3α-(4'-Substituted phenyl)tropane-2β-carboxylic acid methyl esters: Novel ligands with high affinity and selectivity at the dopamine transporter

Full text of DOI:10.1021/jm960515u

J . Med. Chem. 1996, 39, 4139-4141
4139
Sch em e 1
3r-(4′-Su bstitu ted p h en yl)tr op a n e-
2â-ca r boxylic Acid Meth yl Ester s: Novel
Liga n d s w ith High Affin ity a n d
Selectivity a t th e Dop a m in e Tr a n sp or ter
Christopher R. Holmquist,†
Kathryn I. Keverline-Frantz,† Philip Abraham,†
J ohn W. Boja,‡ Michael J . Kuhar,‡ and
F. Ivy Carroll*,†
Chemistry and Life Sciences, Research
Triangle Institute, P.O. Box 12194,
Research Triangle Park, North Carolina 27709, and
National Institute on Drug Abuse, Addiction Research
Center, P.O. Box 5180, Baltimore, Maryland 21224
Received J uly 16, 1996
Since their initial preparation by Clarke and co-
workers1 over 23 years ago, the 3â-(substituted phenyl)-
tropane-2â-carboxylic acid methyl ester class of com-
pounds 1 have been widely employed in structure-
activity relationship (SAR) studies at the cocaine binding
site on the dopamine transporter (DAT).2 Since neither
Clarke’s nor any other reported method provided the
3R-phenyl analogs, the SAR studies did not include this
isomer. Recently, we reported the synthesis of the first
3R-(substituted phenyl)tropane-2â-carboxylic acid meth-
yl esters 2 by samarium iodide reduction of 3-aryl-2-
carbomethoxytropenes 3.3 In this paper we describe a
more efficient synthesis of several new 3R-(substituted
phenyl)tropane-2â-carboxylic acid methyl esters 2 and
present the results of the first monoamine transporter
binding studies on this series of compounds.
reaction conditions, complete epimerization at C-2 to
form the 2â,3R-stereoisomer is observed. This is in
agreement with previously reported observations on 3R-
phenyl-2R-(3′-methyl-1′,2′,4′-oxadiazol-5′-yl)tropane (5e,
X ) H)5 and is presumably driven by the ability of the
piperidine ring to adopt an equatorially substituted
twist-boat conformation (Figure 1).
1
Analysis of the H NMR and COSY spectra of methyl
esters 2a -e (Table 2), using pyridine-d5 for chemical
shift dispersion, shows weak coupling between H1 and
H2 (J 1,2 ) ∼1.7 Hz), while H2 couples to H3 with a
coupling constant of 9.4-9.7 Hz. These observations are
consistent with a twist-boat conformation in which H2
is close to orthogonal with H1 and has a near trans-
diaxial relationship to H3. This contrasts sharply with
1
allococaine (6) where the H and 13C NMR data show
that this compound possesses a chair conformation.6 As
in the 2â,3â-isomers 1, the equatorial proton at C-4 of
the 2â,3R-isomers 2 is deshielded relative to its axial
The route used to synthesize the 3R-(substituted
phenyl)tropane-2â-carboxylic acid methyl ester (2a -e)
analogs is shown in Scheme 1, and the physical proper-
ties are listed in Table 1. Addition of a solution of
(1R,5S)-2-(3′-methyl-1′,2′,4′-oxadiazol-5′-yl)-8-methyl-8-
azabicyclo[3.2.1]oct-2-ene (4)4 in anhydrous tetrahydro-
furan or ether to a -78 °C solution of the appropriate
aryllithium followed by quenching with trifluoroacetic
acid at -78 °C formed 3R-(substituted phenyl)tropane-
2R-(3′-methyl-1′,2′,4′-oxadiazol-5′-yl)tropanes 5. In some
cases (X ) CH3, I) the 2R,3â-isomer was also formed;
this isomer could either be removed by flash column
chromatography or carried through the next reaction.
Conversion of the oxadiazole to the methyl ester was
accomplished by reduction with nickel boride and
hydrochloric acid in refluxing methanol. Under the
† Research Triangle Institute.
‡ National Institute on Drug Abuse.
F igu r e 1.
S0022-2623(96)00515-8 CCC: $12.00 © 1996 American Chemical Society

