The effect of the pyridyl nitrogen position in pyridylpiperazine sigma ligands

Article abstract of DOI:10.1016/j.bmcl.2010.02.087

A series of pyridylpiperazines was synthesized and analyzed for sigma receptor binding affinity to determine the optimal pyridyl nitrogen position and chain length for the σ₁ and σ₂ receptor recognition. The (3-pyridyl)piperazines and (4-pyridyl)piperazines favor σ₁ receptors, while previously studied (2-pyridyl)piperazines favor σ₂ receptors.

Full text of DOI:10.1016/j.bmcl.2010.02.087

Bioorganic & Medicinal Chemistry Letters 20 (2010) 2564–2565
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
The effect of the pyridyl nitrogen position in pyridylpiperazine sigma ligands
Lidiya Stavitskaya a, Michael J. Seminerio b, Marilyn M. Matthews-Tsourounis a, Rae R. Matsumoto b,
Andrew Coop a,
*
a Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA
b Department of Basic Pharmaceutical Sciences, West Virginia University, PO Box 9500, 2036 Health Sciences North, Morgantown, WV 26506, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyridylpiperazines was synthesized and analyzed for sigma receptor binding affinity to deter-
Received 11 January 2010
Revised 22 February 2010
Accepted 23 February 2010
Available online 1 March 2010
mine the optimal pyridyl nitrogen position and chain length for the
(3-pyridyl)piperazines and (4-pyridyl)piperazines favor r1 receptors, while previously studied (2-pyri-
dyl)piperazines favor r2 receptors.
r1 and r2 receptor recognition. The
Ó 2010 Published by Elsevier Ltd.
Keywords:
Methamphetamine
Sigma receptors
Antagonism
The continued growth in the abuse of methamphetamine neces-
sitates the urgent development of pharmacotherapies. No pharma-
cotherapies for methamphetamine abuse currently exist and
efforts have mainly focused on the development of therapies for
the dopaminergic systems.1–4 Our studies have utilized the fact that
methamphetamine interacts with sigma receptors5,6 and sigma
antagonists attenuate both the stimulant and neurotoxic effects of
methamphetamine. Although sigma receptors were first thought
Recent studies showed that CM156 (3-(4-(4-cyclohexylpiperazin-
1-yl)butyl)benzo[d]thiazole-2(3H)-thione) exhibits better affinity
for the sigma receptor however, it has poor metabolic stability.25
Studies performed previously by our laboratory have showed that
N-(2-pyridyl)piperazines not only have the tendency to favor r2
receptors but they also favor sigma receptors over opioid and NMDA
receptors with low affinity for the dopamine receptor.29,30 Specifi-
cally, compound 5, 1-(2-phenylethyl)-4-(2-pyridyl)piperazine, pro-
duced protective actions against cocaine induced convulsions which
provides evidence that compound 5 is an antagonist.29,31 Moreover,
1-(3-phenylpropyl)-4-(2-pyridyl)piperazine, 6, has 17-fold prefer-
to be a subtype of opioid receptors, they are now considered to be
8
a unique class of receptors7 comprised of two subtypes,
r1 and r2
r
1 Receptors have been cloned9,10 and are involved in intracellular
signaling, synaptic transmission, modulation of inositol phosphates,
protein kinases, and calcium.11–15 In addition,
1 antagonists reduce
the convulsive, lethal, locomotor stimulatory and rewarding actions
of cocaine in mice.16–20
2 Receptors have not yet been cloned; how-
ever they appear to be comprised of heterodimers and are smaller in
sizecomparedto r1
21–23 Furtherstudies havedemonstrated thatr1
ence for the
r2 receptor, over r1.
30 In an effort to design a pharma-
r
cophore for selective r2 antagonism in this series, we have
investigated the effect of pyridyl nitrogen position and chain length
in the phenylalkylpiperazinepyridine series.
Compounds 1–4 (Fig. 1) were prepared by the alkylation of the
corresponding halogenated alkyl phenyls with the appropriate
pyridinylpiperazine in the presence of K2CO3 in DMF at room tem-
perature and purified as oxalate salts from methanol.30 All salt tar-
gets were characterized using NMR and MS and all elemental
analyses of salts were within 0.4%.
r
.
selective antagonists reduce the stimulant effects of methamphet-
amine, while AC927 (N-phenethylpiperidine), a mixed r1 and r2
antagonist, attenuates the locomotor stimulant and neurotoxic ef-
fects of methamphetamine in mice.6,24 A selective
r
2 antagonist is
therefore urgently required to further study the relationship be-
tween 2 antagonism and methamphetamine neurotoxicity.
Truly selective 2 antagonists continue to be the goal of several
research groups.25–27 One of the major disadvantages of the current
2 antagonists is their ability to bind to the dopamine receptors, opi-
In vitro competition binding assays were preformed as follows.
Preparation of rat brain membrane and binding assays for the r1
and r2 receptor were performed as previously described in de-
r
r
tail.32,33 In brief,
r
1 receptors were labeled with 5 nM [3H](+)-pen-
r
tazocine. The r2 receptors were labeled with 3 nM [3H]di-o-
tolylguanidine (DTG) in the presence of 300 nM (+)-pentazocine
to block r1 receptors. Nonspecific binding was determined in the
oid receptors, and N-methyl-D
-aspartate (NMDA) receptors.28
presence of 10
lM haloperidol. Ten concentrations of each sigma
* Corresponding author.
E-mail address: acoop@rx.umaryland.edu (A. Coop).
compound (0.1–10,000 nM) were used in the assays. The com-
0960-894X/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2010.02.087

