1'-benzyl-3,4-dihydrospiro[2H-1-benzothiopyran-2,4'-piperidine] (Spipethiane), a potent and highly selective σ1 ligand

Full text of DOI:10.1021/jm970740r

© Copyright 1998 by the American Chemical Society
Volume 41, Number 10
May 7, 1998
Communications to the Editor
notetralines8,9 and arylethylenediamine-related com-
1′-Ben zyl-3,4-d ih yd r osp ir o[2H-1-
pounds,10,11 respectively.
ben zoth iop yr a n -2,4′-p ip er id in e]
(Sp ip eth ia n e), a P oten t a n d High ly
Selective σ1 Liga n d
Very recently, the existence of σ sites has been
confirmed by the cloning of a guinea pig σ1 receptor12
and a human σ1 receptor.13 The amino acid sequence
of these cloned receptors, having a single putative
transmembrane domain, bears significant homology
(93% identity and 96% similarity) to each other. Inter-
estingly, the amino acid sequence of this receptor shows
no homology to known mammalian proteins but shares
30% identity with a gene product of yeast, a gene that
encodes a sterol C8-C7 isomerase of the ergosterol
biosynthetic pathway. On this basis, it has been
advanced that a possible common denominator of σ
receptor function might be sterol biosynthesis.6 How-
ever, other evidence indicates that σ receptors might be
coupled to G-proteins as well.14
Wilma Quaglia,† Mario Giannella,†
Alessandro Piergentili,† Maria Pigini,† Livio Brasili,‡
Rosanna Di Toro,§ Lorena Rossetti,§
Santi Spampinato,§ and Carlo Melchiorre*,|
Department of Chemical Sciences, University of Camerino,
Via S. Agostino 1, 62032 Camerino (MC), Department of
Pharmaceutical Sciences, University of Modena,
Via Campi 183, 41100 Modena, Department of
Pharmacology, University of Bologna, Via Irnerio 48,
40126 Bologna, and Department of Pharmaceutical
Sciences, University of Bologna, Via Belmeloro 6,
40126 Bologna, Italy
The growing interest about σ receptor ligands can be
related to the fact that these receptors may represent
new targets for the development of therapeutic agents
for the treatment of various mental, motor, and other
disorders.1 However, a major problem in σ receptor
research is the lack of specific σ ligands as most of these
agents bind at other receptor systems including sero-
tonin 5-HT2, dopamine D2, PCP (1-(1-phenylcyclohexyl)-
piperidine), and muscarinic receptors, thus making still
unclear as to whether their pharmacological properties
are due to the interaction with σ sites. Consequently,
it is of paramount importance to make available selec-
tive ligands not only for the characterization of the σ
sites but also for the development of new therapeutically
useful agents. A vast array of structurally unrelated
compounds interact with σ sites, suggesting that these
receptors may be primordial, which makes it inherently
difficult to determine the structural requirements lead-
ing to receptor subtypes selectivity.3-5 Among the
variety of these structures, spirotetralines 1 were
reported to be potent σ ligands.15 However, these
Received October 31, 1997
Much effort has been devoted to the solution of the
so-called “sigma (σ) enigma”.1 Since the introduction
of the term “σ receptor” in 1976,2 many ligands display-
ing high affinity for these sites have been discovered.3-5
However, after more than two decades of research, little
is known about the biochemical and molecular nature
of these sites. The σ receptor concept itself has been
questioned for the lack of a specific endogenous agonist
and for its undefined biological role.5,6 Thus, σ sites
should not be classified as receptors in the sense of being
agonist-activated mediators of signal transduction, and
the debate continues over whether σ sites are true
receptors or a membrane bound enzyme.6 The situation
has been complicated further by the observation that σ
sites do not constitute a homogeneous population and
they can be divided into at least two different subtypes,
namely σ1 and σ2.5,7 However, additional σ sites have
been proposed on the basis of their distinct pharmaco-
logical profiles versus the previously defined σ1 and σ2
subtypes. Thus a putative σ3 and another site were
shown to display high affinity for certain phenylami-
† University of Camerino.
