Synthesis of tropane and nortropane analogues with phenyl substitutions as serotonin transporter ligands

Article abstract of DOI:10.1016/S0968-0896(01)00083-9

The effects of structural modifications of β-carboxymethoxy-3β-phenyl tropane analogues were evaluated on in vitro affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at the 4′-position of the phenyl ring, affording 2β-carbomethoxy-3β-(4′-alkylphenyl) tropane, diminished the affinity for the DAT whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 3′-position of the 4′-alkylphenyl, affording 2β-carbomethoxy-3β-(3′-iodo-4′-alkylphenyl) tropane, and N-demethylation, affording 2β-carbomethoxy-3β-(3′-iodo-4′-alkylphenyl) nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the most selective cocaine derivative, 2β-carbomethoxy-3β-(3′-iodo-4′-isopropylphenyl) nortropane (8d) labeled with iodine-123 or carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET. Copyright

Full text of DOI:10.1016/S0968-0896(01)00083-9

Bioorganic & Medicinal Chemistry 9 (2001) 1849–1855
Synthesis of Tropane and Nortropane Analogues with Phenyl
Substitutions as Serotonin Transporter Ligands
Patrick Emond,* Julie Helfenbein, Sylvie Chalon, Lucette Garreau, Johnny Vercouillie,
Yves Frangin, Jean Claude Besnard and Denis Guilloteau
´ ´
INSERM U316, Laboratoire de Biophysique Medicale et Pharmaceutique, Universite Franc¸ois Rabelais, 31 Avenue Monge,
37200 Tours, France
Received 7 August 2000; accepted 19 March 2001
Abstract—The effects of structural modifications of 2b-carbomethoxy-3b-phenyl tropane analogues were evaluated on in vitro
affinity to the dopamine (DAT) and serotonin (5-HTT) transporters in rat brain tissue. The introduction of a large alkyl group at
the 40-position of the phenyl ring, affording 2b-carbomethoxy-3b-(40-alkylphenyl) tropane, diminished the affinity for the DAT
whereas moderate 5-HTT affinity was obtained. The introduction of an iodine at the 30-position of the 40-alkylphenyl, affording 2b-
carbomethoxy-3b-(30-iodo-40-alkylphenyl) tropane, and N-demethylation, affording 2b-carbomethoxy-3b-(30-iodo-40-alkylphenyl)
nortropane, improved affinity and specificity for the 5-HTT. It could be assumed from these results that the combination of these
three modifications of tropane structure yielded highly selective compounds for the 5-HTT. Of the new compounds synthesized, the
most selective cocaine derivative, 2b-carbomethoxy-3b-(30-iodo-40-isopropylphenyl) nortropane (8d) labeled with iodine-123 or
carbon-11, could be a potential ligand for exploration of the 5-HT transporter by SPET or PET. # 2001 Published by Elsevier
Science Ltd.
Introduction
degenerative disorders such as Alzeihmer’s disease, the
The serotonin transporter (5-HTT) plays a major role in
the regulation of synaptic serotonin levels. The sero-
tonin system is involved in several neurologic and
psychiatric disorders,1,2 but its precise role in these dis-
eases remains to be clarified. Although several findings
have shown that disturbances in serotoninergic activity
could be a major etiological factor in depression, it is
still unclear whether the fundamental defect is at the
presynaptic or postsynaptic level, or both.3 In neuro-
5-HTT may serve as a marker for the degeneration of
5-HT neurons, as its distribution closely follows that
of 5-HT nerve endings.4 In vivo exploration of the
5-HTT by positron emission tomography (PET) or
single photon emission tomography (SPET) would
therefore greatly improve understanding of changes in
the 5-HT system occurring in disease, and also help
in the diagnosis and therapeutic follow-up of these
diseases.
*Corresponding author. E-mail: emond@univ-tours.fr
0968-0896/01/$ - see front matter # 2001 Published by Elsevier Science Ltd.
PII: S0968-0896(01)00083-9

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P. Emond et al. / Bioorg. Med. Chem. 9 (2001) 1849–1855
The natural (ꢀ) isomer of cocaine (1) is well known to
interact with dopamine, serotonin and norepinephrine
transporters (DAT, 5-HTT and NET) with slight DAT
selectivity.5 Several attempts have been made in recent
years to obtain cocaine derivatives with enhanced affinity
and selectivity for one of these monoamine transporters.
