 3H, piperidine CH3), 0.95-1.15 (m, 2H,
NCH2CH2), 1.34 (d, 3H, CH3), 1.45-1.77 (m, 3H, piperidine
CH and NCH2CH2), 2.40-2.70 (m, 2H, CHCO and 1 of
N(CH2)2), 2.75-3.15 (m, 2H, CHCO and 1 of N(CH2)2), 3.87
(bb, 1H, 1 of N(CH2)2), 4.54 (bb, 1H, 1 of N(CH2)2), 4.82-4.96
(m, 1H, OCH), 6.75-7.24 (m, 4H, aromatic); GC/MS m/z 297
(M+ + 2, 2), 295 (M+, 6), 168 (100); FT-IR 1639 cm-1 (CdO).
(-)-(S)-4-Meth yl-1-[3-(4-ch lor op h en oxy)-1-oxobu tyl]p i-
p er id in e [(-)-(S)-2c]: 52% yield; [R]D ) -18 (c ) 1.5, MeOH).
P r ep a r a tion of Ar yloxya lk ylp ip er id in e Hyd r och lo-
r id es (12-14). Gen er a l P r oced u r e. A solution of borane-
methyl sulfide complex (BMS, 12 mmol) in anhydrous THF (3
mL) was carefully added dropwise to a stirred and cooled
solution of the appropriate amide 2 (3 mmol) in anhydrous
THF (15 mL). The reaction mixture was refluxed with stirring
for 4h, cooled to 0 °C, and carefully added with methanol (15
mL) dropwise to destroy the boran complex excess. Then 6 N
HCl (15 mL) was added, and the resulting mixture was
refluxed with stirring for 1h. After distilling off the organic
solvents, the mixture was allowed to cool at room temperature
and alkalized with 6 N NaOH. The aqueous solution was
extracted with CHCl3 (3 × 40 mL), and the combined organic
extracts were washed with brine (1 × 40 mL), dried over Na2-
SO4, and filtered. Evaporation of the solvent in vacuo afforded
the desired piperidines as pale yellow oils in quantitative
yields. The corresponding hydrochloride salts were prepared
by adding a HCl saturated ethereal solution to an ethereal
solution of the amine. Recrystallization solvent, [R]D, crystal-
lization formula and melting point are listed in Table 1. All of
the title compounds were obtained as white crystalline pow-
ders.
(-)-(R)-3-(4-Ch lor op h en oxy)-2-m eth yl-1-p r op a n ol [(-)-
1
(R)-4b]: 31% yield; [R]D ) -8 (c ) 1.8, MeOH); H NMR (90
MHz): δ 1.05 (d, 3H, CH3), 1.80 (bb, 1H, OH, D2O exchanged),
1.90-2.30 (m, 1H, CH), 3.70 (d, 2H, CH2OH), 3.93 (d, 2H,
ArOCH2), 6.70-7.30 (m, 4H, aromatic); GC/MS m/z 202 (M+
+ 2, 7), 200 (M+, 22), 128 (100).
(+)-(S)-3-(4-Ch lor op h en oxy)-2-m eth yl-1-p r op a n ol [(+)-
(S)-4b]: 30% yield; [R]D ) +10 (c ) 1.8, MeOH).
P r ep a r a tion of Ar yloxya lk ylsu lfon a tes (5a ,b). Gen er a l
P r oced u r e. A solution of methanesulfonyl chloride (4.6 mmol)
in anhydrous CH2Cl2 (5 mL) was added dropwise to a stirred
and ice-bath cooled solution of 4a (or 4b) (4.2 mmol) and
triethylamine (6.8 mmol) in anhydrous CH2Cl2 (15 mL). The
reaction mixture was stirred at 0 °C for 3 h and then was
carefully poured into ice-water. The organic layer was sepa-
rated and washed with cold 10% HCl (2 × 10 mL) followed by
brine (2 × 10 mL), NaHCO3 saturated solution (2 × 10 mL),
and finally with brine (2 × 10 mL). Then it was dried over
Na2SO4 and filtered. The solvent was evaporated in vacuo to
afford 5a (or 5b) as a pale yellow oil which was used for the
next step without any further purification.
O-Met h a n esu lfon yl-3-(4-ch lor op h en oxy)-1-p r op a n ol
(5a ): 81% yield; GC/MS m/z 266 (M+ + 2, 20), 264 (M+, 51),
137 (100).
(S)-O-Meth a n esu lfon yl-3-(4-ch lor op h en oxy)-2-m eth yl-
1-p r op a n ol [(S)-5b]: 83% yield; GC/MS m/z 280 (M+ + 2, 12),
278 (M+, 30), 128 (100).
