2beta-Substituted analogues of 4'-iodococaine: synthesis and dopamine transporter binding potencies.

Article abstract of DOI:10.1021/jm980061w

A series of 2beta-substituted analogues of 4'-iodococaine (3) was synthesized and evaluated in an in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2beta-position of 3 gave the carboxylic acid 15 that served as the intermediat

Full text of DOI:10.1021/jm980061w

2380
J . Med. Chem. 1998, 41, 2380-2389
2â-Su bstitu ted An a logu es of 4′-Iod ococa in e: Syn th esis a n d Dop a m in e
Tr a n sp or ter Bin d in g P oten cies
Kwasi S. Avor, Satendra Singh, Thomas W. Seale,† Buddy Pouw, and Garo P. Basmadjian*
Department of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, and Department of Pediatrics, Psychiatry and
Behavioral Sciences, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190
Received J anuary 27, 1998
A series of 2â-substituted analogues of 4′-iodococaine (3) was synthesized and evaluated in an
in vitro dopamine transporter (DAT) binding assay. Selective hydrolysis at the 2â-position of
3 gave the carboxylic acid 15 that served as the intermediate for the synthesis of compounds
4, 5, and 6-11. The 2â-alkyl derivatives were obtained from ecgonine methyl ester (17) through
a series of reactions leading to the aldehyde 20. Wittig reaction of 20 with methyltriphenyl-
phosphorane followed by hydrogenation and benzoylation gave the products 12 and 13. The
binding affinity of 4′-iodococaine (3) was 10-fold less than that of cocaine. The hydroxymethane,
acetate, amide, benzyl ester, oxidazole, and ethane derivatives of 3 exhibited decreased binding
while the vinyl, phenyl, and ethyl esters showed a moderate increase in binding affinity. Only
the isopropyl derivative 8 exhibited a 2-fold increase in binding affinity compared with 4′-
iodococaine (3). Hydroxylation of 8 at the 2′-position gave 14 which enhanced not only the
binding potency at the DAT by another 2-fold but also the selectivity at the DAT over the
norepinephrine and serotonin transporters. Compound 14 failed to stimulate locomotor activity
in C57BL/6J mice over a wide dose range and blocked cocaine-induced locomotor stimulant
action.
In tr od u ction
Cocaine (1, Figure 1), a naturally occurring local
anesthetic first isolated from the coca leaves (Eryth-
roxylon coca) has been recognized to be a potent central
nervous stimulant and binds to specific sites in the
mammalian brain.1-5 The behavioral effects of cocaine
are characterized by reinforcement of responding and
drug seeking,6,7 drug discrimination ability,7,8 and lo-
comotor activity stimulation.9 While cocaine inhibits
the neuronal uptake of dopamine,10 serotonin,11 and
noradrenaline,12 the rewarding properties of cocaine
clearly require activation of the dopaminergic system.
Because of the need to curb the current epidemic of
cocaine usage, considerable effort has been expended to
finding a better understanding of the chemistry and
F igu r e 1.
pharmacology of this drug. Improved understanding of
and transporter selectivities in the phenyltropanes.17-20
the complex neuropharmacological mechanisms under-
Compound 14 was synthesized on the basis of our
lying the addictive action of cocaine6-8 and the limited
observation that 2′-hydroxylation increased binding
success of current therapies for cocaine addiction13 have
affinities of cocaine and 4′-iodococaine to the DAT by
led to the search for direct-acting cocaine antago-
10-11-fold.21
nists.8,14,15
Earlier, we reported that 4′-iodococaine (3, Figure 1)
possessed reduced locomotor activity in mice and re-
Ch em istr y
The synthesis of 4′-iodococaine (3) followed the pub-
lished procedure with some modification.21 Procedures
used for the synthesis of compounds 4-11 are sum-
marized in Scheme 1. Hydrolysis of 3 by refluxing in
water gave 4′-iodobenzoylecgonine (15), which was
reduced with diborane to obtain the 2â-methanol 4. The
alcohol 4 was treated with acetic anhydride to give the
acetate 5. Treatment of 15 with N,N-formyldiimidazole
or oxalyl chloride gave the imidazolide 16a or the acid
chloride 16b, respectively.17 The N-methylamide 6 was
prepared by treating 16a with a mixture of methyl-
amine hydrochloride and sodium carbonate. By treating
duced dose-dependent cocaine-induced locomotor stimu-
lation when coadministered with cocaine.16 Although
the binding potency of 3 was 10-fold less than that of
cocaine, the in vivo biological profile stimulated our
interest in modifying the structure of 4′-iodococaine in
such a way as to obtain analogues that might increase
the binding potency at the dopamine transporter (DAT)
(Figure 2). The choice of different substituents at the
2â-position was based on literature precedence, as these
functionalities have led to improved binding affinities
† Department of Pediatrics, Psychiatry and Behavioral Sciences.