As the introduction of an alkyl or an iodine on the
phenyl group and N-demethylation of the tropane
structure markedly influence the binding properties at
the 5-HTT, we evaluated whether the combination of
these substitutions would yield compounds with high
affinity and specificity for the 5-HTT. We report the
synthesis of tropane and nortropane derivatives with the
general structure 5 and in vitro binding properties at the
DAT and the 5-HTT.
The substitution of the benzoyl group of cocaine by a
40-iodinated phenyl at the 3b position of the tropane
structure leads to 2b-carbomethoxy-3b-(40-iodophenyl)
tropane, also called b-CIT (2), a compound with high
binding affinity for the DAT and the 5-HTT.6 In the
research for high specific radioligands for exploration of
the DAT by SPET, several b-CIT analogues differently
substituted on the nitrogen or phenyl ring have been
investigated. Among them, N-(3-iodoprop-2-enyl)-2b-
Results
Chemistry
All compounds described, were prepared as outlined in
Scheme 1 using ecgonidine methyl ester as starting
material. Compounds 6a–e were obtained by 1-4
Michael addition on ecgonidine methyl ester with the
corresponding Grignard reagent, as previously descri-
bed.16 Iodination of the aromatic ring of compounds
6a–e was carried out using a mixture of yellow mercuric
oxide, perchloric acid and acetic acid.11 The structure
assignments of compounds 7a–e were elucidated by
NMR hydrogen carbon three-bond correlation which
exhibits interaction between only one aromatic hydro-
gen and the first carbon of the alkyl group linked to the
phenyl ring. Moreover, correlation between the carbon
3 of the tropane structure and two aromatic hydrogens
corroborates these assignments. Compounds 8a–e were
prepared by N-demethylation of compounds 7a–e. This
reaction involved the formation of the corresponding
carbamate using 2,2,2-trichloroethylchloroformate, fol-
lowed by treatment with a Zn–acetic acid mixture
according to previously reported procedures.17
carbomethoxy-3b-(40-substitutedphenyl)
nortropane
derivatives with a chlorine (IPT), fluorine (Altropane)
or methyl (PE2I) as substituant exhibit high affinity and
selectivity for the DAT.7ꢀ10 As appropriate structural
modifications on b-CIT lead to high affinity and selec-
tive compounds for the DAT, it might be assumed that
other structural modifications could afford compounds
with high affinity and selectivity for the 5-HTT.
Boja et al.11 first reported that the N-demethylation of
2b-carbomethoxy-3b-(40-substituted phenyl) tropane
derivatives leads to compounds (3) with enhanced affi-
nity for the 5-HTT and no significant change in affinity
for the DAT; for example the N-demethylated analogue
of b-CIT (nor-b-CIT) is 10 times more selective for the
5-HTT than b-CIT.11 Although nor-b-CIT retains good
affinity for the DAT, its use has been proposed to
explore the 5-HTT distribution in vivo in humans.12,13
Moreover, nor-b-CIT derivatives in which iodine is
replaced by alkyl, alkenyl or alkynyl groups show
higher affinity for the 5-HTT than their N-methylated
analogues.14 These results confirm that N-demethyla-
tion of the tropane structure yield compounds with
enhanced affinity for the 5-HTT.
In vitro binding assays
Affinity of the described compounds for monoamine
transporters was determined by in vitro competitive
binding assays. [3H] GBR-12935 and [3H] paroxetine
were used as specific ligands for the DAT and 5-HTT
sites, respectively. The results are expressed as inhibition
constants and are summarized in Table 1.
Blough et al. recently reported the synthesis of a nor-
tropane structure with an iodine and an ethyl at the 30
and 40 position of the phenyl ring, respectively: 2b-carbo-
methoxy-3b-(30-iodo-40-ethylphenyl) nortropane (4,
EINT).15 This compound presents high affinity and
specificity for the 5-HTT in vitro. In addition EINT
inhibits the in vivo accumulation of [125I]-b-CIT in rat
cerebral regions known to be rich in 5-HTT such as the
hypothalamus and thalamus.
