Trifluoromethoxyl substituted phenylethylene diamines as high affinity σ receptor ligands with potent anti-cocaine actions

Article abstract of DOI:10.1021/jm7013666

The phenylethylene diamines are a class of σ receptor ligands with excellent selectivity over other biological systems and with anti-cocaine actions that involve antagonism of σ₁ receptors. In order to increase the potency of the aromatic methoxyl substituted analogues, trifluoromethoxyl groups were introduced to prevent metabolic demethylation. The para-substituted trifluoromethoxyl substituted analogues were shown to have increased σ receptor affinity and represent the most potent anti-cocaine phenylethylene diamines yet described.

Full text of DOI:10.1021/jm7013666

3322
J. Med. Chem. 2008, 51, 3322–3325
Trifluoromethoxyl Substituted Phenylethylene Diamines as High Affinity σ Receptor Ligands
with Potent Anti-Cocaine Actions
Trudy A. Smith,† Xiaowen Yang,† Huifang Wu,† Buddy Pouw,‡ Rae R. Matsumoto,‡ and Andrew Coop*,†
Department of Pharmaceutical Sciences, UniVersity of Maryland School of Pharmacy, 20 Penn Street, Room 637 HSFII, Baltimore, Maryland
21201, and College of Pharmacy, UniVersity of Oklahoma Health Sciences Center, P.O. Box 26901, Oklahoma City, Oklahoma 73190
ReceiVed October 31, 2007
The phenylethylene diamines are a class of σ receptor ligands with excellent selectivity over other biological
systems and with anti-cocaine actions that involve antagonism of σ1 receptors. In order to increase the
potency of the aromatic methoxyl substituted analogues, trifluoromethoxyl groups were introduced to prevent
metabolic demethylation. The para-substituted trifluoromethoxyl substituted analogues were shown to have
increased σ receptor affinity and represent the most potent anti-cocaine phenylethylene diamines yet described.
Introduction
affinity,22 we considered that the introduction of electron
withdrawing trifluoromethoxyl groups would prevent metabolic
demethylation while increasing lipophilicity, thereby possibly
leading to improved potency as anti-cocaine agents.
Cocaine abuse remains a major public health problem1,2 and
is responsible for more serious intoxications and deaths than
any other illicit drug, primarily as no effective treatments for
cocaine overdose are currently available.3 Previous studies aimed
at developing anti-cocaine small molecule therapeutics have
primarily focused on reversing the effects of cocaine on the
dopaminergic system, yet success has been limited.3–5 It is now
becoming apparent not only that the behavioral effects of cocaine
are due to actions at the dopamine transporter but that there is
a contribution from other monoamine transporters and also
receptors to which it binds.6,7 Our approach to develop agents
that attenuate the effects of cocaine is to prevent the access of
cocaine to σ receptors, to which cocaine binds at concentrations
that are achievable in vivo,7–9 and because they are located in
key organ systems (i.e., brain, heart) that mediate the drug’s
actions.10
Synthesis
The synthesis of the analogues closely followed the proce-
dures used for the methoxyl analogues reported previously.21,22
The trifluoromethoxyl substituted analogues (Scheme 1) were
prepared from the relevant trifluoromethoxyphenyl acetic acid
through coupling with the relevant diamine21 followed by
reduction of the amide with alane. The intermediate amides were
isolated and purified for the ortho and para analogues but were
not isolated and purified in the case of the meta analogues
(23–26). All compounds were converted to water soluble salts
and evaluated in binding assays and mouse convulsion assays
using procedures previously reported.21,22
The σ receptors were first postulated by Martin11 and suffered
from a complicated history, but they are now recognized as
unique binding sites that are distinct from other known
receptors10,12 and have been shown to consist of σ1 and σ2
receptors through pharmacological methods.13–16 The σ1 receptor
has been cloned,17 and antisense oligodeoxynucleotides against
σ1 receptors attenuate the effects of σ1 agonists.18 Early
generations of σ receptor antagonists were reported to attenuate
cocaine-induced locomotor stimulation and convulsions with
varying results, but newer generations of potent and selective
σ-1 receptor antagonists and antisense oligodeoxynucleotides
(to σ1) unequivocally block the toxic and locomotor stimulatory
effects of cocaine.19
Results and Discussion
Table 1 shows that all 12 compounds possess high affinity
at σ1 receptors with at least 4-fold preference over σ2 receptors.