‡ University of Modena.
§ Department of Pharmacology, University of Bologna.
| Department of Pharmaceutical Sciences, University of Bologna.
S0022-2623(97)00740-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/11/1998

1558 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Sch em e 1. Synthesis of Spiropiperidines 2-5a
Communications to the Editor
amine (R1A and R1B), and 10 µM (+)-NANM (PCP). The
following reference compounds were used: (+)-penta-
zocine (σ1 receptors), haloperidol (σ2 and D2 receptors),
clozapine (5-HT2 receptors), methoctramine (muscarinic
M2 and M3 receptors), morphine (opioid receptors),
prazosin (R1A- and R1B-adrenoreceptors), and methaphit
(PCP receptors). Moreover, the affinity of compounds
1 and 2 for the σ-like site known as σ331,32 was evaluated
on guinea pig brain homogenates prepared as re-
ported,32 in competition for sites labeled by [3H]ket-
anserin (1 nM) in the presence of 10 µM serotonin to
mask 5-HT receptors. Previously, Booth et al.33 have
reported that ketanserin displays high affinity for σ3
binding sites (Ki ) 0.38 nM) while serotonin does not
recognize this site (Ki < 5000 nM). Therefore, lacking
a σ3 radiolabeled ligand, we decided to adopt this
strategy to label σ3 sites occurring in guinea pig brain
homogenates. Binding estimates were expressed as IC50
or Ki values derived using the Cheng-Prusoff equation34
and calculated using the LIGAND or EBDA programs.35
a
Bz ) benzoyl, Bn ) benzyl; reaction conditions: (a) BH3‚Me-
SMe, diglyme, 120 °C, 14 h; then MeOH, room temperature, 5 h,
HCl, 120 °C, 3 h; (b) 30% H2O2, CH3COOH, room temperature,
18 h; (c) 30% H2O2, CH3COOH, room temperature, 42 h.
ligands displayed also significant affinity for serotonin
5-HT2 receptors which may add therapeutic value for
treating psychotic disorders but in the meantime may
complicate the characterization of σ sites. We thought
it worthwhile to modify the structure of 1 to improve
affinity for σ1 receptors such as to discriminate hopefully
among σ sites and other receptor systems. We report
here the synthesis and preliminary characterization in
binding and functional experiments of 1′-benzyl-3,4-
dihydrospiro[2H-1-benzothiopyran-2,4′-piperidine] (2,
spipethiane) and of its corresponding sulfoxide (3) and
sulfone (4). To verify the role of the sulfur atom of 2 in
the interaction with σ sites, 1′-benzyl-3,4-dihydrospiro-
[2H-1-benzopyran-2,4′-piperidine] (5) has been included
in this study. Compound 5 has been disclosed to be an
inhibitor of histamine release,16 but no data on its σ
binding affinity has been published.
Since σ3 ligands are supposed to stimulate tyrosine
hydroxylase (TH) activity in minces of rat corpus
striatum at 0.1 µM, we investigated 1 and 2 following
the procedure described for certain phenylaminotetra-
lines.31,32
Resu lts a n d Discu ssion . The results, expressed as
Ki values, of spiropiperidines 2-5 are shown in Table 1
together with those of 1 and standard compounds. It
can be seen that replacing the carbonyl group of 1 by
sulfur or oxygen, affording 2 or 5, respectively, or
converting 2 into the corresponding analogues 3 and 4
alters markedly both affinity and selectivity toward σ1
receptors. This finding clearly indicates that the inser-
tion of a heteroatom such as sulfur or oxygen into the
tetrahydronaphthalene ring of 1 is highly effective
toward σ1 receptors. However, the most striking result
of the present investigation is the superpotent affinity
and selectivity toward σ1 receptors displayed by spi-
pethiane (2). Interestingly, spipethiane as well as
analogues 3-5 turned out to be devoid of significant
affinity for the other receptor systems so far investi-
gated. Particularly, spipethiane (2) showed a low af-
finity for the σ3 binding site (IC50 ) 632 ( 18 nM; n )
3), whereas the reference compound 1 displayed a 15-
fold higher affinity for this binding site (IC50 ) 42 ( 6
nM; n ) 3). Furthermore, 1 and 2 were not able to
increase TH activity (p > 0.05) up to 0.1 µM concentra-
tion. An analysis of affinity estimates in Table 1 reveals
that the replacement of the carbonyl group of 1 by either
sulfur as in 2 or oxygen as in 5 leads to an increase in
affinity for σ1 receptors, while producing a slight (2-fold
for 5) to marked (42-fold for 2) decrease in affinity for
σ2 receptors. Thus, spipethiane (2) was 19-fold less
potent than 5 at σ2 receptors, and consequently it was
markedly more selective than 5 toward σ1 receptors.