Discussion
The cocaine derivative b-CIT, which binds with high
affinity to the DAT and the 5-HTT has been used to

P. Emond et al. / Bioorg. Med. Chem. 9 (2001) 1849–1855
1851
Scheme 1. Synthesis of tropane and nortropane analogues.
Table 1. Ki values in displacing binding of [3H] GBR-12935 and [3H] Paroxetine in rat brain membranes
Affinity (Ki, nM)
Selectivity
5-HTT
Compound
R1
R2
X
DAT
DAT/5-HTT
6a
7a
8a
6b
7b
8b
6c
7c
8c
6d
7d
8d
6e
7e
8e
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
CH3
CH2CH3
CH2CH3
CH2CH3
H
I
I
H
I
I
H
I
I
H
I
I
32ꢁ4
46ꢁ6
>500
<0.1
0.6
3.6
>14.3
17.5
17.5
>2.1
>1.6
>7.4
>1.8
>12.8
>20.0
>4.0
>2.6
>8.8
80ꢁ17
111ꢁ25
31ꢁ2
>500
35ꢁ10
19ꢁ3
333ꢁ75
263ꢁ55
15ꢁ8
CH2CH2CH3
CH2CH2CH3
CH2CH2CH3
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
>500
239ꢁ47
316ꢁ13
70ꢁ21
275ꢁ35
39ꢁ5
>500
>500
>500
>500
>500
>500
25ꢁ6
CH3
CH3
H
H
I
I
126ꢁ37
135ꢁ31
57ꢁ8
352ꢁ22
>500
explore these monoamine transporters by PET or
SPET.13,18 In order to improve the selectivity for the
5-HTT, several groups have explored the effects of
structural modifications on tropane. In particular N-
demethylation, the introduction of an alkyl group at the
40 position and an iodine atom at the 30 position of the
phenyl ring have been shown to affect the binding prop-
erties of such compounds to DAT and 5-HTT.11,14,15,19
It is hypothesized that the combination of these sub-
stitutions could improve affinity and specificity for the
5-HTT. The binding study of test compounds 6a–e
which were N-methylated and 40-phenyl substituted by
alkyl groups show that only 6a (R2=CH3) had moder-
ate affinity for the DAT (Ki=32 nM) whereas the Ki
values of test compounds 6b–e were higher than 500 nM.
In contrast, 6a exhibited weak affinity for the 5-HTT
(>500 nM) whereas 6b–e presented moderate to low
affinity (Ki=35–275 nM). From these results it may be
concluded that the DAT binding site does not tolerate
an alkyl substituent at the phenyl ring which is larger
than a methyl group. In contrast, the 5-HTT binding
site seems to accommodate larger alkyl groups in this

1852
P. Emond et al. / Bioorg. Med. Chem. 9 (2001) 1849–1855
position. These results comply with the DAT pharma-
cophore model proposed by Carroll et al., which
associates large steric bulk around the aryl ring with
decreased DAT ligand affinity.20 However, it has to be
emphasized that high affinity for both DAT and 5-HTT
was obtained for 40-unsaturated substituants such as
vinyl, isopropenyl, (E/Z) propenyl, ethynyl or propy-
nyl.14 Thus, in contrast to 40-unsaturated substituants,
the introduction of large alkyl group at the 40-position of
the tropane phenyl ring inhibits DAT binding, affording
an increase in 5-HTT specificity.
lead to compounds with good affinity and selectivity for
the 5-HT transporter site, has thus been confirmed. In
view of the in vitro results, compounds 8b and 8d
labeled with iodine-123 or carbon-11 could be useful
ligands for scintigraphic exploration of the 5-HTT.
Evaluation of these compounds in non-human primates
is currently being performed.
Experimental
NMR spectra were recorded on a Bruker DPX Avance
200 spectrometer (200 MHz for H, 50.3 MHz for 13C).