4140 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21
Communications to the Editor
Ta ble 1. Chemical Yields and Physical Properties for Oxadiazoles 5 and Methyl Esters 2
synthesis
oxadiazole
yield
(%)
methyl
ester
yield
(%)
molecular
formulaa,b
melting
[R]D (deg)
(c, CH3OH)
pointa (°C)
5a
5b
5c
5d
5e
85
2a
2b
2c
2d
2e
86
45
54
51
60
C20H26FNO8‚0.5H2Oc
65 dec
-34.4 (0.54)
-38.9 (1.30)
-39.9 (0.45)
-43.1 (0.55)
-48.1 (1.38)
23d
81
C23H28INO5S
204.6-205.3
182.4-183.8
174.8-175.4
178-179
C
23H28ClNO5S
65e
86
C24H31NO5S
f
C
16H22ClNO2
a
Compounds were characterized as the tosylate salts unless otherwise noted. b C, H, and N analyses were within 0.4% of their theoretical
values. c Characterized as the tartrate salt. The 2R,3â-isomer was recovered in 20% yield. e The 2R,3â-isomer was recovered in 15%
d
yield. f Characterized as the HCl salt.
Ta ble 2. 1H NMR Selected Chemical Shifts and Coupling
Constants for the Free Bases of Compounds 2a -d
coupling
constants (Hz)
chemical shifts (ppm)a
4eq 4ax
2. Furthermore, the 2â,3R-isomers are only 1.5-5.9
times less potent at the DAT than the analogous 2â,3â-
isomers. These results contrast sharply with allococaine
(6), the 2â,3R-stereoisomer of cocaine (7), which is 60
times less potent than cocaine at the DAT.10 Appar-
ently, the preference of 2â,3R-esters 2 for the twist-boat
conformation allows the amino, aryl, and carbomethoxy
groups to adopt similar positions to the corresponding
groups in 1 and may explain the relatively high dopam-
ine binding affinities exhibited by esters 2 relative to
allococaine (6). It is interesting to note that the p-
iodophenyl analog 2b (RTI-352) is only slightly less
potent than 1b (RTI-55) but 7 times more selective for
the DAT relative to the 5-HT transporter. Since [123I]-
RTI-55 has proven to be a valuable SPECT (single-
photon emission-computed tomography) imaging agent,11
we plan to conduct further studies with 2b to determine
if it possesses properties that would make it a better
SPECT imaging agent than [123I]RTI-55.
compd
X
1
2
3
5
J 1,2 J 2,3 J 3,4
eq
2a
2b
2c
2d
2e
F
I
3.41 2.65 3.63 2.37 1.32 3.09 1.8 9.7 7.9
3.40 2.66 3.57 2.35 1.29 3.07 1.7 9.4 7.9
3.41 2.65 3.59 2.35 1.30 3.08 1.7 9.4 8.0
Cl
CH3 3.42 2.72 3.65 2.40 1.35 3.09 1.7 9.3 8.1
3.43 2.73 3.68 2.41 1.40 3.10 1.6 9.5 8.1
H
a
Chemical shifts are reported relative to Si(CH3)4 in pyridine-
d5 at 500 MHz.
counterpart, indicating that the aromatic ring lies
perpendicular to the axis of the piperidine ring.
The IC50 values for the inhibition of ligand binding
to the dopamine, serotonin, and norepinephrine trans-
porters by 3R-(p-substituted phenyl)tropane-2â-carboxy-
lic acid methyl esters 2a -e are listed in Table 3. For
comparison, the previously reported IC50 values for the
corresponding 2â,3â-isomers 1a -e, as well as values for
cocaine (7) and allococaine (6), are also listed. The IC50
values for dopamine and serotonin represent inhibition
of 0.5 nM [3H]WIN 35,428 and 0.2 nM [3H]paroxetine,
respectively, as previously described.7 Norepinephrine
IC50 values represent inhibition of 0.5 nM [3H]nisoxetine
binding to the norepinephrine transporter.8,9
Ack n ow led gm en t. This research was supported by
the National Institute on Drug Abuse, Grant DA05477.
The substituted aryl 2â,3R-isomers 2a -d are more
selective for the DAT relative to the 5-HT transporter
than the 2â,3â-isomers 1a -d . The unsubstituted ana-
log 2e possessed DAT selectivity similar to WIN 35,065-
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for 5a -d and 2a -d (7 pages). Ordering information is found
on any current masthead page.
Ta ble 3. Comparison of Transporter Binding Potencies for Stereoisomers of WIN 35,065-2 Analogs
IC50 (nM)a
ratiob
5-HT/DA
DA
NE
5-HT
compd
X
isomer
[3H]WIN 35,428
[3H]nisoxetine
[3H]paroxetine
NE/DA
6 (allococaine)c
6160 ( 900
89.1 ( 4.8
14 ( 1.4
21 ( 0.57
1.26 ( 0.04
2.85 ( 0.16
1.12 ( 0.1
2.4 ( 0.2
7 (cocaine)d
3298 ( 293
835 ( 45
1230 ( 91
36 ( 2.7
1045 ( 89
810 ( 59
1a e,f
2a
F
F
I
I
Cl
2â,3â
2â,3R
2â,3â
2â,3R
2â,3â
2â,3R
2â,3â
2â,3R
2â,3â
2â,3R
60
59
29
18
33
25
35
27
40
21
58
241
3.3
23
40
415
140
417
87
5060 ( 485
4.21 ( 0.3
64.9 ( 1.97
44.5 ( 1.3
998 ( 120
240 ( 27
1be
2b
52.4 ( 4.9
37 ( 2.1
1ce
2c
Cl
60.1 ( 2.4
60 ( 0.53
275 ( 24
920 ( 73
2080 ( 285
1d e
2d
CH3
CH3
H
1.71 ( 0.31
10.2 ( 0.8
23 ( 5
4250 ( 422
2000 ( 64
5700 ( 721
1eg,h
2e
H
101 ( 16
57
a
b
Data are mean ( standard error of three or four experiments performed in triplicate. Ratios of IC50 values. c IC50 values taken from
ref 10. IC50 values taken from ref 7. e IC50 values taken from ref 12. f This compound is WIN 35,428. This compound is WIN 35,065-2.
IC50 values taken from ref 13.
d
g
h

Communications to the Editor
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 21 4141
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phenyl)tropane-2-carboxylic acid methyl esters. Tetrahedron
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J M960515U