Oxidation of 2 into the corresponding sulfoxide 3 and
sulfone 4 caused a significant (40-50-fold) decrease in
affinity for σ1 receptors whereas only a small (4-fold)
decrease in affinity for σ2 receptors. This finding
parallels the results observed by Gilligan et al.36 for
compounds which are structurally related to spi-
pethiane. However, these open analogues displayed
also a significant affinity for D2 and 5-HT2 receptors that
is not observed with the compounds used in the present
Ch em istr y. The compounds were synthesized by
standard procedures (Scheme 1) and were characterized
1
by H NMR and elemental analysis.17 Reduction of 618
and 718 with borane afforded 219 and 5,20 respectively.
Treatment of sulfide 2 with different amounts of H2O2
gave the corresponding sulfoxide 321 and sulfone 4.22
P h a r m a cology. Compounds 1-5, in the form of
hydrogen oxalate salts, were evaluated for in vitro
activity on σ1, σ2, serotonin 5-HT2, dopamine D2, mus-
carinic M2, muscarinic M3, opioid, and PCP receptors
and R1A- and R1B-adrenoreceptors. The detailed meth-
ods have been published previously.23-30 The following
specific ligands, tissue sources, and procedures were
used: (a) σ1 receptors, [3H]-(+)-pentazocine, guinea pig
brain;23 (b) σ2 receptors, [3H]DTG in the presence of 200
nM (+)-N-allylnormetazocine (NANM), guinea pig
brain;24 (c) serotonin 5-HT2 receptors, [3H]ketanserin,
guinea pig frontal cortex;25 (d) dopamine D2 receptors,
[3H]spiperone, rat striatum;26 (e) muscarinic M2 recep-
tors, [3H]NMS, rat heart;27 (f) muscarinic M3 receptors,
[3H]NMS, rat submaxillary gland;27 (g) total opioid
receptors, [3H]naloxone, rat whole brain;28 (h) R1A
-
adrenoreceptors, [3H]prazosin, rat submaxillary gland;29
(i) R1B-adrenoreceptors, [3H]prazosin, rat liver;29 (j) PCP
receptors, [3H](+)NANM in the presence of 5 µM halo-
peridol, rat brain.30 Nonspecific binding for each recep-
tor was defined by inclusion of 1 µM haloperidol (σ1, σ2,
and D2), 1 µM methylsergide (5-HT2), 1 µM atropine (M2
and M3), 1 µM naloxone (total opioid), 10 µM phentol-

Communications to the Editor
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1559
investigation. The fact that the ligands currently used
to investigate σ receptors lack not only a clear subtype
selectivity but also σ receptor specificity may explain
the difficulties in characterizing σ receptor subtypes
with classic pharmacological studies. The results pre-
sented in this paper clearly show that the use of
spipethiane (2) might help the pharmacological identi-
fication of σ receptor subtypes.
To our knowledge, spipethiane (2) represents, until
now, one of the most potent and selective σ1 receptor
ligands, and it might be a valuable tool for the charac-
terization of σ receptors.
Our future work in this area will include studies
directed at gaining a better understanding of the
intriguing trends noted above. In addition, we hope to
develop relevant structure-activity relationships for σ
receptor subtypes through the synthesis of chiral com-
pounds related to those presented in this paper. These
studies should contribute to clarify the structural
requirements for selective binding of spiropiperidines
to σ receptor subtypes.