The introduction of the iodine atom at the 30 position
(7a–e) on the whole seem does not influence the affinity
at the DAT site to any great extend when compared to
compounds 6a–e. On the other hand, although no
increase in 5-HTT binding potency was observed for
compounds 7c and 7e, compounds 7a, 7b, and 7d pre-
sented 2- to 7-fold higher 5-HTT binding potency com-
pared to non-iodinated derivatives 6a, 6b, and 6d. F or
2b-carbomethoxy-3b-phenyl tropane (WIN 35,065-2)
and its iodinated analogue 2b-carbomethoxy-3b-(30-
iodophenyl) tropane (RTI-92),15 similar results have
been observed; while RTI-92 and WIN 35,065-2 are
equipotent at the DAT (26 and 33 nM), the affinity of
RTI-92 at the 5-HTT is ca. 50-fold higher than for WIN
35,065-2 (38.8 vs 2000 nM). These findings lead to the
conclusion that the introduction of an iodine on the
phenyl ring of the tropane structure can contribute to
enhancement of 5-HTT affinity and selectivity compared
to DAT.
1
CDCl3 was used as solvent; chemical shifts are expres-
sed in ppm relative to TMS as an internal standard.
Mass spectra were obtained on a CG–MS Hewlett
Packard 5989A spectrometer (electronic impact at 70
eV). The thin-layer chromatographic (TLC) analyses
were performed using Merck 60F-254 silica gel plates.
Flash chromatography was used for routine purification
of reaction products using silica gel (230–400 mesh).
Visualization was accomplished under UV or in an
iodine chamber. All chemicals and solvents were of
commercial quality and were purified following
standard procedures.
Chemistry general procedure of synthesis of 2ꢀ-
carbomethoxy-3ꢀ-(30-iodo-40-substituted phenyl) tropane
(7a-e)
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-methylphenyl) tropane
7a. 2b-carbomethoxy-3b-40-tolyl tropane 6a (1 g, 3.65
mmol) was dissolved in a mixture of acetic acid (12.5
mL), perchloric acid (4.2 mL) and mercuric oxide yel-
low (790 mg, 3.66 mmol). A solution of iodine (2.32 g,
9.15 mmol) in a mixture of CH2Cl2 (33.3 mL) and acetic
acid (16.8 mL) was added dropwise. The reaction was
stirred at room temperature overnight. The solid was
separated by filtration and the filtrate was diluted with
H2O (16.8 mL) and CH2Cl2 (33.3 mL) and cooled in an
ice bath. The mixture was basified with concentrated
NH4OH. The organic layer was separated and the aqu-
eous layers were extracted with CH2Cl2 (3ꢂ30 mL). The
crude product was purified by flash-chromatography
(hexane/AcOEt/Et3N, 70/20/10) to give 580 mg (40%,
As the introduction of an alkyl group at the 40 position
and an iodine at the 30 position of the aromatic ring
enhance the affinity and the specificity of tropane struc-
tures for the 5-HTT overall, we synthesized compounds
8a–e in order to assess whether N-demethylation would
increase 5-HTT affinity and selectivity. The rank order
of 5-HTT affinity is ethyl (8b) > isopropyl (8d) >
methyl (8a) > butyl (8e) > propyl (8c). Except for the
40-ethyl analogue (8b), which exhibited the same 5-HTT
affinity as 7b, other 2b-carbomethoxy-3b-(30-iodo-40-
substituted phenyl) nortropanes had higher affinity for
the 5-HTT than their N-methyl analogues. These results
corroborate those previously published11,14 and confirm
the hypothesis that N-demethylation results in com-
pounds with enhanced 5-HTT affinity. The best
selectivity and affinity for the 5-HTT are obtained with
N-desmethyl-30-iodophenyl derivatives.
1
1.46 mmol) of a yellow oil. H NMR, d 1.52–1.62 (m,
3H, H-4a, H-6a, H-7a), 1.96–2.10 (m, 2H, H-6b, H-7b),
2.14 (s, 3H, N–CH3), 2.28 (s, 3H, Ph–CH3), 2.43 (td,
3
1H, 3J3ꢀ4b=2J4aꢀ4b=12.6 Hz, J4b-5=3.8 Hz, H-4b),
2.77–2.88 (m, 2H, H-2, H-3), 3.26 (m, 1H, H-5), 3.45 (s,
3
3H, O–CH3), 3.49 (m, 1H, H-1), 7.04 (d, 1H, J=7.9
0
0
3
4
Hz, H-5 ), 7.13 (dd, 1H, J=7.9 Hz, J=1.6 Hz, H-6 ),
Conclusion
7.6 (d, 1H, J=1.6 Hz, H-20); 13C NMR, d 25.1, 25.7,
4
In conclusion, substituted tropane derivatives were syn-
thesized and evaluated for their in vitro affinity for DA
and 5-HT transporters in the rat brain. The introduc-
tion of an alkyl group larger than a methyl at the
40-phenyl position hinders the DAT–ligand interaction,
whereas moderate to high 5-HTT affinity was obtained.