S0022-2623(98)00061-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/23/1998

2â-Substituted Analogues of 4′-Iodococaine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2381
tert-butyldimethylsilyl chloride and imidazole by modi-
fication of a published procedure22 to give the protected
ester 18. The ester 18 was reduced with Dibal-H20 to
give the 2â-methanol 19, which was subjected to Swern
oxidation23 using DMSO and oxalyl chloride in CH2Cl2
at -78 °C to obtain the aldehyde 20. The unstable
aldehyde 20 was not purified but converted into the
alkene 2120 by a Wittig reaction using methyltriphen-
ylphosphorane generated in situ from methyltriphen-
ylphosphonium bromide and butyllithium in THF. The
tert-butyldimethylsilyl protecting group was removed
from the resulting alkene 21 with 75% acetic acid to
obtain the 3â-alcohol 22. Addition of 4-iodobenzoyl
chloride to 22 gave the benzoylated alkene 12. Attempts
to reduce 12 to an alkane via catalytic hydrogenation
resulted in a hydrodehalogenated product. The depro-
tected alkene 22 was reduced by catalytic hydrogenation
to the 2â-ethane 23 and then treated with 4-iodobenzoyl
chloride to obtain the iodobenzoyl alkane 13.
In Scheme 3, ecgonine (24) was reacted with 2-pro-
panol in an acid-catalyzed esterification and then ben-
zoylated with 4-iodosalicyloyl chloride21 to give the 2′-
hydroxylated 2â-isopropyl ester 14.
Resu lts
The 4′-iodococaine analogues were tested for their
ability to displace [3H]WIN 35,428 (2, Figure 1), and the
IC50 values for inhibiting 4 nM of radioligand binding
to the DAT are listed in Table 1. As apparent from the
table, most of the analogues have low binding affinity
compared with the lead compound 3 except esters 7, 8,
and 9 and the unsaturated analogue 12. The isopropyl
ester 8 showed approximately a 2-fold increase in
binding affinity compared to that of 3, but it was still
lower than that of cocaine (249 ( 37 nM). Apparently
F igu r e 2.
16a or 16b with the appropriate alcohols, the esters
7-1017 were obtained. The 3-aryl-1,2,4-oxadiazole 11
was obtained by treating 16b with benzamidoxime.18
Scheme 2 summarizes the synthesis of compounds 12
and 13. Ecgonine methyl ester (17) was treated with
Sch em e 1

2382 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Avor et al.
Sch em e 2
Ta ble 1. Dopamine Transporter Binding Affinities of
4′-Iodococaine Analogues
compound
IC50 (nM)a
compound
IC50 (nM)a
cocaine (1)
WIN 35428 (2)
249 ( 37
24 ( 4
8
9
1377 ( 10
2019 ( 253
4602 ( 325
3459 ( 60
2165 ( 253
2692 ( 486
663 ( 70
3
4
5
6
7
2522 ( 4
10
11
12
13
14
6214 ( 1269
2995 ( 223
>100000
2031 ( 190
a
Data are mean ( standard error of mean (SEM) of two to three
experiments performed in triplicate.
Sch em e 3
F igu r e 3. Locomotor activity of compound 14 and of cocaine
(20 mg/kg). Values are mean ( sem of six different mice for
each drug dosage. *p < 0.05 for decreased locomotor activity
compared with saline-treated mice (Tukey-Kramer multiple
comparisons test).
serotonin transporters with NE/DA and 5-HT/DA ratios
of 53 and 7, respectively (Table 2).
Compound 14 failed to stimulate locomotor activity
at a molar equivalent dose of cocaine from 10 to 110
mg/kg (Figure 3). The effect of coadministration of
compound 14 and cocaine on locomotor activity was also
investigated to determine how effective this compound
is in blocking the stimulant action of cocaine. It
antagonized the locomotor stimulant action of cocaine
(20 mg/kg) at a low dose of 10 mg/kg with no change in
reduction up to 80 mg/kg. A significant reduction in
locomotor activity was observed at a dose of 110 mg/kg
(Figure 4).
a variety of ester groups at the 2â-position can be
accommodated without substantially altering the bind-
ing affinity. A further 2-fold enhancement in binding
affinity was observed for the 2′-hydroxylated derivative
14. In contrast to 2′-hydroxycocaine, 4′-iodococaine, and
2′-hydroxy-4′-iodococaine, compound 14 showed de-
creased binding affinities for the norepinephrine and
Discu ssion
The replacement of the carbomethoxy group of 3 with
a methylenehydroxy group (4) resulted in a 2.5-fold loss

2â-Substituted Analogues of 4′-Iodococaine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2383
Ta ble 2. Binding Affinity of Analogues at Dopamine, Norepinephrine, and Serotonin Transporters
IC50 (nM)a
dopamine*
transporter
norepinephrine**
transporter
serotonin***
transporter
NE/DA
ratio
5-HT/DA
ratio
compound
cocaine (1)
249 ( 37
24 ( 4
25 ( 4
2522 ( 4
215 ( 19
663 ( 1
2500 ( 70
258 ( 40
48 ( 2
18458 ( 1073
1021 ( 75
34838 ( 796
615 ( 120
690 ( 16
143 ( 21
1052 ( 23
195 ( 10
4507 ( 13
10.0
10.7
1.9
7.3
4.7
4.1
28.8
5.7
0.4
0.9
WIN 35,428
2′-hydroxycocaine
4′-iodococaine
2′-hydroxy-4′-iodococaine
14
52.5
6.8
a
IC50 values are mean ( standard error of mean (SEM) of two to three experiments performed in triplicates. Radioligand used: *[3H]WIN
35,428, **[3H]nisoxetine, and ***[3H]paroxetine.
