Synthesis and structure-activity relationships of 1-aralkyl-4- benzylpiperidine and 1-aralkyl-4-benzylpiperazine derivatives as potent σ ligands

Article abstract of DOI:10.1021/jm049433t

In the attempt to define more accurately structure-affinity relationships for σ₁ and σ₂ ligands, we synthesized and tested on σ subtype receptors a series of aralkyl derivatives of 4-benzylpiperidine, in which the effect of modificat

Full text of DOI:10.1021/jm049433t

266
J. Med. Chem. 2005, 48, 266-273
Synthesis and Structure-Activity Relationships of 1-Aralkyl-4-Benzylpiperidine
and 1-Aralkyl-4-Benzylpiperazine Derivatives as Potent σ Ligands
Luca Costantino,*,† Francesca Gandolfi,† Claudia Sorbi,†,| Silvia Franchini,† Orazio Prezzavento,‡
Franco Vittorio,‡ Giuseppe Ronsisvalle,‡ Amedeo Leonardi,§ Elena Poggesi,§ and Livio Brasili*,†
Dipartimento di Scienze Farmaceutiche, Universita´ di Modena and Reggio Emilia, Via Campi 183, 41100 Modena, Italy,
Dipartimento di Scienze Farmaceutiche, Universita´ di Catania, Viale A. Doria 6, 95125 Catania, Italy, and Recordati S.p.A.,
Divisione Ricerca e Sviluppo, Via Civitali 1, 20148, Milano, Italy
Received July 16, 2004
In the attempt to define more accurately structure-affinity relationships for σ1 and σ2 ligands,
we synthesized and tested on σ subtype receptors a series of aralkyl derivatives of 4-benzylpi-
peridine, in which the effect of modifications on the aralkyl moiety was studied in a systematic
way. The affinity of the compounds here described varied to a great extent, with a σ2/σ1
selectivity ranging from 0.1 to 9. Thus, to confirm the ability of the piperazine derivative to
bind to σ1 receptors in a different way than piperidines, we synthesized and tested a series of
piperazine compounds; the comparison of their affinity with that of the corresponding
piperidines strongly supports the possibility of a different binding mode. While the compounds
here described are on the whole selective for σ vs serotonin 5-HT1A and dopamine D2 receptors,
9aa, 9ba and 9ab possess a remarkable affinity for both σ and 5-HT1A receptors, with Ki in
the nanomolar range, and are selective with respect to D2 receptors. They displayed also a
partial agonist profile in a human 5-HT1A [35S]GTPγS binding assay, suggesting their potential
use as atypical antipsychotic agents.
Chart 1
Introduction
Sigma receptors were first described by Martin as a
subtype of opioid recptors;1 now it is known that these
receptors are a distinct class, divided into two sub-
classes, σ1 and σ2.2 Several functions for σ1 receptors
have been discovered; among these there are modula-
tory roles on K+ and Ca2+ channels and on dopaminer-
gic, NMDA, serotoninergic, muscarinic neurotransmis-
sion, while σ2 receptors are involved in regulation of cell
proliferation and maintenance of cell viability, and may
contribute to the acute motor side effects of antipsy-
chotic drugs;2,3 however, this last activity was attributed
to σ1 sites too.4
Several classes of structurally unrelated compounds
interact with σ receptors.5,6 Both subtypes have high to
moderate affinity for typical neuroleptics, with halo-
peridol (1, Chart 1) exhibiting the highest affinity for
both sites.2 Other high-affinity σ ligands are ditolylguani-
dine (2), (+) pentazocine (3), and compound 4, a very
potent and selective ligand for σ1 receptors (σ1 Ki ) 0.5
nM; σ2 Ki ) 416 nM).7 While several selective, high-
affinity σ1 ligands are available, σ2 ligands are not
characterized to the same extent. Spiro[2]benzopyran-
1,4′-piperidine 5 (Chart 1) is the most potent and σ2
selective ligand described so far (σ1, IC50 ) 53 nM; σ2,
IC50 ) 0.90 nM).8 There is great interest in the develop-
ment of selective σ2 ligands: it appears that this
receptor subtype is involved in regulation of cell prolif-
eration and maintenance of cell viability, suggesting a
therapeutic use as novel antineoplastic agents. More-
over, σ2 receptor antagonists have been demonstrated
to limit the motor extrapyramidal side effects caused
by typical antipsychotic agents.2,3
Substituted 4-benzylpiperidine and 1-benzylpipera-
zine derivatives were shown to be high-affinity σ ligands
(Ki in the nanomolar range) with a slight preference for
* To whom correspondence should be addressed. Phone: 0039-059-
2055139. Fax: 0039-059-2055131. E-mail: brasili.livio@unimore.it.
† Universita´ di Modena and Reggio Emilia.
‡ Universita´ di Catania.
§ Recordati S.p.A.
| Current Address: Eurand S.p.A., Area Science Park, Padriciano
99, 34012, Trieste, Italy.
10.1021/jm049433t CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/17/2004

Benzylpiperidines and -piperazines as σ Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 267
Chart 2
Scheme 1a
σ1 over σ2 receptors.9-11 One of the proposed pharma-
cophores for σ1 binding includes an amine site, flanked
by two hydrophobic domains, the primary hydrophobic
site that bind phenyl “B” and a secondary binding site
that bind phenyl “A” (see compound 6, Chart 2). This
pharmacophoric model has been proposed for phenyl-
alkylamines as σ1 ligands,10,11 which is able to accom-
modate both phenylalkylpiperidines and phenylalkyl-
piperazines. Where two N atoms occur in a compound,
such as in piperazine derivatives, the N atom attached
to the longer chain is more important than the other
for the binding to this receptor subtype.11
Recently, a great number of arylalkylbenzylpiperazine
derivatives have been synthesized. Some compounds
showed a remarkable affinity and a strong selectivity
toward serotonin 5-HT1A and dopamine D2 receptors,
but the selectivity among σ receptor subtypes was not
studied, despite the affinity in the nanomolar range of
several of the reported compounds, and no clear SAR
was established.13,14
a (a) SOCl2 (for 23 and 24) or TsCl (for 17-22 and 25-28); (b)
4-benzylpiperidine or 1-benzylpiperazine; (c) L.G. Leaving group.
determine their selectivity. This aspect is particularly
important, since piperidine/piperazine derivatives are
known to bind at σ and also at 5-HT1A and D2 recep-
tors.9,16
Thus, in the attempt to define structure-affinity
relationships for 4-benzylpiperidine derivatives as σ1
and σ2 ligands, we synthesized and tested on σ subtype
receptors our lead compound 6 (Chart 2), which dem-
onstrated good affinity for both σ1 and σ2 receptor
subtypes (σ1 Ki ) 0.4 nM; σ2 Ki ) 3.3 nM).11 Then we
synthesized and tested the less symmetrical compounds
of general formula A (Chart 2), in the attempt to
optimize the interactions with the “phenyl B” site and
to avoid the binding in the flipped mode. In these
compounds the chain of three atoms connecting the
nitrogen of the piperidine and the aromatic ring of the
lead 6 was mantained and the effect of modifications
was studied in a systematic way. Moreover, a methoxy
group was inserted on the available positions of the
aromatic moiety (Ar in the General formula A, Chart
2) in order to test the space around it; this substitution
could be of great interest, since a strong effect depending
on the position of a methoxy group was observed in a
series of (tetralinopropyl)piperazines σ ligands.15
In addition, we synthesized and tested a series of
piperazine derivatives of general formula B (Chart 2),
to compare their affinity with that of the corresponding
piperidines.