In addition, iodination of the phenyl ring at the
30-position and N-demethylation improved the affinity
and specificity for the 5-HTT. The hypothesis, that the
combination of all these structural modifications might
27.4, 31.8, 33.9, 52.5, 62.0, 65.1, 100.8, 129.1, 137.7, 138.5,
142.5, 171.9; MS m/z 399 (M+, 9), 97 (34), 96 (37), 83
(100), 82 (79), 42 (30). Anal. calcd for C17H22INO2: C,
51.14; H, 5.55; N, 3.51. Found: C, 51.22; H, 5.51; N, 3.52.
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-ethylphenyl)
tropane
7b. Compound 7b was prepared from 6b (650 mg, 2.27
mmol) to give an oil (310 mg, 34%) after purification by
flash chromatography (hexane/AcOEt/Et3N, 50/50/2);
3
1H NMR, d 1.09 (t, 3H, J=7.5 Hz, CH3–CH2), 1.44–

P. Emond et al. / Bioorg. Med. Chem. 9 (2001) 1849–1855
1853
1.69 (m, 3H, H-4a, H-6a, H-7a), 1.83–2.04 (m, 2H, H-
6b, H-7b), 2.14 (s, 3H, N–CH3), 2.44 (td, 1H,
20); 13C NMR, d 13.8, 22.3, 25.1, 25.7, 32.3, 32.9, 33.9,
39.9, 41.8, 51.1, 52.5, 62.1, 65.2, 100.3, 127.2, 128.5,
138.2, 142.4, 142.6, 171.9; MS m/z = 441 (M+, 5), 410
(1), 382 (2), 97 (33), 96 (33), 83 (100), 82 (76), 42 (28).
Anal. calcd for C20H28INO2: C, 54.43; H, 6.39; N, 3.17.
Found: C, 54.37; H, 6.38; N, 3.19.
3
3J3ꢀ4b=2J4aꢀ4b=12.2 Hz, J4bꢀ5=2.7 Hz, H-4b), 2.59
(q, 2H, J=7.5 Hz, CH2–CH3, 2.77–2.90 (m, 2H, H-2,
3
H-3), 3.27 (m, 1H, H-5), 3.45 (s, 3H, O–CH3), 3.42–3.48
3
0
(m, 1H, H-1), 7.04 (d, 1H, J=8.0 Hz, H-5 ), 7.14 (dd,
1H, J=8.0 Hz, J=1.7 Hz, H-60), 7.58 (d, 1H, J=1.7
Hz, H-20); 13C NMR, d 14.4, 25.1, 25.7, 32.9 , 33.5, 33.9,
41.8, 51.1, 52.5, 62.1, 65.2, 100.1, 127.4, 127.8, 139.2,
142.6, 143.6, 171.9; MS m/z 413 (M+, 7), 97 (33), 96
(34), 83 (100), 82 (77), 42 (28). Anal. calcd for
C18H24INO2: C, 52.31; H, 5.85; N, 3.39. Found: C,
51.49; H, 5.89; N, 3.41.
3
4
4
General procedure of synthesis of 2ꢀ-carbomethoxy-3ꢀ-
(30iodo-40substituted phenyl) nortropane (8a–e). Com-
pounds 8a–e have been prepared from compounds 7a–e
as described previously.9
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-tolyl) nortropane 8a.