Ack n ow led gm en t. This work was supported by
grants from Bologna and Camerino Universities.
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of the calculated value. Chromatographic separations were
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(19) A solution of 618 (1.4 g, 4.15 mmol) in dry diglyme (42 mL) was
treated with a 10 M solution of BH3‚MeSMe (2.45 mL) in dry
diglyme (3 mL). After 14 h at 120 °C under a stream of dry
nitrogen, excess borane was destroyed by careful addition of
MeOH (15 mL). The resulting mixture was left to stand for 5 h,
treated with HCl gas, and then heated at 120 °C for 3 h. Removal
of the solvent gave a residue that was purified by column
chromatography, eluting with cyclohexane-ethyl acetate (9:1)
to give 2 as the free base: 0.6 g (47% yield); mp 63-64 °C; 1H
NMR (CDCl3) δ 1.72-1.95 (m, 4, 3′- and 5′-CH2), 1.98 (t, 2,
3-CH2), 2.41-2.82 (m, 4, 2′- and 6′-CH2), 2.9 (t, 2, 4-CH2), 3.58
(s, 2, CH2Ph), 6.95-7.43 (m, 9, ArH). It was characterized as
the oxalate salt: mp 213-214 °C (from 2-PrOH/EtOH). Anal.
(C20H23NS‚C2H2O4‚0.5H2O) C, H, N, S.
(20) This compound was obtained from 718 following the procedure
described for 2. The free base (oil) was purified by column
chromatography, eluting with cyclohexane-ethyl acetate (8:2):
49% yield; 1H NMR (CDCl3) δ 1.58-1.94 (m, 6, 3-, 3′-, and 5′-
CH2), 2.39-2.73 (m, 4, 2′- and 6′-CH2), 2.78 (t, 2, 4-CH2), 3.57
(s, 2, CH2Ph), 6.80-7.40 (m, 9, ArH). It was characterized as
the oxalate salt: mp 208-210 °C (from EtOH). Anal. (C20H23
-
NO‚C2H2O4) C, H, N. This compound was synthesized by a
different method:16 mp (HCl salt) 240-241 °C.
(21) A solution of 2 (0.25 g, 0.808 mmol) and 30% H2O2 (0.36 mL) in
AcOH (2.27 mL) was left at room temperature for 18 h, made
basic with 2 N NaOH, and extracted with CHCl3. Removal of
the dried solvent (Na2SO4) gave an oil that was purified by
column chromatography, eluting with ethyl acetate-MeOH (96:
4) to give 3 as the free base: 0.12 g (46% yield); 1H NMR (CDCl3)
δ 1.50-2.36 (br m, 6, 3-, 3′-, and 5′-CH2), 2.37-2.90 (br m, 4, 2′-
and 6′-CH2), 2.97 (br m, 2, 4-CH2), 3.59 (br s, 2, CH2Ph), 7.18-
7.50 (m, 8, ArH), 7.73 (dd, 1, 8-H). It was characterized as the
oxalate salt: mp 214-215 °C (from EtOH). Anal. (C20H23
NOS‚C2H2O4) C, H, N, S.
-
(22) This compound was obtained from 2 following the procedure
described for 3 using a 3-fold greater amount of 30% H2O2 and
a reaction time of 42 h. The free base was purified by column
chromatography eluting with cyclohexane-ethyl acetate (1:1):
54% yield; mp 143-145 °C; 1H NMR (CDCl3) δ 1.80 (m, 2, 3′-
CH2), 2.35 (m, 4, 2′- and 5′-CH2), 2.45 (t, 2, 3-CH2), 2.89 (m, 2,
6′-CH2), 2.98 (t, 2, 4-CH2), 3.58 (s, 2, CH2Ph), 7.13-7.60 (m, 8,
ArH), 7.97 (dd, 1, 8-H). It was characterized as the oxalate salt:
mp 220-222 °C (from EtOH). Anal. (C20H23NO2S‚C2H2O4) C, H,
N, S.
J M970740R