All the chiral compounds were tested as racemates.
Chemistry
Compounds 9ad, 9bd, 10ac, and 10bc were prepared
by the reaction of the appropriate alkyl chloride 35 and
36 with 4-benzylpiperidine or 1-benzylpiperazine (Scheme
1); the other target compounds reported in Scheme 1
(7ab-7ac, 8aa, 8ba, 9aa, 9ba, 9ab, 9bb, 9ac, 9bc, 13-
16) were prepared in an analogous way, but in this case
the alcohols 17-22 and 25-28 were converted into the
corresponding tosylates (Scheme 1).
Compounds 10aa, 10ab, 10ba, 10bb, 11, and 12 were
prepared by the Mannich reaction (Scheme 2); reduction
of 11 by means of H2, Pd/C afforded 7aa (Scheme 2).
Compounds 8ab and 8bb were prepared according to
Scheme 3. The â-benzoylpropionic acid 45 was converted
into Mannich bases 46 and 47. The subsequent reduc-
tion of the carbonyl group adjacent to the aromatic ring
was performed with hydrogenolysis in acidic media, to
afford 48 and the debenzylated product 49. Compounds
48 and 49 were then cyclized with polyphosphoric acid
to afford 8ab and 50; this last compound was then
converted into the final product 8bb by the treatment
with 1 equiv of benzyl bromide.
The compounds were then tested for binding at σ2 and
also to serotonin 5-HT1A and dopamine D2 receptors, to

268 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1
Costantino et al.
Scheme 2a
first modifying the ring and then modifying the propyl
chain connecting the aromatic ring and the nitrogen.
The presence of an oxygen atom or of a carbonyl
(compounds 8aa, 8ab) in place of X does not influence
the affinity of 7ab.
The presence of an oxygen in place of the CH2 of the
propyl chain at the position adjacent to the aromatic
ring (compounds 9aa, 9ab) lowers the affinity; in fact,
7ab and 8aa are 1 order of magnitude better ligands
than the corresponding oxygen isosters; however, the
affinity is strongly influenced by other substituents. In
fact, while compound 9ac showed an affinity similar to
its CH2 counterpart 8ab, compound 9ad, which pos-
sesses a carbonyl and the double bond, showed a marked
decrease in affinity for both σ1 and σ2 receptor subtypes.
The presence of a carbonyl group on the propyl chain
at the position adjacent to the aromatic ring is negative
especially for the affinity to σ1 receptors (compounds
10aa, 10ab, and 10ac). From the data obtained for
compounds 11 and 12, it seems that a carbonyl adjacent
to the aromatic ring is tolerated only if it is inserted in
a ring greater than cyclopentane; evidence of this
hypothesis is the lack of affinity for both σ1 and σ2 of
compound 11, while 12 maintains a discrete affinity
(Table 1). The compounds 10ab, 10ac, and, in particu-
lar, 10aa were selective among σ receptor subtypes (σ2/
σ1 of 0.5, 0.2, and 0.1, respectively).
a (a) Formaldehyde, 4-benzylpiperidine or 1-benzylpiperazine;
(b) H2, Pd/C.
Results and Discussion
The synthesized 4-benzylpiperidine derivatives (Table
1) were evaluated for their affinity at both σ1 and σ2
receptors as well as for 5-HT1A and D2 receptors. Most
of the compounds exhibited high affinity (in the nano-
molar range) at σ receptor subtypes and possess practi-
cally no affinity at both 5-HT1A and D2 receptors.
Compound 6, here considered as a lead, showed a good
σ affinity in our experimental assays, even if the
selectivity σ2/σ1 is slightly different than that reported
in the literature (σ1 Ki ) 0.4 nM, σ2 Ki ) 3.3 nM, ref 11;
σ1 Ki ) 1.40 nM, σ2 Ki ) 0.49 nM, Table 1).
The affinities of the compounds showed that, com-
pared to the lead 6, the rigidification of the propyl chain
within a five-membered ring (compound 7aa) or within
a six-membered ring (compound 7ab) showed no influ-
ence on σ1 affinity; however, it should be noted that the
presence of a five-membered ring lowers the affinity 25
times for σ2 receptor subtype, an effect not present in
the compound carrying a six-membered ring. On the
other hand, the presence of a seven-membered ring
(compound 7ac) showed lower affinity on both σ1 and
σ2 receptors than the other two compounds.
Moreover, a methoxy group was inserted on the
benzene ring of the tetrahydronaphthalene moiety of the
piperidine compound (7ab) in order to test the space
around it. The effect exerted by the methoxy group is
in accordance with that reported in ref 15, where a
detrimental presence of a 5- and 7-methoxy substituent
was observed, even if this effect is influenced by the
length of the chain connecting the aromatic moiety to
the basic nitrogen. In this case, the negative effect was
limited to the presence of a 5-methoxy group (compound
13). The 8-substituted derivative (compound 16) showed
also a decrease in affinity, but this position was not
examined earlier. The presence of a methoxy group
On the basis of the observed affinities, it was decided
to modify the tetrahydronaphthalene moiety of 7ab,
Scheme 3a
a (a) Formaldehyde, 4-benzylpiperidine or 1-benzylpiperazine; (b) H2, Pd/C; (c) polyphosphoric acid; (d) benzyl bromide.

Benzylpiperidines and -piperazines as σ Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 269
Table 2. Binding of 1-aralkyl-4-benzylpiperazine Derivatives
Table 1. Binding of 1-Aralkyl-4-benzylpiperidine Derivatives
a Ki values agreed to (20%. b Binding assays were performed
using 3.0 nM [3H]pentazocine. c Binding assays were performed
using 3.0 nM [3H]ditolylguanidine. d Ki ratio. e Binding assays
were performed using 1.2 nM [3H]-8-OH-DPAT. f Binding assays
were performed using 0.2 nM [3H]spiperone. g N.D., not deter-
mined.
