Design, synthesis and biological evaluation of 7-azatricyclodecanes: Analogues of cocaine

Article abstract of DOI:10.1016/S0960-894X(99)00685-X

The synthesis and biological activity of a series of azatricyclodecane analogues of cocaine are described. All compounds studied in this series exhibit nanomolar potency and good selectivity for the serotonin transporter versus the dopamine transporter. (

Full text of DOI:10.1016/S0960-894X(99)00685-X

Bioorganic & Medicinal Chemistry Letters 10 (2000) 297±300
Design, Synthesis and Biological Evaluation of
7-Azatricyclodecanes: Analogues of Cocaine
Amir P. Tamiz, Miles P. Smith and Alan P. Kozikowski*
Drug Discovery Program, Institute of Cognitive and Computational Science, Georgetown University Medical Center,
3970 Reservoir Road, NW, Washington, DC. 20007-2197, USA
Received 29 October 1999; accepted 6 December 1999
AbstractÐThe synthesis and biological activity of a series of azatricyclodecane analogues of cocaine are described. All compounds
studied in this series exhibit nanomolar potency and good selectivity for the serotonin transporter versus the dopamine transporter.
# 2000 Elsevier Science Ltd. All rights reserved.
The ability of cocaine to bind at the dopamine trans-
porter (DAT) and to inhibit the reuptake of dopamine
(DA) has been implicated in the reinforcing properties
of this drug.1 While cocaine self-administration appears
to be best correlated with its activity at the DAT,
cocaine is also a potent inhibitor of the serotonin
(SERT) and norepinephrine (NET) transporters. In
fact, serotonergic systems have been implicated in
compulsive cocaine seeking behavior (craving), and
5-HT-based agents have been investigated as possible
medications for the treatment of cocaine abuse.2 To
date, a number of potent cocaine analogues have been
synthesized in order to better understand the pharma-
cological properties of this drug.3 However, the precise
binding interaction of these analogues with speci®c
monoamine transporters has been a matter of much
discussion.4,5 Nevertheless, transporter speci®city has
been exploited in order to identify a number of trans-
porter selective inhibitors as therapeutics for the treat-
ment of several neurological disorders including
depression6±9 and Parkinson's disease.10
We have reported recently on the synthesis of a series of
rigid tricyclic tropane analogues in which the con-
formation of the nitrogen lone pair is ®xed by means of
a tether to either the 3- or 2-carbon bridge of the
tropane moiety.11,12 In this work, we demonstrated that
the selectivity of these rigid tropane analogues for the
monoamine transporters inhibitors was in¯uenced by
the orientation of the nitrogen lone pair. Tropane based
compounds with the nitrogen lone pair localized over
the 2-carbon bridge of the tropane ring (front-bridged)
exhibit improved potency and selectivity for the SERT
(Fig. 1). We now describe a facile synthesis of the tri-
cyclic intermediates 11 and 12 (Scheme 1) bearing the
tether to the 2b-position of the tropane moiety. As is
disclosed herein, such compounds can be readily syn-
thesized in enantiomerically pure form starting from
( )-cocaine as the chiral edduct. Data are provided that
reveal these analogues to possess good levels of anity
and selectivity for the SERT (Table 1).
Chemistry
Tricyclic compounds 13±17 were synthesized as depicted
in Scheme 1. Tropanes 3±6 were prepared using known
literature procedures.14 N-demethylation of 3 and 4 was
accomplished in two steps by treatment with ACE
chloride in dichloroethane15 in the presence of proton
sponge (1.5 mol equiv), followed by methanolysis of the
Figure 1.
*Corresponding author. Tel.: +1-202-687-0686; fax: +1-202-687-
0617; e-mail: kozikowa@giccs.georgetown.edu
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(99)00685-X