4, where there was loss of hydrogen bond acceptors, the
oxadiazole 11 did not show dramatic loss in binding
potency, therefore supporting the fact that there is an
electrostatic interaction between the 2â-substituents
and the binding sites on the receptor. The 3-aryl-1,2,4-
oxadiazoles of the tropanes also exhibited binding
potencies similar to those of the parent esters.18
The vinyl analogue 12 that is also a substrate for
electrostatic interaction comparable with the ester group
showed a binding affinity similar to that of the parent
compound 3. With the hydrogenation of the double bond
in 12, there was a total loss of the electrostatic interac-
tion, and one might have expected a dramatic reduction
in binding potency, but the loss in binding potency
between 12 and 13 was not significant. This result
correlated with what Kozikowski and co-workers20 had
observed in the phenyltropane derivatives. This obser-
vation cannot be explained in terms of specific hydrogen
bond donor group within the cocaine recognition site as
compound 13 lacked a hydrogen bond donor or acceptor
group. Kozikowski and co-workers20 offered an expla-
nation for the existence of a hydrophobic pocket in the
vicinity of the C-2 position of cocaine. They concluded
that without hydrogen bond acceptors, hydrophobic
interactions become important in the region of cocaine
recognition site surrounding the C-2 substituents.
F igu r e 4. Coadministration of various doses of compound 14
and locomotor stimulating dose of cocaine (20 mg/kg). Values
are mean ( sem of six different mice for each drug dosage. *p
< 0.05 for decreased locomotor activity compared with cocaine-
treated mice (Tukey-Kramer multiple comparisons test).
of binding potency compared with the parent compound
3. Conversion of the alcohol to the acetate 5 restored
the loss in binding affinity; this agrees with the results
obtained by Lewin et al.17 According to these investiga-
tors, there are specific hydrogen bond donor groups
present within the cocaine recognition site for the
binding of the carbomethoxy group. It can be seen that
there was a loss of one hydrogen bond accepting oxygen
in the alcohol while with the addition of the second
oxygen in the acetate restored the binding affinity. The
amide derivative 6 showed an IC50 greater than 100 µM,
a loss in potency far greater than that of the amide
derivative of cocaine,17 while the phenyltropane ana-
logue showed an increase in binding affinity.19 This
cannot be explained in terms of hydrogen bonding; the
magnitude of the reduction pointed to other factors, such
as the possibility that the amide group may orient itself
whereby there was no contribution to binding or may
even interfere with binding. The low binding potency
of 6 suggested that the hydrogen bonds are highly
specific.17
Overall, the binding potency of the 2â-substituted
cocaine derivatives is higher than that of the 4′-
iodococaine analogues while the tropanes exhibited even
a much stronger binding affinity. The main difference
between these compounds is the N-para substituent
distance that may be a critical factor. The shortest
length is observed for the 4′-substituted tropanes while
the longest is for the 4′-iodo substitution. The tropanes
and cocaines seem to fit properly at the binding site on
the DAT, while the 4′-IC derivatives are too big to fit
into the corresponding site, resulting in poor binding
affinity. The high binding potency of the tropanes is
also attributed to decreased conformational flexibility,
decreased aqueous solvation, and increased pKas.24 No
correlation between binding affinity and lipophilicity
was observed for the 4′-IC derivatives.
Increase in binding affinity of 14 followed the trend
observed by Singh et al.21 with the 2′-hydroxylation of
cocaine and 4′-iodococaine. It was postulated that the
hydroxyl group may engage in an intermolecular hy-
drogen bonding with the serine residues at the active
site of the dopamine transporter. As can be seen from
Table 2, hydroxylation of cocaine at the 2′-position
increased the binding affinity to DAT by 10-fold, to the
NE by 52-fold, and to the 5-HT by 4-fold, indicating that
With the restoration of the two hydrogen bond accep-
tors in the esters 7-10, there was little change in
binding affinity, and it was no surprise that the ester 8
showed the highest binding potency (2-fold) of all the
analogues evaluated in this study. This general trend
was also observed with the 2â-substituted cocaine and
the phenyltropane analogues.17 The isopropyl ester of
4′-iodinated phenyltropane showed the highest binding
affinity of the 2â-substituted esters. Unlike the alcohol

2384 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Ta ble 3. Calculated Molecular Physical Parametersa
Avor et al.
