N-nrylalkylpiperidines as high-affinity sigma-1 and sigma-2 receptor ligands: Phenylpropylamines as potential leads for selective sigma-2 agents

Article abstract of DOI:10.1016/S0960-894X(01)00788-0

To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2 receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a potential pharmacophore for selective sigma-2 ligands.

Full text of DOI:10.1016/S0960-894X(01)00788-0

Bioorganic & Medicinal Chemistry Letters 12 (2002) 497–500
N-Arylalkylpiperidines as High-Affinity Sigma-1 and Sigma-2
Receptor Ligands: Phenylpropylamines as Potential Leads for
Selective Sigma-2 Agents
Dean Y. Maeda,a Wanda Williams,b Wes E. Kim,a Linn N. Thatcher,a
Wayne D. Bowenb and Andrew Coopa,*
aDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 North Pine Street,
Baltimore, MD 21201, USA
bLaboratory of Medicinal Chemistry National Institute of Diabetes, Digestive, and Kidney Diseases Building 8,
Room B1-23, Bethesda, MD 20892, USA
Received 24 September 2001; accepted 19 November 2001
Abstract—To delineate the differences between the structural requirements necessary for recognition at sigma-1 and sigma-2
receptors, a range of phenethyl- and phenylpropylpiperidines were evaluated in binding assays. Phenethylpiperidines were found to
favor sigma-1 receptors, whereas phenylpropylpiperidines tend to favor sigma-2 receptors. It appears that phenylpropylamine is a
potential pharmacophore for selective sigma-2 ligands. # 2002 Elsevier Science Ltd. All rights reserved.
Sigma receptors were first described by Martin as a
subtype of opioid receptor.1 It is now known that sigma
receptors are a distinct class, comprising sigma-1 and
sigma-2 subtypes2 that are unrelated to the sites descri-
bed in earlier studies. The sigma-1 receptor has recently
been cloned and represents a unique protein,3 but
sigma-1 pharmacology has been notoriously compli-
cated to understand due to the ligands employed inter-
acting with other systems.4 However, through the use of
a series of arylethylenediamines, which are selective for
sigma receptors over other systems,5,6 and other selec-
tive ligands, it is known that sigma-1 receptors mod-
ulate many physiological systems (Fig. 1).7À11
Sigma-2 receptor pharmacology has been similarly
complicated and suffers from the fact that the receptor
has not yet been cloned. Sigma-2 receptors have been
implicated in the side effects of typical antipsychotic
Figure 1. Arylalkylamine-based sigma receptor ligands.
*Corresponding author. Tel.: +1-410-706-2029; fax: +1-410-706-0346; e-mail: acoop@rx.umaryland.edu
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00788-0

