1,4-Dibenzylpiperazines possess anticocaine activity

Article abstract of DOI:10.1016/S0960-894X(02)01034-X

N,N-Dibenzylpiperazines have high affinity for sigma receptors, and we aimed to increase their anticocaine activity by introducing substituents known to enhance such activity in other sigma ligands. Ligands with high affinity for sigma-1 receptors resulte

Full text of DOI:10.1016/S0960-894X(02)01034-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 749–751
1,4-Dibenzylpiperazines Possess Anticocaine Activity
Abby Foster,a Huifang Wu,a Weibin Chen,a Wanda Williams,b Wayne D. Bowen,b
Rae R. Matsumotoc 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
cDepartment of Pharmaceutical Sciences, University of Oklahoma Health Science Center College of Pharmacy,
1110 North Stonewall Avenue, Oklahoma City, OK 73117, USA
Received 5 June 2002; accepted 24 October 2002
Abstract—N,N-Dibenzylpiperazines have high affinity for sigma receptors, and we aimed to increase their anticocaine activity by
introducing substituents known to enhance such activity in other sigma ligands. Ligands with high affinity for sigma-1 receptors
resulted, but their activity in attenuating cocaine-induced convulsions did not correlate with sigma-1 binding affinity, and may be
more closely related to their sigma-2 binding affinities.
# 2003 Elsevier Science Ltd. All rights reserved.
Cocaine abuse continues as a major problem, and
development of efficacious treatment agents is urgently
required.1 The development of a potential maintenance
therapy has been the focus of numerous research
groups,1,2 but fewer have focused on the development of
medications for the treatment of acute cocaine over-
dose. The stimulant effects of cocaine on the cardio-
vascular system are well documented, and are usually the
cause of death from cocaine overdose.2 The dopamine
hypothesis of cocaine1 has been an important model for
explaining the rewarding properties of the drug, but this
hypothesis is incomplete. As it is now widely recognized
that the actions of cocaine are due to its interactions
with numerous biological systems,1,2 we have focused
on targeting other systems in order to attenuate the
toxicity of cocaine.3À5 One such system is the sigma
receptor system, and the affinity of cocaine for sigma
receptors makes this system physiologically relevant.6
lethality, convulsions, and increased locomotor effects
caused by cocaine.3À5,9 The phenylethylenediamines
[such as BD1008 (1)] are a class of sigma-1 antagonists
which are selective for sigma sites over other systems,10
and the potency of these agents at attenuating cocaine-
induced convulsions is quite good.3À5,9,11
It was recently shown that a simple piperazine [1-benzyl-
4-(2-naphthyl)piperazine (2)] demonstrated good affi-
nity for sigma-1 receptors, and weak antagonism of the
locomotor effects of stimulants (methamphetamine) was
reported.12 We considered that the introduction of the
optimum substituents for anti-cocaine activity from the
phenylethylenediamine system into this dibenzylpiper-
azine system may yield more potent compounds for
attenuating the convulsive effects of cocaine. Sub-
stituents chosen included the substituents which yield
the greatest activity in the phenylethylene diamine system;
mono- and di-substituted chlorinated, and methoxyl
substituted rings.3À5,9,11
The sigma receptor system was first described by Mar-
tin as a subtype of opioid receptors,7 but it is now
known that the sigma system is a unique receptor sys-
tem, comprised of sigma-1 and sigma-2 sites.8 Previous
work has shown that sigma-1 antagonists attenuate the
The desired products (3–10, Fig. 1) were all prepared by
reaction of 1-benzylpiperazine with the relevant benzyl
halides in DMF in the presence of NaHCO3 at room
temperature for 24 h. The reaction mixture was parti-
tioned between water and Et2O, and the organic layer
collected. After removal of the solvent, all amines were
converted to water soluble salts. Table 1 summarizes the
*Corresponding author. Tel.: +1-410-706-2029; fax: +1-410-706-
0346; e-mail: acoop@rx.umaryland.edu
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(02)01034-X

750
A. Foster et al. / Bioorg. Med. Chem. Lett. 13 (2003) 749–751
Figure 1. Structures of the sigma ligands.
Table 1. Pharmacological and physical data for sigma ligands
Compd
Ki (nM) ÆSEM
Ki (nM) ÆSEM
AD50, mg/kg
Attenuation of cocaine
induced convulsions, mice
Salt form
Melting point
(ꢀC)
Sigma-1
Sigma-2
1a
3b
4
2.0Æ1.0
5.81Æ0.48
0.39Æ0.01
0.47Æ0.04
5.3Æ1.49
0.46Æ0.14
1.40Æ0.16
0.58Æ0.15
7.6Æ3.7
8.0Æ2.0
1274Æ24.4
107.8Æ1.7
161Æ18.6
527Æ120
2
23
17
27
15
8
—
—
Oxalate
2HCl
2HCl
Oxalate
2HCl
2HCl
2HCl
2HCl
233–235
267–268
235–238
207–209
285–286
287–288
289–290.5
254–256
5c
6
7
8
9
10
56.4Æ9.21
187Æ16.7
7.54Æ1.17
123Æ11.0
29
d
16
aData from ref 5.
bPreviously prepared in ref 13.
cPreviously prepared in ref 14.
dAgonist activity, exacerbated the convulsive effects of cocaine.
salt form, the solvent, and the melting point of the salts.
All free bases displayed NMR and mass spectral data
consistent with the assigned structures, and combustion
analysis of all salts were Æ0.4% of theory (Atlantic
Microlabs, Norcross, GA, USA).
and actually exacerbates the convulsions caused by
cocaine. Since some of the phenethylene diamines with
3,4-dichloro substitutions also have agonist activity
(e.g., BD1031 and BD1052);5,9 it appears that this sub-
stitution conveys improved affinity for sigma receptors,
but it is not a critical determinant of agonist versus
antagonist actions.
The compounds were assayed for affinity to sigma-1 and
sigma-2 sites through competition assays as previously
described,8 and the results are shown in Table 1. Anti-
cocaine activity in mice was assessed through the
attenuation of convulsions caused by the administration
of cocaine (60 mg/kg, ip) as previously described,3 and
the results are also shown in Table 1.
In summary, the potent anticocaine activity of 7 makes
this compound a useful lead for the development of
future anticocaine medications. Further studies aimed
at determining which additional biological systems these
compounds interact with are currently underway.
All compounds were shown to possess high affinity for
sigma-1 receptors, with four compounds (4, 5, 7, and 9)
possessing subnanomolar affinity. Interestingly, the
potency in in vivo assays did not appear to mirror the
sigma-1 affinities. For example, the 4-methoxy sub-
stituted analogue (5) was far less potent than the
3-chloro analogue (7), even though they possessed the
same high sigma-1 affinity. Affinity at sigma-2 receptors
was more variable within the group, with 3-chloro ana-
logue (7) possessing the greatest sigma-2 affinity of the
antagonist compounds. The fact that 7 also possesses the
greatest potency in in vivo assays, as discussed above,
tends to imply that sigma-2 is more important for attenu-
ating the convulsive effects of cocaine in this series.15,16
Acknowledgements
The authors would like to express their gratitude to the
National Institute on Drug Abuse (NIDA, NIH) for
financial support of this work (DA-13978, DA-11979).
Rachel Stephens is acknowledged for her expert tech-
nical assistance during some of the behavioral studies.
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