Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands

Article abstract of DOI:10.1016/j.bmcl.2013.09.038

Selective σ₂ ligands continue to be an active target for medications to attenuate the effects of psychostimulants. In the course of our studies to determine the optimal substituents in the σ₂- selective phenyl piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that 1-(3-chlorophenyl)-4- phenethylpiperazine actually had preferentially increased affinity for dopamine transporters (DAT), yielding a highly selective DAT ligand.

Full text of DOI:10.1016/j.bmcl.2013.09.038

Bioorganic & Medicinal Chemistry Letters 23 (2013) 6920–6922
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Chlorophenylpiperazine analogues as high affinity dopamine
transporter ligands
William C. Motel a, , Jason R. Healy b, , Eddy Viard b, Buddy Pouw c, Kelly E. Martin a,d, Rae R. Matsumoto b,c
,
Andrew Coop a,
⇑
a Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, 20 North Pine Street, Baltimore, MD 21201, USA
b Department of Basic Pharmaceutical Sciences, West Virginia University, School of Pharmacy, One Medical Center Drive, Morgantown, WV 26506, USA
c Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, College of Pharmacy, Oklahoma City, OK 73190, USA
d Carolinas Medical Center, Department of Pharmacy, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective r2 ligands continue to be an active target for medications to attenuate the effects of psycho-
stimulants. In the course of our studies to determine the optimal substituents in the 2-selective phenyl
piperazines analogues with reduced activity at other neurotransmitter systems, we discovered that
1-(3-chlorophenyl)-4-phenethylpiperazine actually had preferentially increased affinity for dopamine
transporters (DAT), yielding a highly selective DAT ligand.
Received 30 April 2013
Revised 6 September 2013
Accepted 12 September 2013
Available online 15 October 2013
r
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Sigma receptor
Dopamine transporter
Structure–activity relationships
Neurotransmitter
Cocaine
Methamphetamine
Drugs that have the capability to suppress the stimulant and
toxic activities of psychomotor stimulants are urgently required,
yet little success has been achieved.1–6 Our studies have shown that
have historically been of concern for off-target interactions of
ligands.
r
selective sigma (r) receptor antagonists can attenuate stimulant
and neurotoxic effects of cocaine and methamphetamine in
rodents.7–11 However, elucidation of the specific receptor subtypes
(
r1 and
ligands.12
In earlier studies, simple piperazine analogues demonstrated
r2) involved are hampered by the paucity of r2-selective
anti-psychostimulant activity with affinity for both
r receptor
Figure 1. Template compound UMB38 and chloro-substituted analogues.
subtypes.13–16 We expanded the library of piperazine analogues
through the exploration of an electron withdrawing pyridyl ring
linked to the piperazine, yielding N-(2-pyridyl)piperazine ana-
logues, which favors the r2 receptor subtype over the r1 receptor
Table 1
Competition binding study results for
r
receptors and dopamine transporters
r2 DAT
4.9 0.8*
16.73 9148 1008 0.0090
Compound r1
r2
r1/
r1/DAT
subtype.17,18 To further explore
r
2-selective piperazine analogues,
we introduced electron withdrawing chloro-substituents into the
2-selective 1-(3-phenylpropyl)-4-(2-pyridyl)piperazine (UMB38)
UMB38
82 0.2*
2
3
4
5
6
7
0.15 0.01
6.47 0.48
1.85 0.20
0.56 0.06
4.93 0.52
56.32 4.16 0.003
82.31 6.77 0.079
33.30 2.02 0.056
0.13 0.01
0.04 0.01
1.15
161.75
0.31
0.0012
n.d.
0.000045
r
6
0.33
scaffold to create a series of ligands that were pharmacologically
evaluated at both the r1 and r2 receptor subtypes in addition to
commonly tested neurotransmitter receptors and transporters that
7.79 0.52
0.072
482 24
>10,000
2647 158
12.59 1.17 0.39
0.12 0.003 10.89 0.97 0.011
Values are reported as Ki S.E.M. (nM). A value of >10,000 indicates less than 30% of
the radioligand was displaced at the 10,000 nM ligand concentration. DAT = dopa-
⇑
mine transporter; n.d. = not determined. r1/r2 and r1/DAT are selectivity ratios,
Corresponding author. Tel.: +1 410 706 2029; fax: +1 410 706 4012.
E-mail address: acoop@rx.umaryland.edu (A. Coop).
These authors contributed equally to the work.
respectively.
*
Data from previously reported compound Ref. 17
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.09.038

W. C. Motel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 6920–6922
6921
Table 2
Competition binding study results for neurotransmitter receptors and transporters
Compound
5-HT2
D2
SERT
NET
Opioid
PCP/NMDA
UMB38
1238 61
940 87
>10,000
>10,000
802 68
372 13
409 29
488 36
1104 92
>10,000
790 33
1107 35
>10,000
>10,000
>10,000
>10,000
>10,000
4830 391
>10,000
>10,000
4600 495
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
2
3
4
5
6
7
484
53
6
7
67
6
327 23
834 56
518 52
952 98
498 50
391 48
77
128
7
9
660 19
>10,000
Values are reported as Ki S.E.M. (nM). A value of >10,000 indicates less than 30% of the radioligand was displaced at the 10,000 nM ligand concentration. 5-HT2 = serotonin
receptor subfamily; D2 = dopamine receptor subtype; SERT = serotonin transporter; NET = norepinephrine transporter; PCP/NMDA = phencyclidine/N-methyl- -aspartate.
D
The analogues (2–7, Fig. 1) were prepared by the reaction of the
appropriate phenyl piperazine and the appropriate brominated
phenyl alkane in DMF in the presence of NaHCO3 at room temper-
ature for 24 h. The product was extracted from water into diethyl
ether and concentrated. Yields of pure free bases were observed
between 87% and 97%. After removal of the solvent, all amines
were converted into water-soluble oxalic acid salts. All free bases
displayed NMR and mass spectral data consistent with the as-
signed structures, and combustion analysis of all salts were 0.4%
of the theoretical calculation (Atlantic Microlabs, Norcross, GA,
USA). A more detailed chemical description can be found in the
Supplementary data section. The synthesized ligands were
evaluated using competition binding assays as previously
described.9,16,19
Although not the result expected, the SAR herein uncovered one
of the highest affinity and most selective ligands for DAT (3) to
date. This compound has the potential to increase our understand-
ing of DAT, while informing that such substituents are not appro-
priate for r2 selective ligands.
Acknowledgments
This study was supported by the National Institutes of Health
(DA011979, DA013978). Mr. J.H. was supported by a diversity sup-
plement from the National Institutes of Health (DA013583).
Supplementary data
This series of piperazine analogues showed high-to-moderate
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.201
3.09.038.
affinity for both r1 and r2 receptor subtypes (Table 1).
r Binding
affinities have previously been published for 3, 6 and 7; however,
said binding affinities were obtained using [3H]di-o-tolylguanidine
(DTG) without the inclusion of (+)-pentazocine, conditions that do
not differentiate affinities between the r1 and r2 receptor
subtypes.20 While the primary objective of this research was to
identify electron withdrawing chloro-substituents that optimize
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