Table 3. Potency (pD2) and Relative Effectiveness Values in
the [35S]GTPγS Binding Assay at 5-HT1A Human Cloned
Receptors of Selected Compounds
[
35S]GTPγS binding
% Emax
a
compd
pD2
a Ki values agreed to (20%. b Binding assays were performed
using 3.0 nM [3H]pentazocine. c Binding assays were performed
using 3.0 nM [3H]ditolylguanidine. d Ki ratio. e Binding assays
were performed using 1.2 nM [3H]-8-OH-DPAT. f Binding assays
were performed using 0.2 nM [3H]spiperone. g N.D., not deter-
mined.
9aa
9ba
9ab
7.89
6.29
8.20
61.9
41.0
41.7
a Emax: maximal stimulation achieved expressed as a percentage
of the maximal 5-HT response.
influences also the selectivity σ2/σ1 (changing from 0.1
for compound 13 to 3, 1, and 2 for compounds 14, 15,
and 16, respectively); thus its presence at position 5 of
the tetrahydronaphthalene moiety favors σ2 affinity.
Then, the corresponding benzylpiperazines were stud-
ied (Table 2). On the whole, it should be noted that, in
agreement with that reported in previous works,11,13
piperazine derivatives bind to σ receptor subtypes with
stronger affinity with respect to the corresponding
piperidine derivatives and are better ligands for σ1 than
σ2 receptors (see Tables 1 and 2).
Moreover, while among piperidine derivatives the
nature of the heterocyclic substituent influences mark-
edly the affinity (10ab, σ1, Ki ) 700 nM; σ2, Ki 370 nM),
the corresponding piperazine derivative is a high-
affinity σ ligand (10bb, σ1 Ki of 18.0, σ2 Ki of 32.8 nM);
the same effect is shared by compounds 9ad and 10ac
(compare with 9bd and 10bc, respectively).
aromatic ring here considered but depends on the
nature of the ring in which the propyl chain is inserted.
On the whole, the compounds here described showed
a marked selectivity vs serotonin 5-HT1A and dopamine
D2 receptors. Only compounds 9aa, 9ba, and 9ab
(Tables 1 and 2) behave as high-affinity ligands for
5-HT1A receptors; these compounds were then tested for
the evaluation of their potency (pD2) and relative
intrinsic activity in the [35S]GTPγS binding assay (Table
3). The piperidine derivatives 9ab and 9aa were found
to be potent, partial agonists at the h5-HT1A receptor,
with a pD2 of 8.20 (Emax 41.7%) and 7.89 (Emax 61.9%),
respectively. The affinity for 5-HT1A could be partic-
ularly interesting, since this receptor subtype has
been, as a therapeutic target for the development of
improved antipsychotic drugs:6,17 several clinically ef-
fective antipsychotics bind in vitro, with moderate to
high affinity, proposed to cloned human 5-HT1A recep-
tors.18,19 Moreover, OPC-14523 (affinities for σ1, σ2, and
The selectivity vs σ2 receptor subtype is not influenced
by the nature of the propyl chain adjacent to the

270 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1
Costantino et al.
then refluxed for 1 h. After cooling, EtOAc (20 mL) and a
saturated solution of K2CO3 up to alkaline pH were added to
the reaction mixture. The mixture was extracted with EtOAc
(3 × 20 mL), the organic phases were dried (Na2SO4), and the
solvent was removed under reduced pressure. The residue was
then purified by column chromatography (CH3OH/EtOAc 0.75/
9.25).
3-[(4-Benzylpiperidinyl)methyl]chromone 10ac: 1H
NMR δ 8.22 (1H, m), 8.00 (1H, s), 7.63 (1H, m), 7.33 (7H, m),
3.45 (2H, s), 2.98 (2H, m), 2.56 (2H, d, J ) 6.33), 2.08 (2H, m),
1.55 (5H, m). The compound was converted to the HCl salt by
dissolving it in anhydrous ether, and then a saturated ethereal
solution of HCl was added. The salt thus obtained was
recrystallized from CH3OH/diethyl ether: mp 227-228 °C
(dec); IR (cm-1) (Nujol) 1634. Anal. (C22H23NO2‚HCl) C, H, N.
3-[(4-Benzylpiperazinyl)methyl]chromone 10bc: 1H
NMR δ 8.26 (1H, m), 7.98 (1H, t, J ) 1.0), 7.68 (1H, m), 7.35
(7H, m), 3.55 (2H, s), 3.54 (2H, d, J ) 1.0), 2.56 (8H, m). The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH/diethyl ether: mp 275-278 °C (dec); IR (cm-1) (Nujol)
1647. Anal. (C21H22N2O2‚2HCl) C, H, N.
Synthesis of Tosylates 29-34 and 37-40. General
Procedure. To a solution of the hydroxymethyl derivatives
17-22 and 25-28 (3 mmol) in anhydrous pyridine (4 mL) at
0 °C and with stirring was added p-toluensulfonyl chloride (3
mmol). After 15 min, the cooling bath was removed and the
reaction mixture was left for 15 h at room temperature with
stirring. At the end of the reaction, the mixture was cooled,
acidified with 2 N HCl, and extracted with CH2Cl2 (3 × 20
mL). The organic phases were dried (Na2SO4), the solvent
removed under reduced pressure, and the residue purified by
means of column chromatography (CH2Cl2 100%).
Synthesis of 2-[(4-Benzylpiperidinyl- (7ab, 7ac, 8aa,
9aa-9ac, 13-16) and -piperazinyl)] Derivatives (7bb,
8ba, 9ba, 9bb, 9bc). General Procedure. A solution of the
tosylate 29-34 and 37-40 (1.5 mmol) and the corresponding
4-benzylpiperidine or 1-benzylpiperazine (4.5 mmol) in toluene
(10 mL) was refluxed for 12 h. In the case of compounds 9ac
and 9bc, CH2Cl2 was used instead of toluene; in the case of
9ab and 9bb, anhydrous THF was used. Then the solution
was cooled, treated with a saturated solution of K2CO3 until
alkaline pH was reached, and extracted with CH2Cl2 (4 × 20
mL). The organic phases were dried (Na2SO4), the solvent was
removed by reduced pressure, and the residue thus obtained
was purified by means of column chromatography (CH2Cl2/
CH3OH 9.5/0.5).
1-[2-(1,2,3,4-Tetrahydronaphthylmethyl)]-4-benzylpi-
peridine 7ab: 1H NMR δ 7.21 (9H, m), 2.95 (4H, m), 2.60 (2H,
d, J ) 6.40), 2.43 (1H, m), 2.38 (2H, d, J ) 6.95), 2.00 (4H, m),
1.45 (6H, m). The compound was converted to the HCl salt by
dissolving it in anhydrous ether, and then a saturated ethereal
solution of HCl was added. The salt thus obtained was
recrystallized from CH3OH/diethyl ether: mp 217-220 °C.
Anal. (C23H29N‚HCl) C, H, N.
