Synthesis and binding affinities of 2β-(3-iodoallyloxycarbonyl)-3β-(4-substituted-aryl)tropane analogues as ligands for the dopamine transporter studies

Article abstract of DOI:10.1016/S0960-894X(01)00625-4

Tropane analogues from cocaine, which is known to be one of the most reinforcing and addictive compounds, were designed, synthesized, and characterized for inhibition of presynaptic uptake of dopamine (DA) in brain. Eight new derivatives of 3β-aryl-2β-(3-iodoallyloxycarbonyl)tropanes were synthesized and tested for their potential abilities to displace [³H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428) binding to the rat striatal membranes.

Full text of DOI:10.1016/S0960-894X(01)00625-4

Bioorganic & Medicinal Chemistry Letters 11 (2001) 3077–3080
Synthesis and Binding Affinities of 2ꢀ-(3-Iodoallyloxycarbonyl)-
3ꢀ-(4-substituted-aryl)tropane Analogues as Ligands for the
Dopamine Transporter Studies
Kyoo-Hyun Chung,a,* Choong Hwan Lim,a Dong Reyoul Lee,b Changbae Jinc
and Dae Yoon Chia,b,
*
aDepartment of Chemistry, Inha University, 253 Yonghyundong, Namgu, Inchon, 402-751, Republic of Korea
bFuture Chem. Co., 253 Yonghyundong, Namgu, Inchon, 402-751, Republic of Korea
cBioanalysis & Biotransformation Research Center, Korea Institute of Science and Technology, PO Box 131, Cheongryang
Seoul, 130-650, Republic of Korea
Received 1 June 2001; accepted 18 September 2001
Abstract—Tropane analogues from cocaine, which is known to be one of the most reinforcing and addictive compounds, were
designed, synthesized, and characterized for inhibition of presynaptic uptake of dopamine (DA) in brain. Eight new derivatives of
3b-aryl-2b-(3-iodoallyloxycarbonyl)tropanes were synthesized and tested for their potential abilities to displace [3H]2b-carbo-
methoxy-3b-(4-fluorophenyl)tropane (WIN 35,428) binding to the rat striatal membranes. # 2001 Elsevier Science Ltd. All rights
reserved.
R-Cocaine (1), well known as an addictive drug,1 is a
plant alkaloid purified from the leaves of Erythroxylon
coca. It is known that many cocaine analogues have
high binding affinity for the dopamine transporter
(DAT).2 In addition, the fact that the density of DAT
decreases with the progress of Parkinson’s disease (PD)
calls for the development of PD diagnostic radio-
pharmaceuticals. Noninvasive imaging of the loss of
DAT using a series of cocaine analogues such as
[methyl-11C]CFT (2, [methyl-11C]2b-carbomethoxy-3b-
(4-fluorophenyl)tropane, WIN 35,428),3 [123I]b-CIT (3,
of the mode of action of cocaine has improved drama-
tically. Among them, I-123 labeled b-CIT and IPT are
used in clinical diagnosis for Parkinson’s disease
patients. Many structure–activity data concerning the
substituents at the C2 position of cocaine have already
been disclosed in previous publications.7
Iodoallyl groupof IPT has been used as a bioisoster of
methyl groupfor the introduction of radionucleus iodine.
The goals of the present investigation were to synthesize
E- and Z-iodoallyl ester instead of 2b-carbomethoxy
substituent and to find out the SAR of E- and Z-isomers
with the modification of para position of 3b-phenyl
group.
[
123I]2b-carbomethoxy-3b-(4-iodophenyl)tropane, RTI-
55),4
[
123I]IPT (4, [123I]N-((E)-3-iodopropen-1-yl)-2b-
carbomethyoxy-3b-(4-chlorophenyl)nortropane),5 and
TRODAT6 has recently been achieved by the use of
positron emission tomography (PET) and single photon
emission computed tomography (SPECT).
Indeed, considerable research efforts have been made to
understand the chemistry and the pharmacology of this
cocaine. From the structure–activity relationship(SAR)
of the several hundred cocaine derivatives, the knowledge
*Corresponding author. Tel.: +82-32-860-7686; fax: +82-32-867-
5604; e-mail: dychi@inha.ac.kr
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00625-4