All compounds show selectivity over a range of other biological
targets, chosen because of interactions with cocaine and/or their
involvement in the actions of stimulants,21 but it should be noted
that the ortho-substituted analogues (18–21) are not as selective
because they possess affinity at dopamine D2 receptors in the
100 nM range. However, the para-, ortho- and meta-substituted
analogues all have higher affinity than their methoxyl substituted
analogues reported previously (such as 3 Table 1).21,22 It appears
that the para- and meta-substituted trifluoromethoxylphenyl-
ethylenediamines possess the desired profile for anti-cocaine
agents based on the binding assays. Cocaine-induced convul-
sions are a useful tool to assess σ-active compounds, as σ
antagonists that attentuate cocaine-induced convulsions often
attenuate cocaine-induced locomotor activity.19 Data from our
previously reported21,23 anticonvulsion assays (Table 2) showed
that the para-substituted analogues (9–12) were more potent than
the ortho- and meta-substituted analogues. Indeed, the piperi-
dine-based 11 and 12, which have high affinity for σ1, showed
almost complete reversal of convulsions at 5 mg/kg, whereas
the pyrrolidine-based 9 and 10 only showed activity in 50% of
animals at this dose. The ortho-substituted analogues (18–21)
were less potent, with only 19 and 21 attenuating convulsions
in more than 50% of animals. The meta-substituted analogues
Selective σ1 agonists and antagonists have been described,19
and the phenylethylenediamine class of ligands (typified by
BD1008 (1) (Figure 1)) has been shown to be selective for σ
receptors over all other biological systems, with some selectivity
for σ1 receptors over σ2.19 We have described the aromatic
substituted methoxyl analogues (such as 2 and 3 (Figure 1)) as
high affinity σ ligands that show high potency in reversing the
effects of cocaine in mice, and it is also known that both
N-methyl and N-ethyl substituted analogues are active.20–22 As
electron withdrawing groups have been shown to increase σ1
* To whom correspondence should be addressed. Phone: 410-706-2029.
Fax: 410-706-5017. E-mail: acoop@rx.umaryland.edu.
†
University of Maryland School of Pharmacy.
University of Oklahoma Health Sciences Center.
‡
10.1021/jm7013666 CCC: $40.75
2008 American Chemical Society
Published on Web 05/08/2008

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3323
Figure 1. Phenylethylene diamine-based σ ligands.
Scheme 1a
a Conditions: (a) diamine, DCC; (b) AlH3.
Table 1. Binding Affinities (Ki ( SEM, nM) at σ Receptors, Monoamine Transporters (DAT, SERT, NET), and Dopamine D2 Receptorsa
σ1
σ2
DAT
SERT
NET
DA D2
3b
9
21 ( 0.6
6 ( 1
421 ( 99
36 ( 3
32 ( 6
25 ( 2
26 ( 4
43 ( 4
82 ( 8
58 ( 2
55 ( 3
40 ( 10
43 ( 1
31 ( 9
15 ( 3
12893 ( 1206
6331 ( 356
5525 ( 628
4123 ( 208
2389 ( 146
11970 ( 729
13190 ( 1119
11920 ( 868
9530 ( 949
>10000
52647 ( 3286
7105 ( 373
3791 ( 149
9465 ( 518
3303 ( 296
>100000
>100000
>100000
>100000
>10000
19687 ( 2407
>100000
>100000
>100000
>100000
>100000
>100000
>100000
58100 ( 6400
>10000
>10000
>10000
>10000
>10000
>10000
516 ( 39
266 ( 13
146 ( 6
213 ( 5
>10000
>10000
>10000
>10000
10
11
12
18
19
20
21
27
28
29
30
7 ( 1
2 ( 0.2
2 ( 0.2
10 ( 1
17 ( 3
3 ( 0.1
6 ( 0.1
2 ( 0.4
5 ( 0.8
3 ( 0.1
2 ( 0.6
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
>10000
a At opioid, serotonin 5-HT-2, and NMDA receptors all compounds possessed a Ki of >10000 nM. b Data from ref 21.