498
D. Y. Maeda et al. / Bioorg. Med. Chem. Lett. 12 (2002) 497–500
drugs,12,13 but recent studies have suggested that the
sigma-2 receptor system potentially offers a pharmaco-
logical system capable of modulating apoptosis,14À19
and it is essential that selective agonists and antagonists
are developed to allow full characterization of their role
in apoptosis. However, a wide variety of structural
classes are recognized by sigma receptors and it has
been difficult to determine definitive structure–activity
relationships for the system. In addition, the fact that
many early studies only investigated affinity at sigma-1
receptors,2,6 underscores the necessity for further studies
of simple compounds to determine the structural fea-
tures necessary for preferential recognition at sigma-2
receptors over sigma-1 (Table 1).
that the aromatic group is actually an indole two car-
bons distant from the amine, may account for the rela-
tively low sigma-2 affinity, compared to 7 and 8. 6
contains the necessary phenylpropylamine, but also
contains a phenylbutylamine, a functional group known
to interact preferentially with sigma-1 receptors.26 It is
therefore consistent with the current hypothesis that 6
would be a high-affinity nonselective sigma ligand.
Since few systematic studies have investigated the sigma
receptor binding differences between phenethylamines
and phenylpropylamines without the complication of
elaborate functionality23 or conformational restraint as
is seen in the above examples, we decided to prepare
simple phenylalkylamine-based ligands to study the
sigma receptor system and test our hypothesis. Glennon
has previously investigated phenethylpiperidine (9) and
phenylpropylpiperidine (10),27 and shown that they
have moderate affinity for sigma-1 receptors. We there-
fore decided to initially focus on simple phenylalkyl
piperidines, compare the effects of phenethyl versus
phenylpropyl, and investigate the effect of simple sub-
stitution on the piperidine ring. Only simple substitution
(e.g., methyl, phenyl) was investigated in order to be
able to draw meaningful conclusions, and to determine
potential positions for additional functionalization in
future studies.
We have recently shown that the central amine of the
high-affinity, subtype nonselective, sigma receptor
ligand BD1008 (1)5 is important for sigma-2 affinity.
This is indicated by the observation that the ester 2
showed sigma-1 selectivity over sigma-2, due to much
reduced affinity at sigma-2.20 We now present our stud-
ies into the removal of the terminal amine of 1.
Removing the terminal amine of 1 gives phenethyl-
amines, a sigma pharmacophore as proposed by Glen-
non,21,22 but the assays employed by Glennon in the
early 1990’s are now known to predominantly measure
sigma-1 affinity, and little can be concluded about the
necessity of this pharmacophore for sigma-2 receptors.
Such a phenethylamine is present in the sigma-1-selec-
tive (+)-benzomorphans1,6 and in NE-100 (3)23 a selec-
tive sigma-1 antagonist. Ibogaine (4), a low-affinity
selective sigma-2 agonist,24 also contains an arylethyl-
amine. The sigma subtype non-selective DTG (5)2 can
also be considered to contain an amine two atoms away
from an aromatic ring. However, other monoamines
that bind to sigma receptors do not contain such a
pharmacophore: nonselective haloperidol (6)2 contains
an amine three carbons from one aromatic group, and
four carbons from another, and the high-affinity sigma-2
selective benzylidene-5-phenylmorphans, CB-64D (7)
and CB-184 (8)25 contain an amine three carbons from
both aromatic rings.
The piperidines 10–16 and piperazines 17 and 18 (Fig. 2)
were prepared by simple alkylation of the appropriate
secondary amine with the corresponding phenyl alkyl
halide in DMF in the presence of NaHCO3. After
addition of water, the products were extracted into
Et2O, concentrated under reduced pressure, and then
converted to water soluble oxalate salts. Commercially
available N-phenethylpiperidine (9) was converted
directly to the oxalate salt. All products displayed NMR
and mass spectra consistent with their structure and
gave acceptable CHN analyses (Æ0.4%).28 The ligands
were evaluated in competition assays at sigma-1 and
sigma-2 receptors as described previously.24,25,29
All amines possessed affinity at both sigma-1 and sigma-2
sites, suggesting that the terminal amine does not con-
tribute to subtype selectivity. In contrast to the removal
of the central amine 2, affinity was observed at both
receptors. N-Phenethylpiperidine (9) showed similar
affinity at both sigma-1 and sigma-2, Ki=88 and 112
nM, respectively: these data are in accord with the pre-
vious findings of Glennon.27 The corresponding N-phe-
nylpropyl analogue27 demonstrated 4-fold greater
affinity at sigma-2 sites and slightly lower affinity at
sigma-1. Interestingly, the affinity of these simple com-
pounds at sigma-2 is equal to the affinity of the aryl-
ethylenediamine 1,5,6 and greater than that of the
phenylmorphans 7 and 8.25 Thus, phenylpropylpiperi-
dine (10) is 6-fold selective for sigma-2 over sigma-1,
and this implies that three carbons between the aro-
matic ring and the basic amine is better tolerated by the
sigma-2 receptor than the sigma-1. In general, the
N-phenylpropyl analogues had higher affinity at sigma-
2 than the corresponding N-phenethyl analogues, and
the N-phenethyl analogues possessed higher affinity for
The high sigma-2 affinity and selectivity of the phenyl-
propylamine-containing 7 and 8, together with the low
sigma-2 affinity of the phenethyl containing (+)-benzo-
morphans and 3, led to our current hypothesis that
phenylpropylamines may provide a lead for selective
sigma-2 ligands. That 4 is somewhat sigma-2 preferring
is also consistent with the hypothesis, if the phenyl
group alone is viewed as the aryl group. Indeed, the fact
Figure 2. Target phenylalkylpiperines.