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K.-H. Chung et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3077–3080
Table 1. Structures and binding affinities of the 3b-aryl-2b-(3-iodoallyl ester)tropanes for the dopamine transportera
Compd
IC50 (nM)
MeanꢁSEMa
Compd
IC50 (nM)
MeanꢁSEMb
IC50 (E)/ IC50 (Z)
12Ea
875.9ꢁ73.9
12Za
308.1ꢁ97.9
2.84
12Eb
12Ec
12Ed
46.6ꢁ18.6
566.6ꢁ164.6
189.9ꢁ105.8
12Zb
12Zc
12Zd
4
24.9ꢁ9.0
356.3ꢁ97.1
39.2ꢁ17.3
6.1ꢁ2.1
1.87
1.59
4.84
1
2
510.6ꢁ108.0
149.4ꢁ1.4
aThe inhibition of [3H]WIN 35,428 binding to rat striatal synaptic membranes was measured using 3 nM [3H]WIN 35,428 and 13 concentrations of
the test compounds between 10ꢀ12 and 10ꢀ4 M. Nonspecific binding was defined as that determined in the presence of 100 mM (ꢀ)-cocaine.
bThe values represent meanꢁstandard error of three separate experiments done in duplicate.
et al.12 with slight modifications using crude synaptic
membranes prepared from the rat striatum.13 Competi-
Chemistry
The structures of compounds selected for the synthesis
and binding data on the dopamine transporter are
shown in Table 1. All compounds described herein were
prepared from natural (R)-cocaine, and therefore they
have the same absolute configuration as (R)-cocaine.
Compound 5 were prepared from cocaine based on the
previous reports.8 According with Carroll’s modifica-
tion9 of the original procedure of Clarke et al.,10 the 3b-
intermediate WIN analogues 6a–d were synthesized in
52% yield with 3a-isomers (26%) as shown in Scheme 1.
Transesterification from methyl to tributylstannylallyl
group was conducted step-by-step by sponification, for-
mation of acid chloride using oxalyl chloride, and ester-
ification with (E)- and (Z)-allyl alcohol 9 and 10. (E)- and
(Z)-3-(tri-n-butylstannyl)allyl alcohols (9 and 10) were
prepared from propargyl alcohol (8) in 56% yield with 3:1
ratio of E/Z from by the method by Jung11 (Scheme 2).
tion binding assays were performed to measure the
concentrations of test compounds which inhibited the
specific binding by 50% (IC50 values) using 3 nM
[3H]WIN 35,428 and 13 concentrations of the unlabelled
compounds between 10ꢀ12 and 10ꢀ4 M. Nonspecific
binding was defined as that determined in the presence
of 100 mM (ꢀ)-cocaine. IC50 values were determined
from the competition binding data using computer-
assisted curve fitting with GraphPad Prism 3.0 program.
Table 1 illustrates the in vitro binding affinities of 12Ea–
d and 12Za–d for the dopamine transporter of rat
striatal membranes, including (ꢀ)-cocaine, b-CFT, and
IPT.
Discussion
Recently, the goals of research and the summary of
results regarding C2 modification of cocaine were well
described.2a There are several reports that for the basic
nitrogen and a hydrogen bond of 2b-carbomethoxy
In vitro dopamine transporter binding studies
Binding of [3H]WIN 35,428 to the dopamine transpor-
ter was measured according to the method of Madras

K.-H. Chung et al. / Bioorg. Med. Chem. Lett. 11 (2001) 3077–3080
3079
lipophilicity of hydrophobic alkyl chain may dramati-
cally dropa binding affinity; compound with C2 n-hexyl
chain instead of carbomethoxy is about 128-fold less
potent than the n-butyl analogue. Among 2b-allyloxy-
carbonyl-3b-phenyltropanes, 40-azido-30-iodophenethyl
ester was used for photoaffinity labeling and 40-iso-
thiocyanophenethyl ester was used for conjugation to
solid supporting materials. Thus, bulky ester group at
C2 position were well tolerated without any significant
loss in potency.
We synthesized eight 2b-allyloxycarbonyl-3b-phenyl-
tropanes with E- and Z-3-iodoallyl groupin accordance
with the para position of phenyl group (Table 1). Four
of the compounds showed binding affinities for the
DAT better than parent methyl ester. While, in case of
IPT, E isomer has a better activity than Z isomer, all
Z-isomers of 12 have better binding activities for the
DAT than corresponding E isomers. The ratios of
IC50(E)/IC50(Z) for the same substituents at para position
of 3b-phenyl group are between 1.59 and 4.84.
In summary, when one attaches large groupto tropane
for photoaffinity labeling, conjugation to solid support-
ing materials, fluorescence labeling and even ligand for
0
technetium, the introduction of large groupat 3 -posi-
tion of allyl groupof 2 b-allyloxycarbonyl-3b-phenyl-
tropane as in Z form would be a useful method. More
syntheses of C2 modified tropane derivatives are being
currently pursued.
Scheme 1. Reagents and conditions: (a) 4-X-aryl MgBr (X=H, Cl, F,
CH3), dried Et2O under ꢀ20 ꢂC, 3 h, 68% for 6a (a:b=19:49); 78%
for 6b (a:b=26:52); 72.1% for 6c (a:b=22:50.1); 64% for 6d
(a:b=16:48), (b) dioxane/H2O (1:1), reflux, 2 h, 88% for 7a; 92% for
7b; 88% for 7c; 90.2% for 7d, (c) (COCl)2, dried CH2Cl2, rt, 2 h; (d) 9,
DBU, dried CH2Cl2, overnight; 58% for 11Ea; 63% for 11Eb; 64%
for 11Ec; 62% for 11Ed, (e) 10, DBU, dried CH2Cl2, overnight, 55%
for 11Za; 45% for 11Zb; 62% for 11Zc; 58% for 11Zd; (f) I2, CH2Cl2,
0 ꢂC, 30–60 min, 84% for 12Ea; 86% for 12Eb; 81% for 12Ec; 80% for
12Ed; 85% for 12Za; 84% for 12Zb; 73% for 12Zc; 78% for 12Zd.
Acknowledgements
We are grateful for the support of this work through a
grant from the Korea Science and Engineering Foun-
dation (No. 97-03-01-01-5-L).
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