g, 0.01 mol) in CH2Cl2 (10 mL) was added. After the mixture was
stirred for 10 min, N-methyl-2-(1-pyrrolidinyl)ethylamine24 (0.9 g,
0.007 mol) was added, and the mixture was stirred at room
temperature for 20 min. The mixture was filtered, the filter cake
was washed with CH2Cl2 (3 × 10 mL), and the filtrate was extracted
with 10% aqueous citric acid (50 mL). The citric acid extracts were
washed with CH2Cl2 (2 × 30 mL), basified with NH4OH, and
extracted into CH2Cl2 (3 × 40 mL). The organic layer was washed
with water (2 × 20 mL), dried (Na2SO4), and concentrated to give
(27–30) only showed attenuation of more than 50% of the
animals in the piperidine-based 29 and 30. Consistent with
binding data, the para-substituted analogues show greater anti-
cocaine activity in convulsion assays than their methoxyl
analogues.21,22 Whether an increase in anti-cocaine potency is
due to increased affinity or decreased metabolism is yet to be
determined, but the p-trifluoromethoxyl-substituted phenyleth-
ylenediamines represent the most potent members of this class
in reversing the convulsive actions of cocaine. Though potent
attentuation of convulsive effects is seen, the lack of a dose-
related effect for several of the compounds indicates that further
study is required to fully delineate the mechanism behind these
effects, to allow the design and synthesis of potent pharmaco-
therapeutics for stimulant abuse.
1
a colorless oil (1.68 g, 73%). H NMR (CDCl3) δ 7.27 (m, 2H),
7.15 (m, 2H), 3.71 (m, 2H), 3.40 (m, 2H), 2.94 (d, 2H), 2.56 (m,
8H), 1.76 (s, 3H).
N-Ethyl-N-(2-pyrrolidin-1-ylethyl)-2-[4-(trifluoromethoxy)phe-
nyl]acetamide (6). Yield 77%; 1H NMR (CDCl3) δ 7.28 (m, 2H),
7.15 (m, 2H), 3.71 (m, 2H), 3.45 (m, 4H), 2.61 (m, 6H), 1.78 (m,
4H), 1.14 (m, 3H).
Experimental Section
N-Methyl-N-(2-piperidin-1-ylethyl)-2-[4-(trifluoromethoxy)-
1
N-Methyl-N-(2-pyrrolidin-1-ylethyl)-2-[4-(trifluoromethoxy)-
phenyl]acetamide (5). To a stirred solution of DCC (3.1 g, 0.015
mol) in CH2Cl2 (20 mL), 4-(trifluoromethoxy)phenylacetic acid (2.2
phenyl]acetamide (7). Yield 84%; H NMR (CDCl3) δ 7.28 (m,
2H), 7.16 (m, 2H), 3.72 (m, 2H), 3.50 (m, 2H), 3.00 (m, 3H), 2.38
(m, 6H), 1.54 (m, 4H), 1.43 (m, 2H).

3324 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Brief Articles
Table 2. Number of Mice Convulsing with 60 mg/kg Cocaine after
N-Methyl-N-(2-piperidin-1-ylethyl)-2-[2-(trifluoromethoxy)-
phenyl]acetamide (16). Yield 86%; 1H NMR (CDCl3) δ 7.35 (m,
2H), 7.25 (m, 2H), 3.74 (m, 6H), 3.46 (m, 4H), 2.98 (m, 2H), 2.40
(s, 3H), 1.45 (m, 4H).
N-Ethyl-N-(2-piperidin-1-ylethyl)-2-[2-(trifluoromethoxy)phenyl]-
acetamide (17). Yield 77%; 1H NMR (CDCl3) δ7.35 (m, 2H), 7.25
(m, 2H), 3.73 (m, 2H), 3.44 (m, 6H), 2.42 (m, 6H), 1.48 (m, 4H),
1.17 (m, 3H).
N-Methyl-2-pyrrolidin-1-yl-N-{2-[2-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (18). Yield 81%; mp (dioxalate) 217–219 °C;
1H NMR (CDCl3) δ 7.26 (4H, m), 2.85 (2H, m), 2.63 (6H, m),
2.52 (4H,m), 2.35 (3H, s), 1.77 (4H, m); LCMS (M + 1) 317.
Anal. (C20H27F3N2O9) C, H, N.
N-Ethyl-2-pyrrolidin-1-yl-N-{2-[2-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (19). Yield 66.5%; mp (dioxalate) 190–192 °C;
1H NMR (CDCl3) δ 7.21 (4H, m), 2.82 (2H, m), 2.70 (4H, m),
2.63 (2H, m), 2.59 (2H, m), 2.53 (4H,m), 1.78(4H, m), 1.07 (3H,
m); LCMS (M + 1) 331. Anal. (C21H29F3N2O9) C, H, N.