ylphenidate, and dopamine have been shown to inhibit
[3H]GBR 12935 binding competitively26 and GBR 12935
binds to only one site on the DAT.27 These results
support the hypothesis that [3H]GBR 12935 labels the
dopamine binding site on the transporter. Therefore it
can be predicted that any compound with similar
physical molecular parameters, i.e., a hydrogen donor
at the same distance as the N-OH (para or meta) would
exhibit high binding affinity at the DAT. This may be
the case with 2′-hydroxycocaine since 2′-hydroxy-4′-
iodococaine and 14, with longer distances than dopa-
mine, exhibited poor binding. Compound 14 with the
least compatible distance showed the lowest binding
potency to the DAT.
energy
distance
molecule
(kcal/mol)
(N-hydroxy H) (Å)
14b
169.095-171.338
159.184-161.653
7.253-7.467
6.819-7.467
2′-hydroxy-4′-
iodococaineb
2′-hydroxycocaineb
dopamine
171.563-178.900
74.503-77.689
5.940-7.512
6.817-6.952 (para)
5.190-7.186 (meta)
6.649-8.204 (para)
5.983-7.693 (meta)
7.225-8.456
norepinephrine
121.178-121.447
-0.056 to 0.145
serotonin
a
Using Spartan 5.0, Wavefunction Inc., Irvine, CA, running on
b
an SGI Octane workstation. Maintained a 2 Å distance, indicat-
ing intramolecular hydrogen bonding between the ester oxygen
and the 2′-OH groups on the phenyl ring.
For the NE and 5-HT transporters, 2′-hydrococaine
again fits well within the allowed distance observed for
NE and 5-HT, leading to the increased binding potency
at these transporters. With compound 14, the distance
is out of range, leading to no affinity at these transporter
sites. It should be emphasized that the bulky isopropyl
and iodo groups have contributed to low-energy con-
formers with longer distances, therefore preventing
better fitting and potential hydrogen bonding with the
serine residues at the binding sites of these transport-
ers.
the 2′-hydroxylation enhanced binding potency to dif-
ferent degrees to all the transporters. When 4′-iodoco-
caine and 2′-hydroxy-4′-iodococaine were compared,
although there was an increase in binding to all the
transporters with the 2′-hydroxylation, there was a
preferential enhancement of affinity for the norepineph-
rine transporter. The increase in binding affinity of
2′-hydroxy-4′-iodococaine is still 10-fold less than that
of 2′-hydroxycocaine. The effect of the iodo group in
increasing the N-para substituent distance seems to
play a role in lowering the binding potency of the
hydroxylated 4′-IC analogue. The increase in binding
affinity at the DAT is not limited to the 2′-OH group
alone. A 2′-NH2 functionality introduced in cocaine
showed a comparable binding potency (IC50 18 ( 2 nM)
to the DAT (Singh et al., unpublished results) while the
2′-F exhibited a decreased affinity (IC50 604 ( 67 nM).25
The results again support our contention that a hydro-
gen bond donor at the 2′-position will exhibit a high
binding potency to the DAT. The fluoro group, a
hydrogen bond acceptor, showed reduced binding po-
tency.
With compound 14, there was enhancement in bind-
ing potency to the DAT but not to the norepinephrine
and serotonin transporters; this preferential enhance-
ment of potency for the DAT makes this compound
unique among the hydroxylated derivatives. The C2-
isopropyl group seems to confer selectivity on this
compound as observed by Carroll et al.19
From the binding studies, we wondered what physical
properties could explain the varied binding affinities we
observed. Using computer molecular modeling, the
distance between the nitrogen and the hydroxy group(s)
on the dopamine, norepinephrine, and serotonin mol-
ecules were measured in all possible low-energy con-
formers. This distance was then compared with the
distance between the bridgehead nitrogen of the tropane
molecule and the 2′-hydroxy group (all possible low-
energy conformers) in 2′-hydroxycocaine, 2′-hydroxy-4′-
iodococaine, and 14 (Table 3).
Generally, it has been assumed that an amino func-
tion on the monoamines is required for binding on the
monoamine transporters. With the synthesis and bio-
logical evaluation of aryloxatropanes,28,29 it was ob-
served that these non-amino compounds bind with high
affinity to the DAT, NET, and 5HT. Although this new
finding does not rule out the ionic interaction between
the receptor and the ligands, it clearly suggests that
more than one binding domain for transporter inhibitors
and dopamine may exist on the monoamine transport-
ers. Speculating on whether non-amine compounds will
offer advantage over conventional nitrogen-based com-
pounds is premature.