D. Y. Maeda et al. / Bioorg. Med. Chem. Lett. 12 (2002) 497–500
Table 1. Binding affinity at sigma receptors
499
Amine moiety
N-Phenethyl
Ki (nM) Sigma-1a
Ki (nM) Sigma-2b
N-Phenyl-propyl
Ki (nM) Sigma-1a
Ki (nM) Sigma-2b
Piperidine
9c
11d
13e
15f
17g
88.5Æ13.6
4.15Æ0.11
20.9Æ1.85
5.90Æ0.11
326Æ41.2
112Æ3.3
84.4Æ0.66
33.3Æ0.13
57.3Æ1.3
119Æ3.78
10c
12
14
16
18
143Æ16
25Æ3.0
6.61Æ0.16
12.1Æ0.35
14.2Æ1.1
4.91Æ0.77
3-Methylpiperidine
4-Methylpiperidine
Tetrahydroisoquinoline
(2-Pyridyl)piperazine
5.25Æ3.02
3.35Æ0.58
13.9Æ0.03
82.9Æ0.21
aDisplacement of [3H]-(+)-pentazocine.
bDisplacement of [3H]-DTG in the presence of dextrallorphan.
cPreviously prepared in ref 27.
dPreviously prepared in ref 30.
ePreviously prepared in ref 31.
fPreviously prepared in ref 32.
gPreviously prepared in ref 33.
sigma-1 than the N-phenylpropyl analogues. One
exception to this general trend were the 4-methyl ana-
logues in which the N-phenylpropyl (14) displayed higher
affinity than the N-phenethyl (13) at both receptors.
a phenylpropylamine based structure would be more
likely to result in a high-affinity, sigma-2 selective ligand
than the traditional phenethylamine-based sigma ligands.
Simple changes in the methyl substitution pattern on the
piperidine ring gave rise to major changes in receptor
affinity and selectivity, underscoring the need to study
compounds without elaborate functionality. In the N-
phenethyl series, the greatest affinity at sigma-1 was
observed with the 3-methyl substituent (11), and the
greatest affinity at sigma-2 with the 4-methyl substituent
(13). Whereas, in the phenylpropyl series, the greatest
affinity for sigma-2 was observed with the 3-methyl
analogue (12), and the 3- and 4-methyl substituted
derivatives both demonstrated very high affinity for
sigma-1.
References and Notes
1. Martin, W. R.; Eades, C. E.; Thompson, J. A.; Huppler,
R. E. J. Pharmacol. Exp. Ther. 1976, 197, 517.
2. Quirion, R.; Bowen, W. D.; Itzhak, Y.; Junien, J. L.;
Musacchio, J. M.; Rothman, R. B.; Su, T. P.; Tam, S. W.;
Taylor, D. P. A. Trends Pharmacol. Sci. 1992, 13, 85.
3. Hanner, M.; Moebius, F. F.; Flandorfer, A.; Knaus, H. G.;
Striessnig, J.; Kempner, E.; Glossman, H. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 8072.
4. Izhak, Y. Sigma Receptors; Academic: San Diego, 1994.
5. de Costa, B. R.; Radesca, L.; Di Paolo, L.; Bowen, W. D.
J. Med. Chem. 1992, 35, 38.
6. de Costa, B. R., He, X.-S. In The Sigma Receptors, Neuro-
science Perspectives Series; Itzhak, Y., Ed., Academic: Lon-
don, 1994; p 45.
7. Monnet, F. P.; Debonnel, G.; de Montigny, C. J. Pharma-
col. Exp. Ther. 1992, 261, 123.
8. Gonzalez-Alvear, G. M.; Werling, L. L. Brain Res. 1995,
673, 61.
9. Matsumoto, R. R.; McCracken, K. A.; Pouw, B.; Miller, J.;
Bowen, W. D.; Williams, W.; de Costa, B. R. Eur. J. Phar-
macol. 2001, 411, 261.
10. McCracken, K. A.; Bowen, W. D.; de Costa, B. R.; Mat-
sumoto, R. R. Eur. J. Pharmacol. 1999, 370, 225.
11. Maurice, T.; Lockhart, B. P. Prog. Neuro-Psychopharma-
col. Biol. Psychiatry 1997, 21, 69.
12. Walker, J. M.; Matsumoto, R. R.; Bowen, W. D.; Gans,
D. L.; Jones, K. D.; Walker, F. O. Neurology 1988, 38, 961.
13. Matsumoto, R. R.; Hemstreet, M. K.; Lai, N. L.; Thur-
kauf, A.; de Costa, B. R.; Rice, K. C.; Hellewell, S. B.; Bowen,
W. D.; Walker, J. M. Pharmacol. Biochem. Behav. 1990, 36,
151.
The higher affinity of the 3- and 4-methyl substituted
analogues compared to the unsubstituted analogues,
prompted us to study the tetrahydroisoquinoline and (2-
pyridyl)piperazine analogues. As can be seen, in the
tetrahydroisoquinoline series, the phenethyl (15) dis-
played high affinity at sigma-1 receptors, but lower affi-
nity at sigma-2, whereas the phenylpropyl (16) displayed
high affinity at both receptors, due to a 3-fold increase
in sigma-2 affinity. The (2-pyridyl)piperazines showed
most clearly the tendency for phenylpropylamines to
favor sigma-2 sites: the phenethyl derivative (17) dis-
played only moderate affinity at both receptors, whereas
the phenylpropyl (18) possessed high sigma-2 affinity
(Ki=4.9 nM) and selectivity (17-fold) over sigma-1 sites.
The increase in sigma-2 selectivity when phenylpropyl is
compared to phenethyl is due largely to a 24-fold
increase in sigma-2 affinity. Sigma-1 affinity increased
only 4-fold. Although the degree of sigma-2 selectivity
of 10 (6-fold) and 18 (17-fold) does not approach that of
the benzylidene-5-phenylmorphans 7 and 8 (200- to 500-
fold), it is remarkable that a simple amine with little
functionality and no conformational constraint, pos-
sesses sigma-2 affinity and selectivity to this degree.
14. Vilner, B. J.; de Costa, B. R.; Bowen, W. D. J. Neurosci.
1995, 15, 117.
15. Vilner, B. J.; Bowen, W. D. J. Pharmacol. Exp. Ther.
2000, 292, 900.
16. Vilner, B. J.; Bowen, W. D. Abstr. Soc. Neurosci. 1997, 23,
#905.6.
17. Crawford, K. W.; Vilner, B. J.; Bowen, W. D. Proc. Am.
Assoc. Cancer Res. 1999, 40, 166.
This preliminary systematic investigation of the phenyl-
alkylpiperidines has yielded valuable information into
the structural features tolerated by the two different
sigma receptors, and underscores the fact that even
small changes in structure can result in dramatic chan-
ges in pharmacological profiles. Indeed, it appears that
18. Kinloch, R. A.; Treherne, J. M.; Furness, L. M.; Hajimo-
hamadreza, I. Trends Pharmacol. Sci. 1999, 20, 35.
19. Deigner, H. P.; Kinscherf, R. Curr. Med. Chem. 1999, 6, 399.
20. Maeda, D. Y.; Williams, W.; Bowen, W. D.; Coop, A.
Bioorg. Med. Chem. Lett. 2000, 10, 17.