N-Methyl-2-piperidin-1-yl-N-{2-[2-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (20). Yield 85%; mp (dioxalate) 214–215 °C;
1H NMR (CDCl3) δ 7.21(4H, m), 2.84 (2H, m), 2.61 (4H, m), 2.46
(2H, m), 2.40 (4H, m), 2.34 (3H, s), 1.58 (4H, m), 1.43 (2H, m);
LCMS (M + 1) 331. Anal. (C21H29F3N2O9) C, H, N.
N-Ethyl-2-piperidin-1-yl-N-{2-[2-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (21). Yield 74.5%; mp (dioxalate) 179–181 °C;
1H NMR (CDCl3) δ 7.21 (4H, m), 2.80 (2H, m), 2.69 (4H, m),
2.63 (2H, m), 2.44 (6H, m), 1.59 (4H, m), 1.43 (2H, m), 1.06 (3H,
m); LCMS (M + 1) 345. Anal. (C22H31F3N2O9) C, H, N.
N-Methyl-2-pyrrolidin-1-yl-N-{2-[3-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (27). Yield 6%; mp (HCl) 237–241 °C; 1H NMR
(CDCl3) δ 7.30 (4H, m), 2.76 (4H, m), 2.60 (4H, m), 2.50 (4H,
m), 2.30 (3H, s), 1.70 (4H, m); LCMS (M + 1) 317.1. Anal.
(C16H25Cl2F3N2O) C, H, N.
N-Ethyl-2-pyrrolidin-1-yl-N-{2-[3-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (28). Yield 12%; mp (HCl) 180–183 °C; 1H
NMR (CDCl3) δ 7.27 (4H, m), 2.74 (6H, m), 2.58 (6H, m), 1.76
(4H, m), 1.32 (3H, m), 1.16 (2H, m); LCMS (M + 1) 331.4. Anal.
(C17H27Cl2F3N2O(H2O)0. 5) C, H, N.
N-Methyl-2-piperidin-1-yl-N-{2-[3-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (29). Yield 41%; mp (HCl) 183–185 °C; 1H
NMR (CDCl3) δ 7.00 (4H, m), 2.79 (2H, m), 2.56 (6H, m), 2.40
(4H, m), 2.31 (3H, s), 2.24 (4H, m), 1.33 (2H, m); LCMS (M + 1)
331.4. Anal. (C17H27Cl2F3N2O) C, H, N.
N-Ethyl-2-piperidin-1-yl-N-{2-[3-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (30). Yield 55%; mp (HCl) 250–253 °C; 1H
NMR (CDCl3) δ 7.30 (4H, m), 2.80 (4H,m), 2.60 (4H, m), 2.40
(6H, m), 1.4 (4H, m), 1.23 (3H, m), 0.9 (2H, m); LCMS (M + 1)
345.4. Anal. (C18H29Cl2F3N2O) C, H, N.
Pretreatment with Test Druga
drug pretreatment dose (mg/kg) anticonvulsant effect (% convulsions)
9
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5
10
5
5/10 (50%)
1/10 (10%)
5/10 (50%)
1/10 (10%)
2/10 (20%)
3/10 (30%)
2/10 (20%)
3/10 (30%)
7/10 (70%)
6/10 (60%)
4/10 (40%)
4/10 (40%)
8/10 (80%)
7/10 (70%)
7/15 (47%)
7/10 (70%)
5/10 (50%)
6/10 (60%)
6/10 (60%)
7/10 (70%)
8/10 (80%)
3/10 (30%)
2/8 (25%)
10
11
12
18
19
20
21
27
28
29
30
10
5
10
5
10
5
10
5/7 (71%)
a Control animals (N ) 10) were pretreated with saline and then challenged
15 min later with cocaine, resulting in 100% of the mice exhibiting cocaine-
induced convulsions. Values of e50% represent statistically significant reduc-
tions in cocaine-induced convulsions (Fisher’s exact test).
N-Ethyl-N-(2-piperidin-1-ylethyl)-2-[4-(trifluoromethoxy)phe-
nyl]acetamide (8). Yield 87%; 1H NMR (CDCl3) δ 7.27 (m, 2H),
7.14 (m, 2H), 3.70 (m, 2H), 3.32 (m, 4H), 2.37 (m, 6H), 1.55 (m,
6H), 1.12 (m, 3H).
N-Methyl-2-pyrrolidin-1-yl-N-{2-[4-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (9). A solution of 5 (1.57 g, 0.0047 mol) in THF
(5 mL) was added to a solution of AlH3 (0.23 g, 0.023mol) in
PhCH3. About 5 min, the mixture was carefully poured into aqueous
NaOH (15%, 30 mL). After cooling to room temperature, the
mixture was extracted into CHCl3 (3 × 30 mL). The organic extracts
were washed with brine (30 mL), dried (Na2SO4), and concentrated.