In the behavioral assay, compound 14 retained the
pharmacological properties of the parent compound 4′-
IC despite a 4-fold increase in binding potency at the
DAT. The tropane analogues with high binding potency
at the DAT are potent in stimulating locomotor activity
due to inhibition of dopamine reuptake.30,31 It would
be anticipated, therefore, that with an increase in
binding affinity at the DAT, there would be a corre-
sponding increase in locomotor activity. Consistent with
this premise, 2′-hydroxycocaine with high binding po-
tency at the DAT was more potent in increasing loco-
motor activity than cocaine.32 The lack of locomotor
stimulant action coupled with the blockage of a cocaine-
induced locomotion by compound 14 is very interesting.
It might be speculated that the lack of locomotor
stimulation by compound 14 could be due to a number
of reasons, including rapid metabolism and poor brain
uptake. There is experimental evidence that the hy-
droxy group confers stability on the derivatives of
cocaine. When 2′-OH cocaine was subjected to in vitro
esterase hydrolysis using pig liver esterase, no ecgonine
methyl ester, a hydrolysis product of the benzoyl group,
was observed (Seale et al., unpublished results). It is
believed that the 2′-OH is involved in intramolecular
hydrogen bonding, resulting in the carbonyl function
With 2′-hydroxycocaine, the distance fits well within
the distance of the catecholamines with better compat-
ibility with dopamine. Dopamine binds with high
affinity at the DAT and is believed to be due to the ionic
interaction between the aliphatic nitrogen and the
aspartate residue and the para and meta OH groups
hydrogen bonding with the serine 359 and serine 356,
respectively.21 Evidence for dopamine binding domain
on the DAT came from the fact that cocaine, meth-

2â-Substituted Analogues of 4′-Iodococaine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2385
being locked in the same plane as the phenyl ring. As
a result, the 3â-benzoyl ester group is stable to hydroly-
sis due to reduction in electrophilicity.21 HPLC analysis
showed 2′-OH cocaine to be more lipophilic than cocaine,
therefore with better penetration into the brain. Be-
havior studies showed 2′-OH cocaine to be a more potent
stimulant than cocaine,32 suggesting brain uptake.
Biodistribution studies in mice using 125I-labeled 4′-IC
showed 80% of unmetabolized compound in the brain
30 min postdosing. At the end of 120 min, 23% of the
parent compound was still present (Basmadjian et al.,
unpublished results). From these results, we believe
that compound 14 which combines the features of 2′-
OH cocaine and 4′-IC is entering the brain.
Con clu sion
A series of 2â-substituted analogues of 4′-iodococaine
(3) was synthesized to improve upon the binding po-
tency. From the results, compound 8 showed almost a
2-fold increase in binding affinity compared with the
parent compound 3. Since the parent compound had
very interesting pharmacological profiles but low bind-
ing potency, a 2-fold increase in binding affinity with
the isopropyl ester would help us to evaluate the effect
of binding potency at the DAT on in vivo biological
profile. An initial locomotor activity stimulation screen-
ing of 8 showed no stimulation of locomotion, suggesting
the possibility of modifying 4′-iodococaine to increase
binding affinity and retaining the same behavior phar-
macological profile. A correlation plot of binding poten-
cies of tropanes and cocaines showed a poor correlation.
This raises the issue of whether the search for a cocaine
antagonist is through the high-affinity tropane ana-
logues that are potent inhibitors of dopamine reuptake.
Addition of a hydroxyl group at the 2′-position of
cocaine significantly improved the binding potency 10-
fold at the DAT, while the same substitution in 4′-
iodococaine (3) increased the binding affinity to that of
cocaine.21 Introduction of a hydroxyl group at the 2′-
position of 8 to give 14 resulted in a 2-fold increase in
binding affinity and selectivity for the DAT. The
cocaine-induced locomotor blocking effect of 14 clearly
warrants further investigation into other low DAT
affinity 4′-substituted cocaine derivatives with identical
behavior profiles to 4′-IC. Increasing the binding af-
finity significantly of a low-binding compound is possible
and yet retains the biological profile of antagonizing
cocaine stimulant effect. A successful design should
produce compound(s) that will antagonize cocaine with
diminished dopamine uptake inhibition and with high
specificity to the DAT versus the NE and 5-HT trans-
porters.
Cocaine also has appreciable binding affinity to the
NE and 5HT transporters, complicating the mechanisms
responsible for locomotor activity. However, compound
14 has no binding affinity to these transporters; there-
fore, further studies may offer a less complex explana-
tion. A plausible scenario for the locomotor suppressing
properties of compound 14 may be through the inhibi-
tion of the sodium channels. Local anesthetic effect by
inhibition of the sodium channels has been implicated
in the locomotor-depressing properties of cocaine deriva-
tives.33,34 However, treatment with cocaine can reverse
locomotor inhibition induced by norcocaine or the local
anesthetic, tetracaine. Administration of cocaine did
not reverse the locomotor depressing activity of com-
pound 14, so this mechanism is not likely. Other likely
sites will then be the NE and 5-HT transporters and
sigma sites.35-37 Evidence exists to support the fact that
binding to the NE and 5-HT transporters affect behav-
ior.31 With the low binding potency of compound 14 for
these two transporters, a possible mechanism involving
these transporters seems unlikely. The pharmacological
mechanism(s) which underlies the locomotor antagoniz-
ing effect of compound 14 is not well understood, but
the possibility of blocking the entry of cocaine into the
brain cannot be ruled out.