(R)-O-Meth a n esu lfon yl-3-(4-ch lor op h en oxy)-2-m eth yl-
1-p r op a n ol [(R)-5b]: 96% yield.
P r ep a r a tion of Ar yloxya lk ylp ip er id in e Hyd r och lo-
r id es (15, 16). Gen er a l P r oced u r e. To a solution of NaOH
(4 mmol) in water (10 mL) and 2-propanol (5 mL) was added
4-methylpiperidine (3 mmol). The resulting mixture was cooled
to 0 °C and stirred for 10 min, and then a solution of 5a (or
5b) (3 mmol) in 2-propanol (10 mL) was added dropwise. The
reaction mixture was stirred at 0 °C for 1 h and then warmed
at 50 °C for 4 h; the solvent was removed under reduced
pressure, and the aqueous layer was extracted with Et2O (3
× 20 mL). The collected organic extracts were washed with 1
N NaOH (2 × 10 mL) followed by brine (2 × 10 mL) and
extracted with 6 N HCl (3 × 20 mL). The aqueous phase was
alkalized with 6 N NaOH and extracted with CHCl3 (3 × 30
mL). The organic layer was dried over Na2SO4 and the solvent
was evaporated in vacuo to afford 15 (or 16); pale yellow oils
4-Meth yl-1-[2-(4-ch lor op h en oxy)eth yl]p ip er id in e h y-
d r och lor id e (12): 1H NMR: δ 1.02 (d, 3H, CH3), 1.50-1.70
(m, 1H, CH), 1.75-2.21 (m, 4H, 2 piperidine NCH2CH2), 2.65-
2.85 and 3.10-3.25 (m, 2H, 2 piperidine NCH), 3.36 (q, 2H,
CH2N), 3.38-3.45 and 3.56-3.70 (m, 2H, 2 piperidine NCH),
4.52 (t, 2H, OCH2), 6.78-7.30 (m, 4H, aromatic), 12.45 (br s,
1H, NH+, D2O exchanged); GC/MS m/z (free amine) 253 (M+,
2), 112 (100).
(-)-(R)- a n d (+)-(S)-4-Meth yl-1-[2-(4-ch lor op h en oxy)-
p r op yl]p ip er id in e h yd r och lor id es [(-)-(R)-13, (+)-(S)-13]:
1H NMR: δ 0.98 (d, 3H, piperidine CH3), 1.26 (d, 3H, CH3),
1.44-1.63 (m, 1H, piperidine CH), 1.65-2.10 (m, 4H, 2
NCH2CH2), 2.57-2.83 and 2.97-3.16 (m, 3H, 2 piperidine

2122 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11
Berardi et al.
in 40-62% yields. The corresponding hydrochloride salts were
prepared according to the procedure reported above for com-
pounds 12-14 obtaining white crystalline powders. Recrys-
tallization solvent, [R]D, crystallization formula, and melting
point are listed in Table 1.
4.70 (m, 1H, CHN), 6.75-7.12 (m, 4H, aromatic), 7.61-7.92
(m, 4H, aromatic); GC/MS m/z 331 (M+ + 2, 1), 329 (M+, 4),
202 (100).
(+)-(S)-3-P h th a lim id o-1-(4-ch lor op h en oxy)bu ta n e [(+)-
(S)-9b]: 96% yield; [R]D ) +84 (c ) 1.3, CHCl3).
4-Meth yl-1-[3-(4-ch lor op h en oxy)p r op yl]p ip er id in e h y-
d r och lor id e (15): 1H NMR: δ 1.01 (d, 3H, CH3), 1.45-1.70
(m, 1H, CH), 1.70-1.88 (m, 2H, 2 piperidine NCH2CH), 1.90-
2.25 (m, 2H, 2 piperidine NCH2CH), 2.44 (m, 2H, OCH2CH2),
2.54-2.75 and 2.95-3.25 (m, 4H, 2 piperidine NCH and
CH2N), 3.25-3.38 and 3.50-3.65 (m, 2H, 2 piperidine NCH),
4.02 (t, 2H, ArOCH2), 6.73-7.24 (m, 4H, aromatic), 12.14 (br
s, 1H, NH+, D2O exchanged); GC/MS m/z (free amine) 269 (M+
+ 2, 4), 267 (M+, 11), 112 (100).