Purification by column chromatography (CHCl3/MeOH/NH4OH )
95:5:0.1) gave a yellow oil (1.20 g, 81%): mp (dioxalate) 210–212
1
°C; H NMR (CDCl3) δ 7.12 – 7.21 (m, 4H), 2.79 (m, 2H), 2.63
(m, 2H), 2.59 (m, 4H), 2.54 (m, 4H), 2.33 (s, 3H), 1.77 (m, 4H);
LCMS 317 (M + 1). Anal. (C20H27F3N2O9) C, H, N.
N-Ethyl-2-pyrrolidin-1-yl-N-{2-[4-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (10). Yield 61%; mp (dioxalate) 189–191 °C;
1H NMR (CDCl3) δ 7.12 –7.40 (4H, m), 2.77–2.66 (6H, m), 2.62
(2H, m), 2.57 (2H, m), 2.52 (4H, m), 1.77 (4H, m), 1.05 (3H, m);
LCMS 331 (M + 1). Anal. (C21H29F3N2O9) C, H, N.
N-Methyl-2-piperidin-1-yl-N-{2-[4-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (11). Yield 83.5%; mp (dioxalate) 183–185 °C;
1H NMR (CDCl3) δ 7.12–7.21 (4H, m), 2.78 (2H, m), 2.58-2.62
(4H, m), 2.43 (2H, m), 2.40 (4H, m,), 2.31 (3H, s), 1.58 (4H, m),
1.43 (2H, m); LCMS (M + 1) 331. Anal. (C21H29F3N2O9) C, H,
N.
Radioligand Binding Assays. The assays were performed in
rat brain homogenates using procedures previously published in
detail. The σ1 receptors were labeled with 5 nM [3H](+)-
pentazocine. The σ2 receptors were labeled with 3 nM [3H]DTG
in the presence of 300 nM (+)-pentazocine to block σ1 receptors.
Nonspecific binding was determined in the presence of 10 µM
haloperidol. Ki values were calculated using the Cheng-Prusoff
equation.
Convulsion Assays. Male Swiss Webster mice were pretreated
(ip) with saline or test compound, then challenged 15 min later
with a convulsive dose of cocaine (60 mg/kg, ip). Mice were
observed for the next 30 min for convulsions, which were defined
as a loss of righting reflexes for at least 5 s combined with the
presence of clonic limb movements or popcorn jumping.
N-Ethyl-2-piperidin-1-yl-N-{2-[4-(trifluoromethoxy)phenyl]-
ethyl}ethanamine (12). Yield 86%; mp (dioxalate ·0.25H2O)
143–145 °C; 1H NMR (CDCl3) δ 7.16 (4H, m), 2.75 (2H, m), 2.69
(4H, m), 2.61 (2H, m), 2.42 (6H, m), 1.59 (4H, m), 1.43 (2H, m),
1.04 (3H, m); LCMS (M + 1) 345. Anal. (C22H31F3N2O9 ·0.25H2O)
C, H, N.
Acknowledgment. The authors gratefully acknowledge
NIDA (Grant DA 13978) for financial support of these studies.
A.C. is the recipient of an Independent Scientist Award from
NIDA (Grant K02 DA 19634).
N-Methyl-N-(2-pyrrolidin-1-ylethyl)-2-[2-(trifluoromethox-
y)phenyl]acetamide (14). Yield 87%; H NMR (CDCl3) δ 7.35
1
(m, 2H), 7.25 (m, 2H), 3.75 (m, 2H), 3.52 (m, 2H), 3.01 (m, 2H),
2.59 (m, 8H), 1.78 (s, 3H).
N-Ethyl-N-(2-pyrrolidin-1-ylethyl)-2-[2-(trifluoromethoxy)phe-
nyl]acetamide (15). Yield 82%; 1H NMR (CDCl3) δ 7.34 (m, 2H),
7.25 (m, 2H), 3.72 (m, 2H), 3.35 (m, 4H), 2.53 (m, 6H), 1.76 (m,
4H), 1.22 (m, 3H).
Supporting Information Available: Elemental analysis results
of final testing compounds and general procedures. This material
is available free of charge via the Internet at http://pubs.acs.org.

Brief Articles
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11 3325
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