Exp er im en ta l Section
It can be speculated that the iodo group present in
14 causes an umbrella effect by its size. Thus, despite
its low binding potency at the DAT, it prevents cocaine
from binding by blocking the binding site. This then
explains why compound 14 inhibits the locomotion when
coadministered with cocaine, therefore behaving as a
cocaine antagonist. Further support for the size effect
came from the work of Seale et al., where phenyl25 and
isopropyl groups (Seale et al., unpublished results) at
the 4′-position of cocaine not only failed to stimulate
locomotor activity in mice but caused locomotor depres-
sion when coadministered with cocaine. These com-
pounds, like the iodo derivative, exhibited low binding
affinity at the DAT. This clearly shows that the
bulkiness of the group at the 4′-position antagonizes
cocaine-induced locomotion and is not limited to an iodo
group. Stimulant-induced stereotyped behaviors (re-
petitive biting, sniffing, cage climbing and grooming) in
rodents can occupy so much of the behavior repertoire
that ambulation is decreased. No obvious decrease in
these stereotyped behaviors was observed; therefore, the
apparent antagonism of compound 14 cannot be due to
development of stereotypy at high doses. No lethality
or convulsion was observed at the high doses of the test
compound.
Melting points were determined on
a Thomas Hoover
capillary tube apparatus and are uncorrected. Elemental
analysis was performed by Midwest Microlab Ltd, Indianapo-
lis, IN. NMR spectra were recorded on a Varian XL-300
spectrometer. FAB-MS was performed with a VG instrument,
ZAB-E spectrometer (Manchester, UK). All organic reagents
were obtained from Aldrich Chemical Co., except benzamid-
oxime, which was obtained from TCI America (Portland, OR),
and were used without further purification. HPLC grade
solvents were obtained from Fisher Scientific (St. Louis, MO).
Silica gel (230-400 mesh, 60 Å) used for flash chromatography
was obtained from Aldrich and silica gel chromatography
sheets with a fluorescent indicator used for TLC were obtained
from Eastman Kodak Co., Rochester, NY. [3H]WIN 35,428 was
obtained from Dupont-New England Nuclear, Boston, MA.
3-[(4′-Iod oben zoyl))oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2â-ca r boxylic Acid (15). To 4′-iodo-
cocaine (3, 11.6 g, 27 mmol) was added 200 mL of H2O, and
the oily suspension was refluxed for 18 h, changing to a
solution as refluxing progressed. The solution was cooled to
room temperature and placed in an ice bath. The acid
precipitated out as a white fluffy solid that was filtered off
and washed with H2O. The solid was purified by flash
chromatography over silica gel (100 g) and eluted with EtOAc/
MeOH (70:30) to obtain a white solid (7.50 g, 67%). Mp: 233-
234 °C. FAB-MS (3-NBA matrix): m/ e 416 (MH+, 100). 1H
NMR (CDCl3): δ 7.77 (d, J ) 8.7 Hz, 2H, C(2′,6′)-H), 7.72 (d,
J ) 8.7 Hz, 2H, C(3′,5′)-H), 5.40-5.32 (m, 1H, C(3)-H), 3.62-

2386 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Avor et al.
3.57 (m, 1H, C(1)-H), 3.53-3.45 (m, 1H, C(5)-H), 3.06-3.02
(m, 1H, C(2)-H), 2.48 (s, 3H, NCH3), 2.32-2.17 (m, 4H, C(4,7)-
H2), 1.98-1.96 (m, 2H, C(6)-H2) ppm.
tography over silica gel (20 g), eluting with EtOAc/petroleum
ether (50:50) to obtain an oil (0.60 g, 70%). The oil was
converted to the tartrate salt with 0.30 g of tartaric acid.