4-Benzyl-1-(6,7,8,9-tetrahydrobenzocycloheptan-6-yl-
methyl)piperidine 7ac. The compound was converted to the
HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH/diethyl ether: mp
217-218 °C. Anal. (C24H31N‚HCl) C, H, N.
1-[2-(1,2,3,4-Tetrahydronaphthylmethyl)]-4-benzylpip-
erazine 7bb: 1H NMR δ 7.40 (5H, m), 7.06 (4H, m), 3.60 (2H,
s), 2.90 (3H, m), 2.50 (8H, m), 2.41 (2H, d, J ) 7.06), 2.06 (2H,
m), 1.35 (2H, m). The compound was converted to the HCl salt
by dissolving it in anhydrous ether, and then a saturated
ethereal solution of HCl was added. The salt thus obtained
was recrystallized from CH3OH: mp 280 °C (lit.14 mp 191 °C).
Anal. (C22H28N2‚2HCl) C, H, N.
5-HT1A receptors (IC50, nM), 47, 56, and 2.3, respec-
tively)20 exerts an acute antidepressant-like action, and
this pharmacological activity is achieved by the com-
bined stimulation of σ and 5-HT1A receptors.20 In vivo
assays will then be conducted in order to determine
their potential as new therapeutic agents for the treat-
ment of psychiatric disorders.
Conclusions
The modifications of the propyl chain of the lead
compound 6 led to the 1-aralkyl-4-benzylpiperidines.
These compounds showed a great variation in affinity
for σ1 receptors, ranging from compounds practically
devoid of affinity to compounds with an affinity in the
nanomolar range. Thus, useful information about the
structural characteristics for an optimal interaction with
the “phenyl B” site was obtained. The compounds
showed also selectivity among σ receptor subtypes, with
a σ2/σ1 selectivity ranging from 0.1 (compounds 10aa
and 13) to 9. These results will be the basis of further
modifications in order to obtain more selective com-
pounds. The comparison of the affinities of these com-
pounds with those of the corresponding 1-aralkyl-4-
benzylpiperazines strongly supports the possibility of
a different binding mode of the piperazine derivatives
to σ receptors, as suggested by earlier literature. While
the compounds here described are on the whole selective
for σ vs serotonin 5-HT1A and dopamine D2 receptors,
9aa, 9ba, and 9ab possess a remarkable affinity for
both σ and 5-HT1A receptors, with Ki in the nanomolar
range. They displayed also a partial agonist profile in a
human 5-HT1A [35S]GTPγS binding assay, suggesting
their potential use as atypical antipsychotic agents.
Experimental Section
Chemistry. Melting points were determined on a Buchi 510
capillary melting point apparatus and are uncorrected. El-
emental analyses were conducted at the Microanalysis Labo-
ratory of the Dipartimento di Scienze Farmaceutiche, Modena
University, and the results were within (0.4% of the theoreti-
cal values. 1H NMR spectra were recorded on a Bruker AC200
spectrometer; chemical shifts are reported in ppm relative to
TMS. Only representative 1H NMR spectra were reported; see
also the Supporting Informations. CDCl3 was used as a solvent,
unless otherwise noted. TLC on silica gel plates was used to
check product purity. Silica gel 60 (Merck, 70-230 mesh) was
used for column chromatography. The following were synthe-
sized as previously reported: 2-[(4-benzylpiperidinyl)methyl]-
chromone 9ad13 and 2-[(4-benzylpiperazinyl)methyl]chromone
9bd,13 2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene 17,21
3-hydroxymethylchromane 19,22 2-hydroxymethylchromane
20,23 2-hydroxymethylchromanone 22,24 3-(hydroxymethyl)-
chromone 2425 and 3-(chloromethyl)chromone 36,25 and 6-meth-
oxy-1,2,3,4-tetrahydronaphthalen-2-ylmethanol 26.26 5-Methoxy-
1,2,3,4-tetrahydronaphthalen-2-ylmethanol 25, 7-methoxy-
1,2,3,4-tetrahydronaphthalen-2-yl-methanol 27, 8-methoxy-
1,2,3,4-tetrahydronaphthalen-2-ylmethanol 28, and 6,7,8,9-
tetrahydrobenzocycloheptan-6-ylmethanol 18 were synthesized
in an analogous way, starting from the corresponding com-
mercially available tetralones or benzosuberone, by reaction
with ethyl formate in the presence of tBuOK and subsequent
reduction with borane. The starting material for 28, 8-meth-
oxytetralone was not commercially available and was synthe-
sized starting from 8-naphthosultone as previously reported.27-29
Synthesis of 3-[(4-Benzylpiperidinyl- (10ac) and -pip-
erazinyl)methyl]chromone (10bc). General Procedure.
A solution of 3-chloromethylchromone 36 (2.58 mmol) and
4-benzylpiperidine or 1-benzylpiperazine (25.8 mmol) in CH2-
Cl2 (5 mL) was stirred at room temperature for 15 min and
3-[(4′-Benzylpiperidinyl)methyl]chromane 8aa. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl

Benzylpiperidines and -piperazines as σ Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 271
was added. The salt thus obtained was recrystallized from CH3-
OH/diethyl ether: mp 212-215 °C (dec). Anal. (C22H27NO‚HCl)
C, H, N.
(concentrated HCl), and extracted with diethyl ether (5 × 15
mL). The aqueous phase was then basified (2 N NaOH) and
extracted with diethyl ether (3 × 30 mL). The organic phases
thus obtained were dried (Na2SO4), and the solvent was
removed under reduced pressure. The residue thus obtained
was purified by means of column chromatography (CH2Cl2/
CH3OH 9.5/0.5). Representative 1H NMR spectra were re-
ported.
3-[(4′-Benzylpiperazinyl)methyl]chromane 8ba. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 280-282 °C (dec). Anal. (C21H26N2O‚2HCl) C, H, N.
2-[(4′-Benzylpiperidinyl)methyl]chromane 9aa. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 195-197 °C (dec). Anal. (C22H27NO‚HCl) C, H, N.
2-[(4′-Benzylpiperazinyl)methyl]chromane 9ba. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 288-290 °C (dec), (lit.14 mp >300 °C). Anal.
(C21H26N2O‚2HCl) C, H, N.
4-Benzyl-1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-
piperidine 9ab. The compound (2.65 mmol) was transformed
into the corresponding oxalate salt by treatment with oxalic
acid (5.3 mmol) in anhydrous diethyl ether (50 mL) and was
purified by crystallization (ethanol): mp 172-175 °C. Anal.
(C21H25NO2‚(COOH)2) C, H, N.
1-Benzyl-4-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-
piperazine 9bb. The compound (2.65 mmol) was transformed
into the corresponding oxalate salt by treatment with oxalic
acid (5.3 mmol) in anhydrous diethyl ether (50 mL) and
purified by crystallization (CH3OH): mp 237-239 °C. Anal.