298
A. P. Tamiz et al. / Bioorg. Med. Chem. Lett. 10 (2000) 297±300
Scheme 1. Reagents and conditions: (a) HCl (2 M), re¯ux; POCl3, re¯ux; MeOH, 40 ꢀC; (b) 4-RPhMgBr, (C2H5)2O, 40 ꢀC; TFA, 78 ꢀC; (c)
CH3CH(Cl)OCOCl,1,2-dichloroethane, 1,8-bis-(dimethylamino)naphthalene, re¯ux; MeOH, re¯ux; (d) ethyl bromoacetate, K2CO3, EtOH; (e)
NaH, toluene, 130 ꢀC; (f) aq HCl (10%), re¯ux; (g) Ph3+MeBr , n-BuLi, THF; (h) R1MgBr, CH2Cl2, 0 ꢀC.
resulting carbamate intermediate to a€ord 7 and 8 in
nearly quantitative yields. The resulting tropanes 7 and
8 were then alkylated using ethyl bromoacetate in EtOH
to give the corresponding diesters 9 and 10, respectively
(>60% yield). Treatment of the diesters 9 and 10 with
NaH in re¯uxing toluene gave the ester intermediates
(structure not shown), which were reacted without fur-
ther puri®cation with aq HCl (10%) to give ketones 11
and 12, respectively, in excellent yields.16 Reaction of
the ketone 11 with methylenetriphenylphosphorane
gave tropane 13.12 Reaction of the ketone 11 with
commercially available alkyl or phenyl Grignard
reagents in CH2Cl2 gave tropanes 14±17. Tropanes 14±17
were puri®ed by column chromatography and isolated
as the oxalate salts. The relative stereochemistry of the
isolated products was assigned by NMR methods.17 For
steric reasons, the R1 group is believed to have added to
the less encumbered convex face of the caged ketone 11.
Alcohols 15±17 are more potent at all three transporters
than the ketone 11 from which they were derived. By
simply extending the alkyl appendage of 14 by two car-
bon atoms to give 15, an improvement in the SERT
potency of approximately 4-fold is found, while the
DAT activity remains about the same. Introduction of
the more hydrophobic phenyl substituents as in ana-
logues 16 and 17 leads to a further enhancement in both
the DAT and SERT activity, while the NET activity of
15±17 are roughly comparable. It is also noteworthy to
point out that the introduction of the chlorine atom in
17 slightly improves potency at the DAT while decreas-
ing activity at the NET and SERT in comparison to the
activity found for 16.
We further call attention to the 5-HT/DA transporter
selectivity pro®les exhibited by the front-bridged tro-
pane 15 in comparison to the back-bridged tropane
18.11,13 The noted 5-HT selectivity of 15 is presumably
the result of the stereochemistry of the nitrogen lone
pair, with the SERT exhibiting preference for the
front bridge. By ®xing the direction of the nitrogen lone
pair in the opposite direction as in 18, the tropane
shows selectivity for the DAT. The preference of front-
bridged tropanes for the SERT is thus not altered by
the presence of the sp3 center bearing a hydroxyl group
(Fig. 2).
Structure±Activity Relationships
All ®nal compounds were tested by the Cocaine Treat-
ment Discover Program (CTDP) of the National Institute
of Drug Abuse (NIDA) for their e€ects on [3H]DA,
[3H]NE, and [3H]5-HT uptake in HEK cells expressing
cDNA for the human dopamine, norepinephrine, and
serotonin transporters.18 The transporter activity and
selectivity are provided in Table 1. All of the com-
pounds tested in this series generally exhibit a greater
potency for inhibition of the SERT compared to their
ability to inhibit the DAT. In two cases (13 and 15), the
activity at the NET is better than that measured at the
SERT. While the methylene bearing tricycle 13 is more
potent than the ketone 11 from which it was derived, it
shows poorer selectivity for the SERT in comparison to
the DAT.
In conclusion, a facile synthetic pathway for the con-
struction of 7-azatricyclodecanones is reported. The
chemistry allows for rapid access to cocaine analogues
with a spatially de®ned nitrogen lone pair. The inter-
mediate 7-azatricyclodecanones are readily functional-
ized using standard chemical transformations to
prepare a novel series of compounds with combined
SERT+NET selectivity, and with potencies of <50 nM.
The present work thus broadens the scope of structures
that can be used to better understand the structural
motifs required to achieve potency and selectivity at
speci®c monoamine transporters.
With the exception of compound 14, the alcohols 15±17
exhibit reasonably good SERT potency (IC50 <50 nM).

A. P. Tamiz et al. / Bioorg. Med. Chem. Lett. 10 (2000) 297±300
299
Table 1. IC50 values for the inhibition of monoamine uptake at the respective transporters (nM)a
[3H]DA uptake
[3H]NE uptake
[3H]5-HT uptake
413‹81
5-HT
DA
5-HT
DA
Compd no.
Cocaine
Structure
Ð
301‹50
186‹225
1.4
2.2
11
12
538‹47
110‹28
68‹9.9
0.13
0.62
3320‹840
67‹15
620‹250
2.2‹0.3
296‹59
251‹38
33‹4.9
147‹38
0.076
0.49
0.38
0.4
15
b
13b
14
15
390‹180
0.5
373‹73
89‹36
18‹2.4
11‹4.5
41‹9.5
7.9‹1.0
0.11
0.09
2.3
16
17
0.72
44‹8.0
23‹5.7
13‹1.2
0.3
0.57
aNumbers represetnt the mean‹SEM from at least three independent experiments, each conducted with at least two determinations.
bSee ref 13.
Figure 2.
Acknowledgement
2. Rothman, R. B.; Elmer, G. I.; Shippenberg, T. S.; Rea, W.;
Baumann, M. H. Ann. N.Y. Acad. Sci. 1998, 844, 59±74.
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1999, 42, 2721±2736.
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Parham, K.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. J. Med.
Chem. 1991, 34, 2719±2725.
5. Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar, M. J. In
Drug Design for Neuroscience; Kozikowski, A. P., Ed.; Raven
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259±325.
We are indebted to the NIH, National Institute on Drug
Abuse (DA10458) for support of this work.
References and Notes
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