P r ep a r a tion of Ar yloxya lk yla m in es (10a ,b). Gen er a l
P r oced u r e. Glacial CH3COOH (2.5 mL, 44 mmol) and 55%
NH2NH2‚xH2O (2.5 mL, 44 mmol) were added to a stirred
solution of the appropriate aryloxyalkylphthalimido derivative
9 (6.6 mmol) in MeOH (50 mL). The reaction mixture was
refluxed with stirring for 7 h, and then it was allowed to cool
and stir overnight at room temperature. The solvent was
removed under vacuum, and the residue was alkalized with 6
N NaOH and extracted with ethyl acetate. The organic layer
was dried over Na2SO4 and evaporated to dryness affording
the expected amine. The pale yellow oils 10a ,b (32-77% yields)
were used for the next step without any further purification.
(R)-2-Am in o-1-(4-ch lor oph en oxy)pr opan e [(R)-10a]: 43%
yield; GC/MS m/z 187 (M+ + 2, 3), 185 (M+, 9), 44 (100).
(S)-2-Am in o-1-(4-ch lor oph en oxy)pr opan e [(S)-10a]: 32%
yield.
(+)-(R)- a n d (-)-(S)-4-Meth yl-1-[3-(4-ch lor op h en oxy)-
2-m eth yl-p r op yl]p ip er id in e h yd r och lor id es [(+)-(R)-16,
(-)-(S)-16]: 1H NMR: δ 1.01 (d, 3H, piperidine CH3), 1.27 (d,
3H, CH3), 1.40-1.70 (m, 1H, piperidine CH), 1.70-1.89 (m,
2H, 2 piperidine NCH2CH), 2.02-2.26 (m, 2H, 2 piperidine
NCH2CH), 2.50-2.74 and 3.00-3.24 (m, 4H, OCH2CH, 2
piperidine NCH and 1 of CH2N), 2.74-2.90 (m, 1H, 1 of CH2N),
3.25-3.68 (m, 2H, 2 piperidine NCH), 3.84-3.94 (m, 1H, 1 of
OCH2), 4.00-4.14 (m, 1H, 1 of OCH2), 6.78-7.24 (m, 4H,
aromatic), 11.97 (br s, 1H, NH+, D2O exchanged); GC/MS m/z
(free amine) 283 (M+ + 2, 2), 281 (M+, 5), 112 (100).
(-)-(R)-2-P h th a lim id o-1-p r op a n ol [(-)-(R)-8a ]. A sus-
pension of phthalic anhydride (3.93 g; 26.6 mmol), triethy-
lamine (0.37 mL; 2.65 mmol), and (R)-2-amino-1-propanol 6
(2.00 g, 26.6 mmol) in toluene (40 mL) was placed into a round-
bottomed flask equipped with a Dean-Stark apparatus. The
mixture was refluxed for 5.5 h and then was allowed to cool
to room temperature. The solvent was removed under vacuum
to give a white solid which was dissolved in AcOEt (50 mL)
and washed with 2 N HCl (2 × 20 mL) and NaHCO3 saturated
solution (2 × 20 mL) followed by brine. The organic layer was
dried over Na2SO4 and the solvent evaporated under reduced
pressure to give a white solid (3.68 g) which was purified by
crystallization (petroleum ether/AcOEt) to afford 2.84 g of the
title compound as white crystals (52% yield); [R]D ) -36 (c )
1.3, MeOH); mp 87-88 °C; 1H NMR (90 MHz): δ 1.45 (d, 3H,
CH3), 2.50-3.00 (bb, 1H, OH, D2O exchanged), 3.70-4.20 (m,
2H, CH2OH), 4.30-4.70 (m, 1H, CH), 7.50-7.90 (m, 4H,
aromatic); GC/MS m/z 205 (M+, 0.1), 174 (100); FT-IR 1689
cm-1 (CdO).
(R)-3-Am in o-1-(4-ch lor op h en oxy)bu ta n e [(R)-10b]: 77%
yield; GC/MS m/z 201 (M+ + 2, 3), 199 (M+, 9), 44 (100).
(S)-3-Am in o-1-(4-ch lor op h en oxy)bu ta n e [(S)-10b]: 49%
yield.
P r ep a r a tion of Ar yloxya lk ylp ip er id in d ion es (11a , b).