(C20H24N2O2‚2(COOH)2) C, H, N.
2-[(4′-Benzylpiperidinyl)methyl]chromanone 9ac. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 200-203 °C (dec); IR (cm-1) (Nujol) 1684. Anal.
(C22H25NO2‚HCl) C, H, N.
2-[(4′-Benzylpiperazinyl)methyl]chromanone 9bc. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 258-261 °C (dec); IR (cm-1) (Nujol) 1693. Anal.
(C21H24N2O2‚2HCl) C, H, N.
4-Benzyl-1-(5-methoxy-1,2,3,4-tetrahydronaphthalen-
2-ylmethyl)piperidine 13. The compound was converted to
the HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH/diethyl ether: mp
224-226 °C. Anal. (C24H31NO‚HCl) C, H, N.
2-(4-benzylpiperidin-1-ylmethyl)-1-tetralone 10aa: 1H
NMR δ 8.05 (1H, m), 7.41 (1H, m), 7.20 (7H, m), 2.81 (6H, m),
2.58 (2H, d, J ) 6.42), 2.40 (2H, m), 2.00 (3H, m), 1.40 (5H,
m). The compound was converted to the HCl salt by dissolving
it in anhydrous ether, and then a saturated ethereal solution
of HCl was added. The salt thus obtained was recrystallized
from CH3OH/diethyl ether: mp 163-165 °C; IR (cm-1) (Nujol)
1682. Anal. (C23H27NO‚HCl) C, H, N.
3-[(4′-Benzylpiperidinyl)methyl]chromanone 10ab. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH/diethyl ether: mp 171-172 °C (dec); IR (cm-1) (Nujol)
1682. Anal. (C22H25NO2‚HCl) C, H, N.
2-(4-Benzylpiperazin-1-ylmethyl)-1-tetralone 10ba: 1H
NMR δ 8.06 (1H, m), 7.50 (1H, m), 7.31 (7H, m), 3.51 (2H, s),
3.00 (3H, m), 2.55 (11H, m), 1.96 (1H, m). The compound was
converted to the HCl salt by dissolving it in anhydrous ether,
and then a saturated ethereal solution of HCl was added. The
salt thus obtained was recrystallized from CH3OH: mp 258-
260 °C (dec); IR (cm-1) (Nujol) 1682. Anal. (C22H26N2O‚2HCl)
C, H, N.
3-(4-Benzylpiperazin-1-ylmethyl)chroman-4-one 10bb.
The compound (0.45 mmol) was transformed into the corre-
sponding oxalate salt by treatment with oxalic acid (0.9 mmol)
in anhydrous diethyl ether (50 mL). The salt was then washed
several times with diethyl ether: mp 198-200 °C. Anal.
(C21H24N2O2‚2(COOH)2) C, H, N.
(4-Benzyl-1-oxo-indan-2-yl)methylpiperidine 11. The
compound was converted to the HCl salt by dissolving it in
anhydrous ether, and then a saturated ethereal solution of HCl
was added. The salt thus obtained was recrystallized from CH3-
OH: mp 155-156 °C (dec); IR (cm-1) (Nujol) 1682. Anal.
(C22H25NO‚HCl) C, H, N.
6-(4-Benzylpiperidin-1-ylmethyl)-6,7,8,9-tetrahydroben-
zocycloheptan-5-one 12. The compound was converted to the
HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH/diethyl ether: mp
153-155 °C; IR (cm.-1) (Nujol) 1682. Anal. (C24H29NO‚HCl)
C, H, N.
4-Benzyl-1-(6-methoxy-1,2,3,4-tetrahydronaphthalen-
2-ylmethyl)piperidine 14. The compound was converted to
the HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH/diethyil ether: mp
237-240 °C. Anal. (C24H31NO‚HCl) C, H, N.
4-Benzyl-1-(7-methoxy-1,2,3,4-tetrahydronaphthalen-
2-ylmethyl)piperidine 15. The compound was converted to
the HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH/diethyl ether: mp
211-214 °C. Anal. (C24H31NO‚HCl) C, H, N.
4-Benzyl-1-(8-methoxy-1,2,3,4-tetrahydronaphthalen-
2-ylmethyl)piperidine 16. The compound was converted to
the HCl salt by dissolving it in anhydrous ether, and then a
saturated ethereal solution of HCl was added. The salt thus
obtained was recrystallized from CH3OH: mp 207-209 °C.
Anal. (C24H31NO‚HCl) C, H, N.
Synthesis of Mannich Bases 10aa, 10ab, 10ba, 10bb,
11, 12. General Procedure. A suspension of the carbonyl
compound 41-44 (12.9 mmol), 4-benzylpiperidine, or 1-ben-
zylpiperazine (12.9 mmol) and paraformaldehyde (39.3 mmol)
in absolute EtOH saturated with HCl (4.0 mL) was refluxed
for 7 h. After cooling, the solvent was removed under reduced
pressure, and the residue was treated with water, acidified
(4-Benzylindan-2-yl)methylpiperidine 7aa. A solution
of 11 (0.60 g, 1.9 mmol) in ethanol (60 mL) and few drops of
concentrated HCl was hydrogenated in the presence of Pd/C
(5%, 90 mg) at 75 °C at 2 atm for 5 h. After the reaction
mixture was filtered, the solvent was removed under reduced
pressure and the residue was treated with a saturated solution
of Na2CO3 and extracted with CH2Cl2 (3 × 30 mL). The organic
phases were then dried (Na2SO4), and the solvent was removed
under reduced pressure. The oily product thus obtained was
converted into the HCl salt by dissolving it in anhydrous ether,
and then a saturated ethereal solution of HCl was added. The
salt thus obtained was recrystallized from CH3OH/diethyl
ether: mp 209-211 °C. Anal. (C22H27N‚HCl) C, H, N
3-(4-Benzylpiperidin-1-ylmethyl)-3-benzoylpropion-
ic Acid 46. A suspension of â-benzoylpropionic acid 45 (5.00
g, 28.1 mmol), formaldehyde (35%, 2.4 mL), and 4-benzylpip-
eridine (4.9 mL, 27.9 mmol)) in CH3OH was heated with
stirring at 70 °C for 15 min, and then it was left at room
temperature for 5 days. A solid was formed; it was triturated
with acetone (50 mL), and the residue was collected and
washed with acetone: mp 137-139 °C; IR (cm-1) (Nujol) 2188,
1691, 1659.
3-(4-Benzylpiperidin-1-ylmethyl)-4-phenylbutyric Acid
48. To a solution of 46 (3.00 g, 8.2 mmol) in methanol (80 mL)
containing an excess of dry HCl was added Pd/C (5%, 0.3 g),

272 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1
Costantino et al.
and the mixture was hydrogenated at 2.5 atm at room
temperature. After 5 h, the catalyst was removed by filtra-
tion and the solvent was removed under reduced pressure.