500
D. Y. Maeda et al. / Bioorg. Med. Chem. Lett. 12 (2002) 497–500
21. Glennon, R. A.; Smith, J. D.; Ismaiel, A. M.; El-Ash-
mawy, M.; Battaglia, G.; Fischer, J. B. J. Med. Chem. 1991,
34, 1094.
22. Glennon, R. A.; Ismaiel, A. M.; Smith, J. D.; Yousif, M.;
El-Ashmawy, M.; Herndon, J. L.; Fischer, J. B.; Burke Howie,
K. J.; Server, A. C. J. Med. Chem. 1991, 34, 1855.
23. Nakazato, A.; Ohta, K.; Sekiguchi, Y.; Okuyama, S.;
Chaki, S.; Kawashima, Y.; Hatayama, K. J. Med. Chem. 1999,
42, 1076.
24. Bowen, W. D.; Vilner, B. J.; Williams, W.; Bertha, C. M.;
Kuehne, M. E.; Jacobson, A. E. Eur. J. Pharmacol. 1995, 279,
R1.
25. Bowen, W. D.; Bertha, C. M.; Vilner, B. J.; Rice, K. C.
Eur. J. Pharmacol. 1995, 278, 257.
27. Ablordeppey, S. Y.; Fischer, J. B.; Burke Howie, K. J.;
Glennon, R. A. Med. Chem. Res. 1992, 2ꢀ, 368.
.
.
28. Melting points: 9 oxalate 149–150 C; 10 oxalate 141–
ꢀ ꢀ ꢀ
. . .
142 C; 11 oxalate 172–173 C; 12 oxalate 142–143 C; 13 oxa-
ꢀ
ꢀ
.
.
.
late. 0.33H2O 160–161 C; 14 oxalate 14ꢀ9–151 C; 15 oxalate
ꢀ
.
.
177–1ꢀ78 C; 16 oxalate 0.25H2O 131–132 C; 17 2oxalate 193–
ꢀ
.
193.5 C; 18 2oxalate 189–190 C.
29. Hellewell, S. B.; Bruce, A.; Feinstein, G.; Orringer, J.;
Williams, W.; Bowen, W. D. Eur. J. Pharmacol. 1994, 268, 9.
30. Ganellin, C. R.; Spickett, R. G. W. J. Med. Chem. 1965, 8, 619.
31. Cardonzo, M. G.; Kawai, T.; Iimura, Y.; Sugimoto, H.;
Yamanishi, Y.; Hopfinger, A. J. J. Med. Chem. 1992, 35, 590.
32. Perrio-Huard, C.; Aubert, C.; Lasne, M.-C. J. Chem. Soc.,
Perkin Trans. 1 2000, 311.
26. Ablordeppey, S. Y.; Fischer, J. B.; Glennon, R. A. Bioorg.
Med. Chem. 2000, 8, 2105.
33. Ratouis, R.; Boissier, J. R.; Dumont, C. J. Med. Chem.
1965, 8, 104.