Mp: 180-181 °. FAB-MS (3-NBA matrix): pseudomolecular
ion at m/ e 444 (MH+, 100). 1H NMR (D2O): δ 7.77 (d, J )
7.5 Hz, 2H, C(2′,6′)-H), 7.53 (d, J ) 6.9 Hz, 2H, C(3′,5′)-H),
5.45-5.34 (m, 1H, C(3)-H), 4.42 (s, 2H, tartaric acid), 4.09-
4.02 (m, 1H, C(1)-H), 3.98-3.83 (m, 3H, C(5)-H, OCH2), 3.50-
3.44 (m, 1H, C(2)-H), 2.71 (s, 3H, NCH3), 2.34-2.20 (m, 4H,
C(4,7)-H2), 2.09-2.00 (m, 2H, C(6)-H2), 0.68 (t, J ) 7.2 Hz,
3H, OCH2CH3) ppm. Anal. (C18H22NO4I‚C4H6O6) C, H, N, I.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2-ca r boxylic Acid Isop r op yl Ester
(8). A suspension of 15 (0.50 g, 1 mmol) in 30 mL of isopropyl
alcohol was saturated with HCl gas, and the mixture was
heated to reflux to obtain a solution and cooled to room
temperature. The solution was again saturated with HCl gas
and stirred at room temperature for 48 h. The mixture was
concentrated under reduced pressure and partitioned between
CH2Cl2 and 20% NH4OH solution. The combined organic
extract was washed with H2O and dried over MgSO4. The
residue obtained after removal of solvent was purified by flash
chromatography over silica gel (20 g), eluting with EtOAc to
obtain a clear oil (0.37 g, 81%). The oil was converted to the
tartrate salt with 0.18 g of tartaric acid. Mp: 181-182 °C.
FAB-MS (3-NBA matrix): pseudomolecular ion at m/ e 458
(MH+, 100). 1H NMR (D2O): δ 7.76 (d, J ) 8.4 Hz, 2H, C(2′,6′)-
H), 7.54 (d, J ) 8.7 Hz, 2H, C(3′,5′)-H), 5.40-5.30 (m, 1H, C(1)-
H), 4.82-4.68 (m, 1H, CH(CH3)2), 4.34 (s, 2H, tartaric acid),
4.08-4.01 (m, 1H, C(1)-H), 4.96-3.89 (m, 1H, C(5)-H), 3.48-
3.41 (m, 1H, C(2)-H), 2.72 (s, 3H, NCH3), 2.38-2.21 (m, 4H,
C(4,7)-H2), 2.10-2.00 (m, 2H, C(6)-H2), 0.91 (d, J ) 6.3 Hz,
3H, CH(CH3)2), 0.61 (d, J ) 6.3 Hz, 3H, CH(CH3)2) ppm. Anal.
(C19H24NO4I‚C4H6O6) C, H, N, I.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2-ca r boxylic Acid P h en yl Ester (9).
A mixture of 15 (0.50 g, 1 mmol) and 1,1′-carbonyldiimidazole
(0.20 g, 1 mmol) in dried CH2Cl2 was stirred at room temper-
ature for 18 h to obtain a solution. The solvent was removed
under reduced pressure and the resulting residue taken in 15
mL of acetone and heated under reflux with the phenol (0.09
g, 1 mmol) for 3 h. After removal of solvent in vacuo, the
residue obtained was purified by flash chromatography over
silica gel (20 g), eluting with EtOAc/petroleum ether (50:50)
to obtain a solid (0.45 g, 92%). The free base was converted
to the HCl salt. Mp: 119-120 °C. FAB-MS (3-NBA matrix):
pseudomolecular ion at m/ e 492 (MH+, 100). 1H NMR (D2O):
δ 7.78 (s, 4H, C(2′,3′,5′,6′)-H), 7.41 (d, J ) 7.5 Hz, 8.1 Hz, 2H,
C(3′′,5′′)-H), 7.26 (m, 1H, C(4′′)-H), 7.13 (dd, J ) 2.1 Hz, 5.4
Hz, 2H, C(2′′,6′′)-H), 5.38-5.30 (m, 1H, C(3)-H), 3.88-3.82 (m,
1H, C(1)-H), 3.40-3.34 (m, 1H, C(5)-H), 3.34-3.25 (m, 1H,
C(2)-H), 2.35 (s, 3H, NCH3), 2.30-2.13 (m, 4H, C(4,7)-H2),
1.95-1.70 (m, 2H, C(6)-H2) ppm. Anal. (C22H22NO4I‚HCl‚
3.5H2O) C, H, N, I, Cl.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2-h yd r oxym eth a n e (4). To a stirred
suspension of 15 (2.0 g, 5 mmol) in distilled THF (75 mL) at 0
°C (ice bath) was added dropwise a 1.0 M solution of borane-
THF complex (18.0 mL, 18 mmol) over a period of 20 min with
a clear solution observed after the addition. After the solution
was stirred at 0 °C for 2 h and at room temperature for 1 h,
excess diborane was carefully destroyed by addition of 20 mL
of MeOH. The solution was acidified to pH 1 with 6 N aqueous
HCl and concentrated in vacuo, basified with 6 N NH4OH, and
extracted with CH2Cl2 (4 × 15 mL). It was dried over MgSO4
and concentrated to an oil, which solidified on standing. The