The residue thus obtained was purified by crystallization
(EtOAc): mp 130-132 °C.
The reaction was performed for 150 min at 37 °C and
terminated by filtering the solution through a Whatman GF/B
glass fiber filter which had been presoaked for 1 h in a 0.5%
poly(ethyilenimine) solution. Filters were washed twice with
4 mL of ice-cold buffer.
3-(4-Benzylpiperidin-1-ylmethyl)-1-tetralone 8ab. To
polyphosphoric acid (30.0 g), mantained at 60 °C with stirring,
was added 13c (1.00 g, 2.8 mmol). The temperature was
maintained at 60 °C for 15 min, raised to 120 °C, and
maintained at that temperature for 15 min. After cooling, the
reaction mixture was poured into ice-water, and then NaOH
was added until alkaline pH was reached. The mixture was
then extracted with diethyl ether (3 × 20 mL), the organic
phases were dried (Na2SO4), and the solvent was removed
under reduced pressure: 1H NMR δ 8.01 (1H, m), 7.51 (1H,
m), 7.32 (7H, m), 3.20 (1H, m), 2.81 (4H, m), 2.60 (2H, d, J )
6.22), 2.40 (4H, m), 1.95 (2H, m), 1.50 (5H, m). The product
thus obtained was converted into the HCl salt by dissolving it
in anhydrous ether, and then a saturated ethereal solution of
HCl was added. The salt thus obtained was recrystallized from
CH3OH/diethyl ether: mp 240-242 °C. Anal. (C23H27NO‚HCl)
C, H, N.
3-(4-Benzylpiperazin-1-ylmethyl)-3-benzoylpropion-
ic Acid 47. A suspension of â-benzoylpropionic acid 45 (5.00
g, 28.6 mmol), formaldehyde (35%, 2.4 mL), and 1-benzylpip-
erazine (4.97 mL) in CH3OH (3 mL) was heated at 65 °C 15
min, and then it was left at room temperature for 48 h. The
reaction mixture was then treated with acetone (5 mL) and
the solid thus formed was collected, washed with acetone, and
crystallized from EtOH: mp 155-158 °C.
σ2-Site Binding Assays. σ2-Site binding assays were car-
ried out on guinea pig brain membranes, prepared as described
by Mach et al.33 The membranes were incubated with 3 nM
[3H]DTG [1,3-di-2-tolylguanidine] (31 Ci/mM; Kd ) 9.9 ( 0.8
nM; n ) 3) in the presence of 400 nM (+)-SKF10,047 to block
σ1 sites. Incubation was carried out in 50 mM Tris-HCl (pH
8.0) for 120 min at room temperature. Each assay was
terminated by the addition of ice-cold 10 mM Tris-HCl, pH
8.0, followed by filtration through a Whatman GF/B glass fiber
filter which had been presoaked for 1 h in a 0.5% poly-
(ethylenimine) solution. Filters were washed twice with 4 mL
of ice-cold buffer. Nonspecific binding was evaluated in the
presence of 5 mM DTG. Inhibition constants (Ki values) for
the tested compounds were calculated using the EBDA-
LIGAND program34 purchased from Elsevier/Biosoft.
D2 Receptors Binding Assays. Binding experiments were
performed on rat striatal membranes according to Creese and
co-workers35 with minor modifications. Rats were killed by
decapitation, the brain was quickly removed, and the corpora
striata was dissected. The corpora striata (1.0 g) was homo-
genized with a Brinkman polytron (setting 5 for 3 × 15 s) in
25 mL of 50 mM Tris buffer, pH 7.4. The surnatant was
discarded, and the pellet was washed once. The final pellet
was stored at -80 °C until used. Each tube received, in a final
volume of 3 mL of incubation buffer (50 mM Tris, 120 mM
NaCl, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, and 5.7 mM
ascorbic acid, pH 7.4), rat striatal membranes suspension and
0.2 nM [3H]spiperone. For competitive inhibition experiments,
various concentrations of drugs studied were incubated.
Nonspecific binding was defined using 1 µM haloperidol.
Samples were incubated at 37 °C for 20 min and then filtered
on Whatman GF/B glass microfiber filters.
3-(Piperazin-1-ylmethyl)-4-phenylbutyric Acid 49. A
solution of the acid 47 (1.87 g, 5.11 mmol) in acetic acid (60
mL) was hydrogenated at 2.5 atm at 75 °C in the presence of
Pd/C (5%, 0.150 g) for 3 h; after filtration of the catalyst, the
solvent was removed under reduced pressure. The residue thus
obtained was triturated with diethyl ether: IR (cm-1) (Nujol)
3337, 1686, 1600. The solid thus obtained was used for the
next step without further purification.
Human Cloned 5-HT1A Serotonergic Receptors Bind-
ing Assays. Genomic clone G-21 coding for the human 5-HT1A
serotoninergic receptor is stably transfected in a human cell
line (HeLa).36 HeLa cells were grown as monolayers in Dul-
becco’s modified Eagle’s medium (DMEM), supplemented with
10% fetal calf serum and gentamicin (100 µg/mL) and 7% CO2
at 37 °C. Cells were detached from the growth flask at 95%
confluence by a cell scraper and were lysed in ice-cold 5 mM
Tris and 5 mM EDTA buffer (pH 7.4). Homogenates were
centrifuged at 40 000g for 20 min, and pellets were resus-
pended in a small volume of ice-cold 5 mM Tris and 5 mM
EDTA buffer (pH 7.4) and immediately frozen and stored at
-70 °C until use. On the day of the experiment, cell mem-
branes were resuspended in binding buffer (50 mM Tris (pH
7.4), 2.5 mM MgCl2, and 10 mM pargiline).37 Membranes were
incubated in a final volume of 1 mL for 30 min at 30 °C with
1.2 nM [3H]-8-OH-DPAT, in the absence or presence of
competing drugs: nonspecific binding was determined in the
presence of 10 µM 5-HT. The incubation was stopped by
addition of ice-cold Tris buffer and rapid filtration through
0.2% polyethyleneimine-pretreated Schleicher & Schuell GF52
filters.