L. Stavitskaya et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2564–2565
2565
Supplementary data
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.02.087.
n
RN
1
2
3
R = 4-pyridyl, n = 1
R = 4-pyridyl, n = 2
R = 3-pyridyl, n = 1
References and notes
4 R = 3-pyridyl, n = 2
5* R = 2-pyridyl, n = 1
6* R = 2-pyridyl, n = 2
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Figure 1. Phenylalkylpiperazinepyridines. Reported in Ref. 30.
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a
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r1
r2
r1/r2
1
2
3
41.8 5.9
34.2 2.8
97.2 6.9
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326 41.2
82.9 0.21
69.7 6.3
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440 20
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pounds were incubated for 120 min at 25 °C to measure their abil-
ity to displace the radioligands from their binding sites. Termina-
tion of the reaction was achieved through rapid vacuum filtration
over glass fiber filters which were previously soaked in 1% polyeth-
yleneimine for at least 45 min. Ki values were calculated using the
Cheng–Prusoff equation.34
All compounds possessed affinity at both r1 and r2 receptors
(Table 1). As shown previously, (2-pyridyl)piperazines (5,6) fa-
vored r2 receptors,30 while (3-pyridyl)piperazines (3,4) and (4-
pyridyl)piperazines (1,2) showed preference for
r1 receptors. Sim-
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compounds (1,2) independent of the chain length, whereas the
phenylpropyl linker in both (3-pyridyl)piperazine and (2-pyri-
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dyl)piperazine resulted in higher affinity for both
tors. All new compounds showed significantly lower affinity for r2
receptors than our lead compound 6.
In summary, binding affinity studies showed that the (3-pyri-
dyl)piperazines and (4-pyridyl)piperazines have lower affinity for
r2 receptors, than the previously reported lead compound 6.
Moreover, both new series lost r2 selectivity, indicating that (2-
pyridyl)piperazines are optimal for the development of highly
selective r2 ligands.
r1 and r2 recep-
33. Matsumoto, R. R.; Shaikh, J.; Wilson, L. L.; Vedam, S.; Coop, A. Eur.
Acknowledgements
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This work was supported in part by the NationalInstitute on Drug
Abuse, National Institutes of Health (NIDA, NIH) (DA013978) and
Independent Scientist Award (K02) to A.C. (DA-19634).