Gen er a l P r oced u r e. A solution of 3-methylglutaric acid (5
mmol) in acetyl chloride (5 mL) was stirred under reflux for 3
h. After cooling, the acetyl chloride excess was removed under
reduced pressure. The oily residue was dissolved in dry THF
(5 × 20 mL), and the solvent was distilled off under vacuum
for five times. To the afforded light brown solid was added a
solution of the appropriate amine 10 (5 mmol) in dry THF (10
mL). The reaction mixture was stirred overnight at room
temperature, the solvent was evaporated under vacuum, and
acetyl chloride (5.5 mL) was added to the oily residue. After
refluxing for 5 h, the mixture was evaporated to dryness under
reduced pressure affording a red-brown oil which was dissolved
in CH2Cl2 and washed with Na2CO3 saturated solution, brine,
and 2 N HCl followed by brine. The organic layer was dried
over Na2SO4 and filtered. The solvent was evaporated in vacuo
to afford the desired compound. The brown oils 11a ,b (42-
96% yields) were used for the next step without any further
purification.
Compound (+)-(S)-8a was obtained according to the proce-
dure reported above for the compound (-)-(R)-8a using (S)-
2-amino-1-propanol as starting material.
(+)-(S)-2-P h th alim ido-1-pr opan ol [(+)-(S)-8a]: 49% yield;
[R]D ) +34 (c ) 1.3, MeOH); mp 87-88 °C.
(R)-1-(4-Ch lor oph en oxy)-2-(4-m eth yl-2,6-piper idin dion -
1-yl)p r op a n e [(R)-11a ]: 89% yield; GC/MS m/z 295 (M+, 0.2),
168 (100).
(S)-1-(4-Ch lor oph en oxy)-2-(4-m eth yl-2,6-piper idin dion -
1-yl)p r op a n e [(S)-11a ]: 79% yield.
P r ep a r a tion of Ar yloxya lk ylp h th a lim id o Der iva tives
(9a ,b). Gen er a l P r oced u r e. To a stirred solution of 4-chlo-
rophenol (10 mmol) and triphenylphosphine (10 mmol) in
anhydrous THF (40 mL) was added the appropriate phthal-
imido alcohol 8 (5 mmol) in anhydrous THF (10 mL). After
the mixture was cooled to 0 °C, a solution of diethyl azodicar-
boxylate (DEAD, or diisopropyl azodicarboxylate, DIAD) (10
mmol) in anhydrous THF (10 mL), was added dropwise, and
the reaction mixture was stirred overnight at room tempera-
ture, under N2 atmosphere. The solvent was removed under
vacuum, and the residue was purified on a silica gel column
(petroleum ether/AcOEt 8:2 as eluent) to afford the compound
9a (or 9b); pale yellow oils in 75-98% yields.
(+)-(R)-2-P h th alim ido-1-(4-ch lor oph en oxy)pr opan e [(+)-
(R)-9a ]: 98% yield; [R]D ) +15 (c ) 1.0, MeOH); 1H NMR: δ
1.55 (d, 3H, CH3), 4.13 (q, 1H, 1 of OCH2), 4.50 (t, 1H, 1 of
OCH2), 4.77 (m, 1H, CHN), 6.70-7.20 (m, 4H, aromatic), 7.65-
7.90 (m, 4H, aromatic); GC/MS m/z 317 (M+ + 2, 3), 315 (M+,
10), 188 (100).
(R)-1-(4-Ch lor oph en oxy)-3-(4-m eth yl-2,6-piper idin dion -
1-yl)bu ta n e [(R)-11b]: 96% yield; GC/MS m/z 309 (M+, 1),
182 (100).
(S)-1-(4-Ch lor oph en oxy)-3-(4-m eth yl-2,6-piper idin dion -
1-yl)bu ta n e [(S)-11b]: 42% yield.
P r ep a r a tion of Ar yloxya lk ylp ip er id in e Hyd r och lo-
r id es (17, 18). Gen er a l P r oced u r e. A solution of borane-
methyl sulfide complex (BMS, 25 mmol) in anhydrous THF
(15 mL) was added dropwise to a stirred and cooled solution
of the appropriate aryloxyalkylpiperidindione 11 (5 mmol) in
anhydrous THF (30 mL). The reaction mixture was refluxed
with stirring for 4 h, cooled to 0 °C, and carefully added with
MeOH (40 mL) dropwise to destroy the excess of borane
complex. Then, 2 N HCl (70 mL) was added, and the resulting
mixture was refluxed with stirring for 2 h. After the organic
solvents were distilled off, the mixture was allowed to cool at
room temperature and alkalized with 6 N NaOH. The aqueous
layer was extracted with ethyl acetate (3 × 50 mL), and the
combined organic extracts were washed with brine (1 × 40
mL), dried over Na2SO4, and filtered. Evaporation of the
solvent in vacuo afforded the desired piperidine. Compounds
17 and 18 were obtained as pale yellow oils in 46-96% yields.