Stimulation of [35S]GTPγS Binding at Cloned 5-HT1A
Receptors. The effects of the different compounds tested on
[35S]GTPγS binding were evaluated according to the method
of Stanton and Beer38 with minor modifications. On the day
of the experiment, cell membranes from HeLa cells transfected
with human cloned 5-HT1A receptors were resuspended in
buffer containing 20 mM HEPES, 3 mM MgCl2, and 120 mM
NaCl (pH 7.4). The membranes were incubated with 30 µM
GDP and decreasing concentrations (from 100 µM to 0.1 nM)
of test drugs or 5-HT (reference curve) for 20 min at 30 °C in
a final volume of about 0.5 mL. Samples were then transferred
to ice, with [35S]GTPγS (200-250 pM) added, and then
incubated for 30 min further at 30 °C. Nonspecific binding was
determined in the presence of 10 µM GTPγS. The incubation
was stopped by the addition of ice-cold HEPES buffer and
3-(1-Piperazinylmethyl)-1-tetralone 50. A mixture of 49
(1.30 g, 4.96 mmol) in polyphosphoric acid (40.0 g) was heated
at 120 °C for 15 min; after cooling, the reaction mixture was
diluted into ice/water (300 mL), treated with 5 N NaOH until
alkaline pH, and then extracted with diethyl ether (3 × 40
mL). The organic phases were dried (Na2SO4), and the solvent
was removed under reduced pressure.
3-(4-Benzylpiperazin-1-ylmethyl)-1-tetralone 8bb. To a
suspension of 50 (1.0 g, 4.1 mmol) and K2CO3 (0.56 g, 4.1
mmol) in anhydrous acetone (10 mL) at 0 °C and under stirring
was added benzyl bromide (0.49 mL, 4.1 mmol). The reaction
mixture was maintained at room temperature for 12 h, and
then salts were removed by filtration, and the solvent was
removed under reduced pressure. The residue thus obtained
was purified by means of column chromatography (CH2Cl2/
CH3OH 9.75/0.25): 1H NMR δ 8.01 (1H, m), 7.50 (1H, m), 7.36
(7H, m), 3.60 (2H, s), 3.18 (1H, m), 2.80 (2H, m), 2.50 (12H,
m). The compound was converted to the HCl salt by dissolving
it in anhydrous ether, and then a saturated ethereal solution
of HCl was added. The salt thus obtained was recrystallized
from CH3OH/diethyl ether: mp 262-265 °C (dec); IR (cm-1
(Nujol) 1682. Anal. (C22H26N2O‚2HCl) C, H, N.
)
Radioligand Binding Assays. σ1-Site Binding Assay. σ1-
Site binding assays were carried out on guinea pig brain
membranes according to Matsumoto et al.30 The protein
concentration of the suspension was measured by the method
of Lowry et al.31 and generally ranged from 6.5 to 8.5 mg of
protein/mL. Binding assays were performed as described by
DeHaven et al.32 Each tube contained 500 mg of membrane
protein and was incubated with 3 nM [3H]-(+)-pentazocine (45
Ci/mmol); the value of the apparent dissociation constant (Kd)
was 1.2 ( 0.3 nM (n ) 3) in 50 mM Tris-HCl (pH 7.4). Test
compounds were dissolved in DMSO and then diluted in buffer
to a total volume of 1 mL. Test compounds were added to give
a concentration in the range of 10-5-10-11 M. Nonspecific
binding was assessed in the presence of 10 µM haloperidol.

Benzylpiperidines and -piperazines as σ Ligands
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 1 273
(17) Meltzer, H. Y. The role of serotonin in antipsychotic drug action.
Neuropsychopharmacology 1999, 21 (Suppl. 2), 106S-115S.
(18) Richelson, E.; Souder, T. Binding of antipsychotic drugs to
human brain receptors focus on newer generation compounds.
Life Sci. 2000, 68, 29-39.
(19) Cosi, C.; Koek, W. Agonist, antagonist, and inverse agonist
properties of antipsychotics at human recombinant 5-HT1A
receptors expressed in HeLa cells. Eur. J. Pharmacol. 2001, 433,
55-62.
(20) Tattori, K.; Miwa, T.; Uwahodo, Y.; Yamada, S.; Nakai, M.;
Oshiro, Y.; Kikuchi, T.; Altar, C. A. Antidepressant-like re-
sponses to the combined sigma and 5-HT1A receptor agonist
OPC-14523. Neuropharmacology 2001, 41, 976-988.
(21) Julia, S.; Julia, M.; Huynh, C. Ketones with a cyclopropane
nucleus. IV. Properties of secondary and tertiary alcohols derived
from benzobyciclo[4.1.0]heptene. Bull. Soc. Chim. Fr. 1960, 84-
91.
(22) Gupta, R. C.; Pratap, R.; Prasad, R. C.; Anand, N. Chromene
and chroman 3-carboxamides and some related compounds as
a new class of centrally acting agents. Indian J. Chem. 1982,
21B, 344-347.
rapid filtration on Schleicher and Schuell GF52 filters, using
a Brandel cell harvester. The filters were washed three times
with a total of 5 mL of the same buffer. Radioactivity was
counted by liquid scintillation spectrometry with an efficiency
greater than 90%.
Acknowledgment. This work was supported by a
grant (COFIN) from MIUR (Rome). The authors wish
to thank Ms. Rossella Gallesi for performing elemental
analyses.
Supporting Information Available: Microanalysis data
1
relative to the target compounds and H NMR spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) Martin, W. R.; Eades, C. E.; Thompson, J. A.; Huppler, R. E. J.
Pharmacol. Exp. Ther. 1976, 197, 517-532.
(23) Payard, M.; Mouysset, G.; Tronche, P.; Bastide, P.; Bastide, J.;
Boas, J ). M.; Recherche de composes antiallergiques: Derives
de l’hydroxymethyl-2 chromone et analogues structuraux. Eur.
J. Med. Chem. 1985, 117-120.
(24) Payard, M.; Mouysset, G.; Tronche, P.; Bastide, P.; Bastide, Y.;
Privat, A. M. Synthese et activite` anti-allergique de quelques
alcohols benzopyroniques et apparentes. Eur. J. Med. Chem.
1988, 23, 199-202.
(2) Bowen, W. D. Sigma receptors: Recent advances and new clinical
potential. Pharm. Acta Helv. 2000, 74, 211-218.
(3) Wyrick, S. D.; Booth, R. G. Progress in sigma receptor research.
Drugs Future 1995, 20, 1033-1044.
(4) Matsumoto, R. R.; Pouw, B. Correlation between neuroleptic
binding to σ1 and σ2 receptors and acute dystonic reactions. Eur.
J. Pharmacol. 2000, 401, 155-160.
(25) Klutchko, S.; Cohen, M. P.; Shavel, J.; von Strandtman, M.
Heterocyclic synthesis with â-ketosulfides IV. Synthesis of
3-substituted chromones. J. Het. Chem. 1974, 183-188.
(26) Pearce, B. C.; Parker, R. A.; Deason, M. E.; Dischino, D. D.;
Gillespie, E.; Qureshi, A. A.; Volk, K.; Wright, J. J. K. Inhibitors
of cholesterol biosynthesis: 2. Hypocholesterolemic and anti-
oxidant activities of benzopyran and tetrahydronaphthalene
analogues of the tocotrienols. J. Med. Chem. 1994, 37, 526-541
(27) Boeseken, J.; de Briun, J. A.; van Rijswijk de Jong, W. E. L’action
du 1,8-dihydroxynaphthalene sur la conducibilite` electrique de
l’acide borique. Rec. Trav. Chim. 1939, 58, 3-7; 27.