Compound 8a was prepared from 7a (223 mg,
0.56 mmol) to give an oil (102 mg, 47%) after purifica-
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-n-propylphenyl) tropane
7c. Compound 7c was prepared from 6c (500 mg, 1.66
mmol) to give an oil (340 mg, 48%) after purification by
flash chromatography (hexane/AcOEt/Et3N, 60/40/2);
1
tion by flash chromatography (AcOEt/Et3N: 75/5); H
NMR, d 1.42–1.68 (m, 3H, H-4a, H-6a, H-7a), 1.83–
2.00 (m, 2H, H-6b, H-7b), 2.15–2.29 (td, 1H,
3
3
1H NMR, d 0.95–1.03 (t, 3H, J=7.3 Hz, CH3–CH2),
3J3ꢀ4b=2J4aꢀ4b=13.0 Hz, J4bꢀ5=2.9 Hz, H-4b), 2.26
3
1.52–1.72 (m, 5H, H-4a, H-6a, H-7a, CH3–CH2), 2.10–
2.24 (m, 2H, H-6b, H-7b), 2.24 (s, 3H, N–CH3), 2.54
(s, 3H, Ph–CH3), 2.59 (dd, 1H, J2ꢀ3=5.7 Hz,
3J2ꢀ1=1.9 Hz, H-2), 3.04 (dt, 1H, 3J3ꢀ4b=12.8 Hz,
3
3
(td, 1H , J3ꢀ4b=2J4aꢀ4b=12.2 Hz, J4bꢀ5=2.7 Hz, H-
3J2ꢀ3=3J3ꢀ4a=5.7 Hz, H-3), 3.32 (s, 3H, O–CH3), 3.59
(m, 2H, H-1, H-5), 6.96 (dd, 1H, J=7.8 Hz, J=1.9
3
3
4
4b), 2.64 (t, 2H, J=7.7 Hz, Ph–CH2), 2.87–2.97 (m,
2H, H-2, H-3), 3.37 (m, 1H, H-5), 3.54 (s, 3H, O–CH3),
3.54–3.58 (m, 1H, H-1), 7.11 (d, 1H, J=7.9 Hz, H-50),
Hz, H-60), 7.02 (d, 1Har, J=7.8 Hz, H-50), 7.51 (d,
3
1Har, J=1.9 Hz, H-20); 13C NMR, d 27.4, 27.6, 29.0,
3
4
7.20 (dd, 1H, 3J=7.9 Hz, 4J=1.7 Hz, H-60), 7.68 (d, 1H,
4J=1.7 Hz, H-20); 13C NMR, d 13.8, 23.3, 25.1, 25.7,
32.9, 33.9, 41.9, 42.2, 51.1, 52.5, 62.1, 65.2, 100.4, 127.1,
128.6, 138.2, 142.3, 142.6, 171.9; MS m/z 427 (M+, 8),
97 (38), 96 (37), 83 (100), 82 (81), 42 (30). Anal. calcd
for C19H26INO2: C, 53.40; H, 6.13; N, 3.28. Found: C,
53.54; H, 6.19; N, 3.31.
33.7, 34.8, 50.9, 51.1, 53.5, 56.2, 101.0, 127.0, 129.3,
137.8, 139.3, 141.8, 173.6; MS m/z 385 (M+, 13), 141
(10), 83 (93), 82 (55), 69 (100), 68 (74). Anal. calcd for
C16H20INO2: C, 49.88; H, 5.23; N, 3.64. Found: C,
50.03; H, 5.22; N, 3.63.