The corresponding hydrochloride salts were prepared by
adding a HCl saturated ethereal solution to an ethereal
solution of the amine. Recrystallization solvent, [R]D, crystal-
(-)-(S)-2-P h th alim ido-1-(4-ch lor oph en oxy)pr opan e [(-)-
(S)-9a ]: 96% yield; [R]D ) -15 (c ) 1.0, MeOH).
(-)-(R)-3-P h th alim ido-1-(4-ch lor oph en oxy)bu tan e [(-)-
1
(R)-9b]: 75% yield; [R]D ) -84 (c ) 1.3, CHCl3); H NMR: δ
1.54 (d, 3H, CH3), 2.10-2.25 (m, 1H, 1 of OCH2CH2), 2.50-
2.71 (m, 1H, 1 of OCH2CH2), 3.85-4.00 (m, 2H, OCH2), 4.61-

Chiral 1-[ω-(4-Chlorophenoxy)alkyl]-4-methylpiperidines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 11 2123
(12) Wilke, R. A.; Mehta, R. P.; Lupardus, P. J .; Chen, Y.; Ruoho, A.
E.; J ackson, M. B. Sigma receptor photolabeling and sigma
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(13) Maurice, T.; Urani, A.; Phan, V. L.; Romieu, P. The interaction
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of them were obtained as white crystalline powders.
(+)-(R)- a n d (-)-(S)-4-Meth yl-1-[2-(4-ch lor op h en oxy)-
1-m eth yl-eth yl]p ip er id in e h yd r och lor id es [(+)-(R)-17,
(-)-(S)-17]: 1H NMR: δ 1.04 (d, 3H, piperidine CH3), 1.58 (d,
3H, CH3), 1.50-1.90 and 2.10-2.24 (m, 5H, 2 piperidine
NCH2CH2 and piperidine CH), 2.78-3.10 and 3.18-3.38 (m,
2H, 2 piperidine NCH), 3.42-3.74 (m, 3H, 2 piperidine NCH
and CH3CHN), 4.22-4.36 (dd, 1H, 1 of OCH2), 4.48-4.62 (dd,
1H, 1 of OCH2), 6.80-7.40 (m, 4H, aromatic), 12.20 (bb, 1H,
NH+, D2O exchanged); GC/MS m/z (free amine) 267 (M+, 0.2),
126 (100).
(-)-(R)- a n d (+)-(S)-4-Meth yl-1-[3-(4-ch lor op h en oxy)-
1-m eth yl-p r op yl]p ip er id in e h yd r och lor id es [(-)-(R)-18,
(+)-(S)-18]: 1H NMR: δ 1.02 (d, 3H, piperidine CH3), 1.46 (d,
3H, CH3), 1.40-2.25 (m, 6H, 2 piperidine NCH2CH2, 1 of
OCH2CH2 and piperidine CH), 2.60-2.95 and 2.96-3.30 (m,
3H, 2 piperidine NCH and 1 of OCH2CH2), 3.30-3.60 (m, 3H,
2 piperidine NCH and CH3CHN) 3.90-4.20 (m, 2H, OCH2),
6.80-7.40 (m, 4H, aromatic), 11.80 (bb, 1H, NH+, D2O
exchanged); GC/MS m/z (free amine) 281 (M+, 5), 126 (100).
Biologica l Meth od s. (+)-[3H]-Pentazocine and [3H]-DTG
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Radiolabeled Chemicals Inc. (St. Louis, MO). (+)-Pentazocine
was obtained from Sigma-RBI (Milan, Italy), and DTG and
ifenprodil were purchased from Tocris Cookson Ltd., UK. Male
Dunkin guinea-pigs and Wistar Hannover rats (250-300 g)
were from Harlan, Italy.
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sigma receptors: new family members reveal a role in cholesterol
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(22) Dussossoy, D.; Carayon, P.; Belugou, S.; Feraut, D.; Bord, A.;
Goubet, C.; Roque, C.; Vidal, H.; Combes, T.; Loison, G.; Casellas,
P. Colocalization of sterol isomerase and sigma1 receptor at
endoplasmic reticulum and nuclear envelope level. Eur. J .
Biochem. 1999, 263, 377-385.
Ra d ioliga n d Bin d in g Assa ys. All procedures followed to
perform the binding assays at σ1 site,26 σ2 site,26 and sterol
∆8-∆7 isomerase site (EBP)59 were previously described.50
Ack n ow led gm en t. This study was supported by
Research Grant No. 2001037552-003 from Universita`
degli Studi di Bari and MURST (Italy) for the scientific
program in CO7X field (2002-2003).
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SK-N-SH neuroblastoma cells. J . Pharmacol. Exp. Ther. 2000,
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