(28) Kaye, I. A.; Matthews, R. S.; Scala, A. A. o-Hydroxycarbonyl
compounds. J. Chem. Soc. 1964, 2816-2820.
(5) Abou-Gharbia, M.; Ablordeppey, S. Y.; Glennon, R. A. Sigma
receptors and their ligands: The sigma enigma. Ann. Rep. Med.
Chem. 1993, 28, 1-10.
(6) Maier, C. A.; Wunsch, B. Novel spiripiperidines as highly potent
and subtype selective σ-receptor ligands. Part 1.. J. Med. Chem.
2002, 45, 438-448.
(7) Quaglia, W.; Giannella, M.; Piergentili, A.; Pigini, M.; Brasili,
L.; Di Toro, R.; Rossetti, L.; Spampinato, S.; Melchiorre, C. 1′-
Benzyl-3,4-dihydrospiro[2H-1-benzothiopyran-2′,4′-piperidine]
(Spipethiane), a potent and highly selective σ1 ligand. J. Med.
Chem. 1998, 41, 1557-60.
(8) Moltzen, E. K.; Perregaard, J.; Meier, E. σ Ligands with
subnanomolar affinity and preference for the σ2 binding site. 2.
Spiro-joined benzofuran, isobenzofuran and benzopyran pip-
eridines. J. Med. Chem. 1995, 38, 2009-2017.
(29) Bilger, C.; Demerseman, P.; Royer, R. Synthese des nitro-2-
naphtho[1,2-b]furannes mono-methoxyles sur l’homocyle ex-
terieur. Eur. J. Med. Chem. 1987, 22, 363-365.
(9) Mouitys-Mickalad, A.; Poupaert, J. H.; Spampinato, S.; Lesieur,
D. Synthesis and pharmacological evaluation of 6-piperidino- and
6-piperazinoalkyl-2(3H)-benzothiazolones as mixed σ/5-HT1A
ligands. Bioorg. Med. Chem. Lett. 2002, 12, 1149-1152.
(10) Ablordeppey, S. Y.; Fischer, J. B.; Law, H.; Glennon, R. A.
Probing the proposed phenyl A region of the sigma-1 receptor.
Bioorg. Med. Chem. 2002, 10, 2759-2765.
(30) Matsumoto, R. R.; Bowen, W. D.; Tom, M. A.; Vo, V. N.; Truong,
D. D.; De Costa, B. R. Characterization of two novel sigma
receptor ligands: Antidystonic effects in rats suggest sigma
receptor antagonism. Eur. J. Pharmacol. 1995, 280, 301-310.
(31) Lowry, O. H.; Rosenbrough, N. J.; Farr, A. L.; Randall, R. J.
Protein measurement with the Folin phenol reagent. J. Biol.
Chem. 1951, 193, 265-275.
(32) DeHaven-Hudkins, D. L.; Ford-Rice, Y. Characterization of the
binding of [3H]-(+)-pentazocine to sigma recognition site in
guinea pig brain. Eur. J. Pharmacol. 1992, 227, 371-378.
(33) Macth, R. H.; Smith, C. R.; Childers, S. R. Ibogaine possesses a
selective affinity for sigma-2 receptors. Life Sci. 1995, 57, 57-
62.
(11) Ablordeppey, S. Y.; Fischer, J. B.; Glennon, R. A. Is a nitrogen
atom an important pharmacophoric element in sigma ligand
binding? Bioorg. Med. Chem. 2000, 8, 2105-2111.
(12) Glennon, R. A.; Ablordeppey, S. Y.; Ismaiel, A. M.; El-Ashmawy,
M. B.; Fischer, J. B.; Howie, K. B. Structural features important
for σ1 receptor binding. J. Med. Chem. 1994, 37, 1214-9.
(13) Baziard-Mouysset, G.; Younes, S.; Labssita, Y.; Payard, M.;
Caignard, D.-H.; Rettori, M.-C.; Renard, P.; Pfeiffer, B.; Guardiola-
Lemaitre, B. Synthesis and structure-activity relationships of
novel 2-aminoakylchromones and related derivatives as σ site-
selective ligands. Eur. J. Med. Chem. 1998, 33, 339-347.
(14) Younes, S.; Labssita, Y.; Baziard-Mouysset, G.; Payard, M.;
Rettori, M.-C.; Renard, P.; Pfeiffer, B.; Caignard, D.-H. Synthesis
and structure-activity relationships of novel arylalkyl 4-ben-
zylpiperazine derivatives as σ site selective ligands. Eur. J. Med.
Chem. 2000, 35, 107-121.
(34) McPherson, G. A. Analysis of radioligand binding experiments.
A collection of computer programs for the IBM PC, J. Pharmacol.
Meths. 1985, 14, 213-228.
(35) Creese, I.; Burt, D. R.; Snyder, S. H. Dopamine receptor
binding: Differentiation of agonist and antagonist states with
[3H]dopamine and [3H]haloperidol. Life Sci. 1975, 17, 993-1001.
(36) Fargin, A.; Raymond, J. R.; Regan, J. W.; Cotecchia, S.; Lefkow-
itz, R. J.; Caron, M. G. Effector coupling mechanisms of the
cloned 5-HT1A receptor. J. Biol. Chem. 1989, 284, 14848-14852.
(37) Fargin, A.; Raymond, J. R.; Lohse, M. J.; Kobilka, B. K.; Caron,
M. G.; Lefkowitz, R. J. The genomic clone G-21 which resembles
a â-adrenergic receptor sequence encodes the 5-HT1A receptor.
Nature 1988, 335, 358-360.
(15) Berardi, F.; Ferorelli, S.; Abate, C.; Colabufo, N. A.; Contino,
M.; Perrone, R.; Tortorella, V. 4-(Tetralin-1-yl)- and 4-(naph-
thalen-1-yl)alkyl derivatives of 1-cyclohexylpiperazine as
σ
receptor ligands with agonist σ2 Activity. J. Med. Chem. 2004,
37, 2308-2317.
(38) Stanton, J. A.; Beer, M. S. Characterisation of a cloned human
5-HT1A receptors cell line using [35S]GTPγS binding. Eur. J.
Pharmacol. 1997, 320, 267-275.
(16) Glennon, R. A.; El-Ashmawy, M. B.; Ismaiel, A. M.; Fisher, J.
B. Binding of N-substituted 2-phenylaminoethanes to sigma and
serotonin 5-HT1A receptors. Med. Chem. Res. 1991, 1, 109-114.
JM049433T