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-ethylphenyl) nortropane
8b. Compound 8b was prepared from 7b (230 mg, 0.56
mmol) to give an oil (81 mg, 37%) purification by after
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-isopropylphenyl) tropane
7d. Compound 7d was prepared from 6d (440 mg, 1.46
mmol) to give an oil (475 mg, 76%) after purification by
1
flash chromatography (AcOEt/Et3N, 75/25); H NMR,
3
d
1.08 (t, 3H, J=7.5 Hz, CH3–CH2), 1.41–1.71 (m,
1
flash chromatography (Et2O/Et3N, 95/5); H NMR, d
3H, H-4a, H-6a, H-7a), 1.86–2.03 (m, 2H, H-6b, H-7b),
1.10 [d, 6H, 3J=6.8 Hz, CH(CH3)2], 1.55 (m, 3H, H-4a,
H-6a, H-7a), 2.07 (m, 2H, H-6b, H-7b), 2.14 (s, 3H, N–
CH3), 2.44 (td, 1H, 2J4aꢀ4b=3J3ꢀ4b=12.2 Hz,
3J4bꢀ5=2.7 Hz, H-4b), 2.83 (m, 2H, H-2, H-3), 3.02 (sp,
2.25 (td, 1H, J3ꢀ4b=2J4aꢀ4b=13.0 Hz, J4bꢀ5=3.0 Hz,
3 3
3
H-4b), 2.56 (q, 2H, J=7.5 Hz, CH3–CH2), 2.53–2.65
(m, 2H, N–H, H-2), 3.07 (dt, 1H, 3J3ꢀ4b=13.0 Hz,
3J2ꢀ3=3J3ꢀ4a=5.5 Hz, H-3), 3.33 (s, 3H, O–CH3), 3.42–
3.48 (m, 1H, H-1), 3.62 (m, 2H, H-1, H-5), 6.97 (s,
2Har), 7.3 (s, 1Har); 13C NMR, d 14.4, 27.6, 29.0, 33.5,
33.7, 34.8, 50.9, 51.0, 53.5, 56.2, 100.2, 127.3, 128.0,
138.2, 141.8, 144.5, 173.6; MS m/z 399 (M+, 12), 368
(2), 340 (2), 141 (12), 83 (95), 82 (52), 69 (100), 68 (71),
41(9). Anal. calcd for C17H22INO2: C, 51.14; H, 5.55; N,
3.51. Found: C, 50.98; H, 5.56; N, 3.50.
3
1H, J=6.8 Hz, CH(CH3)2], 3.40 (m, 1H, H-5), 3.43 (s,
3
3H, O–CH3), 3.48 (m, 1H, H-1), 7.03 (d, 1H, J=8.1
Hz, H-50), 7.17 (dd, 1H, J=8.1 Hz, J=1.7 Hz, H-60),
3
4
7.58 (d, 1H, J=1.7 Hz, H-20) ; 13C NMR, d 23.7, 25.8,
4
26.4, 33.7, 34.6, 38.2, 42.6, 51.7, 53.1, 62.8, 65.9, 101.5,
125.8, 128.2, 139.1, 143.3, 148.2, 172.5 ; MS m/z 427
(M+, 8), 396 (1), 368 (3), 97 (38), 96 (41), 83 (100), 82
(91). Anal. calcd for C19H26INO2: C, 53.40; H, 6.13; N,
3.28. Found: C, 53.51; H, 6.17; N, 3.21.
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-n-propylphenyl) nortro-
pane 8c. Compound 8c was prepared from 7c (200 mg,
0.47 mmol) to give an oil (120 mg, 53%) after purifica-
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-n-butylphenyl) tropane
7e. Compound 7e was prepared from 6e (1 g, 3.17
mmol) to give an oil (275 mg, 21%) after purification by
1
tion by flash chromatography (AcOEt/Et3N, 90/10); H
3
NMR, d 0.89 (t, 3H, J=7.3 Hz, CH3–CH2), 1.46–1.66
1
flash chromatography (hexane/Et3N, 90/10): H NMR,
3
(m, 5H, H-4a, H-6a, H-7a, CH3–CH2), 1.98–2.02 (m,
3
d 0.98 (t, 3H, J=7.2 Hz, CH3–CH2–), 1.25–1.77 (m,
2H, H-6b, H-7b), 2.27 (td, 1H , J3ꢀ4b=2J4aꢀ4b=12.4
3
7H, H-4a, H-6a, H-7a? CH3–CH2–CH2), 2.05–2.30 (m,
2H, H-6b, H-7b), 2.28 (s, 3H, N–CH3), 2.58 (td, 1H,
Hz, J4bꢀ5=3.0 Hz, H-4b), 2.47 (broads, 1H, N–H),
2.52–2.64 (m, 3H, H-2, Ph–CH2), 3.06 (dt, 1H,
3
3
2J4aꢀ4b=3J3ꢀ4b=12.0 Hz, J4bꢀ5=2.5 Hz, H-4b), 2.68
3J3ꢀ4b=14.0 Hz, J2ꢀ3=3J3ꢀ4a=6.2 Hz, H-3), 3.34 (s,
(t, 2H, 3J=7.9 Hz, Ph–CH2), 2.89–3.00 (m, 2H, H-2, H-
3), 3.39 (m, 1H, H-5), 3.56 (s, 3H, O–CH3), 3.60 (m, 1H,
3H, O–CH3), 3.61–3.63 (m, 2H, H-1, H-5), 7.02 (s,
2Har), 7.54 (s, 1Har); 13C NMR, d13.6, 23.2, 27.5, 28.9,
33.6, 34.8, 42.1, 50.8, 51.1, 53.5, 56.2, 100.7, 127.1,
128.6, 128.9, 142.7, 144.2, 174.4. Anal. calcd for
0
3
H-1), 7.12 (d, 1Har, J=8.2 Hz, H-5 ), 7.23 (dd, 1Har,
4
3J=8.0 Hz, J=1.2 Hz, H-60), 7.56 (d, J=1.6 Hz, H-
4

1854
P. Emond et al. / Bioorg. Med. Chem. 9 (2001) 1849–1855
C18H24INO2: C, 52.31; H, 5.85; N, 3.39. Found: C,
52.38; H, 5.84; N, 3.38.
nM (Kd=0.5 nM), 0.1 mL of competitors at various
concentrations ranging from 10ꢀ5 to 10ꢀ10 M and 0.5 mL
containing 70 g of membrane protein preparation in a total
volume of 2 mL. Samples were incubated at 22 ꢃC for 1 h,
filtered and treated as described for DAT assays. Non-
specific binding was determined with 10ꢀ6 M fluvoxamine
(a gift from Duphar). Ki values were calculated from IC50
values according to the method of Cheng and Prussoff:23
Ki=IC50 / [1+(L/Kd)] where L is the tracer concentration
and Kd the dissociation constant of this tracer.
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-isopropylphenyl) nortro-
pane 8d. Compound 8d was prepared from 7d (200 mg,
0.47 mmol) to give an oil (140 mg, 72%) after purifica-
1
tion by flash chromatography (AcOEt/Et3N, 90/10); H
3
NMR, d 1.12 [d, 6H, J=6.8 Hz, CH (CH3)2), 1.64 (m,
3H, H-4a, H-6a, H-7a), 1.98 (m, 2H, H-6b, H-7b), 2.27
3
2
(td, 1H, J4bꢀ5=2.6 Hz, J4aꢀ4b=3J3ꢀ4b=12.8 Hz, H-
4b), 2.63 (m, 1H, H-2), 3.05 [m, 3H, H-3, N–H, CH
(CH3)2], 3.34 (s, 3H, O–CH3), 3.64 (m, 2H, H-1, H-5),
7.06 (s, 2Har), 7.55 (s, 1Har); 13C NMR, d 23.7, 28.2,
29.6, 34.3, 35.5, 38.2, 51.5, 51.7, 54.2, 56.9, 101.6, 126.1,
128.1, 139.0, 142.5, 149.1, 174.3; MS m/z 413 (M+ , 10),
382 (1), 354 (2), 141 (13), 83 (92), 82 (57), 80 (11), 69
(100), 68 (94), 43 (20), 41 (26). Anal. calcd for
C18H24INO2: C, 52.31; H, 5.85; N, 3.39. Found: C,
52.13; H, 5.83; N, 3.39.
Acknowledgements
This work was supported by the Region Centre, Poˆ le
´
GBM and INSERM. We thank SAVIT for NMR and
MS analyses, M. C. Furon for technical assistance, and
Doreen Raine for editorial assistance with the English
language.
2ꢀ-Carbomethoxy-3ꢀ-(30-iodo-40-n-butylphenyl) nortro-
pane 8e. Compound 8e was prepared from 7e (200 mg,
0.45 mmol) to give an oil (91 mg, 47%) after purifica-
tion by flash chromatography (Et2O/Et3N, 75/25Ac);
References and Notes
3
1H NMR, d 0.96 (t, 3H, J=7.2 Hz, CH3–CH2–), 1.27–
1.78 (m, 7H, H-4a, H-6a, H-7a, CH3–CH2–CH2), 1.90–
2.17 (m, 2H, H-6b, H-7b), 2.35 (td, 1H,
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