solid was purified by flash chromatography on silica gel (60
g), eluting with 5% MeOH/CH2Cl2 to yield a white solid (1.3
g, 65%). Mp: 95-96 °C. FAB-MS (3-NBA matrix): pseudo-
molecular ion at m/ e 402 (MH+, 100), fragment ion at m/ e
231. 1H NMR (CDCl3): δ 7.79 (s, 4H, C(2′,3′,4′,6′)-H), 5.39-
5.30 (m, 1H, C(3)-H), 3.97 (d, J ) 2.4 Hz, 2H, CH2OH), 3.52-
3.47 (m, 1H, C(1)-H), 3.35-3.29 (m, 1H, C(5)-H), 3.00-2.27
(m, 1H, C(2)-H), 2.28 (s, 3H, NCH3), 2.22-2.14 (m, 2H, C(4)-
H2), 2.96-2.05 (m, 2H, C(7)-H2), 1.80-1.73 (m, 2H, C(6)-H2)
ppm. Anal. (C16H20NO3I) C, H, N, I.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2-a cetoxym eth a n e (5). To a stirred
solution of 4 (0.3 g, 0.7 mmol) and Et3N (0.25 mL, 1.8 mmol)
in 10 mL of CH2Cl2 at room temperature was added dropwise
acetic anhydride (0.15 mL, 1.5 mmol). After 3 h, TLC in EtOAc
showed complete reaction and 10 mL of H2O was added. The
organic phase was separated, and the aqueous phase extracted
with CH2Cl2 (3 × 5 mL). The combined organic extract was
washed with water and dried over Na2SO4. Removal of solvent
gave an oil (0.3 g, 97%) which was converted to the tartrate
salt. Mp: 188-189 °C. FAB-MS (3-NBA matrix): pseudo-
molecular ion at m/ e 444 (MH+, 100). 1H NMR (D2O): δ 7.75
(d, J ) 8.7 Hz, 2H, C(2′,6′)-H), 7.54 (d, J ) 8.4 Hz, 2H, C(3′,5′)-
H), 5.42-5.34 (m, 1H, C(3)-H), 4.33 (s, 2H, tartaric acid), 4.26
(dd, J ) 6.9 Hz, 2H, CH2O), 3.95-3.86 (m, 2H, C(1,5)-H), 2.88-
2.74 (m, 1H, C(2)-H), 2.65 (s, 3H, NCH3), 2.31-2.12 (m, 4H,
C(4,7)-H2), 2.07-2.04 (m, 2H, C(6)-H2), 1.68 (s, 3H, OCOCH3)
ppm. Anal. (C18H22NO4I‚C4H6O6) C, H, N, I.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
b icyclo[3.2.1]oct a n e-2-ca r b oxylic Acid N-Met h yla m id e
(6). A solution of 15 (0.20 g, 0.5 mmol) and 1,1′-carbonyldi-
imidazole (0.40 g, 2 mmol) in 20 mL of dry CH2Cl2 was stirred
at room temperature for 18 h. To the resulting solution were
added methylamine hydrochloride (0.34 g, 5 mmol) and sodium
carbonate (1.06 g, 10 mmol), and the flask was stoppered with
a rubber septum. The slurry mixture was stirred at room
temperature for 18 h; the reaction mixture was then diluted
with 25 mL of H2O and extracted with CH2Cl2 (3 × 20 mL).
The combined organic extract was dried over MgSO4 and
concentated to an oil that was purified by flash chromatogra-
phy over silica gel (6.0 g) and eluted with EtOAc to obtain an
oil (0.18 g, 86%). The oil was converted to the tartrate salt.
Mp: 175-176 °C. FAB-MS (3-NBA matrix): pseudomolecular
ion at m/ e 429 (MH+, 100). 1H NMR (CDCl3): δ 9.42 (br, 1H,
NH), 7.77 (d, J ) 8.4 Hz, 2H, C(2′,6′)-H), 7.69 (d, J ) 8.4 Hz,
2H, C(3′,5′)-H), 5.35-5.26 (m, 1H, C(3)-H), 3.40-3.34 (m, 1H,
C(1)-H), 3.34-3.28 (m, 1H, C(5)-H), 2.93-2.90 (m, 1H, C(2)-
H), 2.88 (d, J ) 8.4 Hz, 3H, NHCH3), 2.29 (s, 3H, NCH3), 2.22-
2.02 (m, 4H, C(4,7)-H2), 1.82-1.62 (m, 2H, C(6)-H2) ppm. Anal.
(C17H21N2O3I‚C4H6O6) C, H, N, I.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2-ca r boxylic Acid Eth yl Ester (7). A
solution of 15 (0.80 g, 1.9 mmol) in 25 mL of ethyl alcohol was
saturated with HCl gas at 0 °C and stirred at room temper-
ature for 48 h. The residue obtained after the solution was
concentrated in vacuo was taken up in 20% NH4OH and
extracted with CH2Cl2 (3 × 20 mL). The organic fraction was
washed with H2O, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash chroma-
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
b icyclo[3.2.1]oct a n e-2â-ca r b oxylic Acid Ben zyl E st er
(10). This compound was prepared according to the procedure
used for the synthesis of 9 using 15 (0.50 g, 1 mmol), 1,1′-
carbonyldiimidazole (1.10 g, 7 mmol), and benzyl alcohol (0.11
g, 1 mmol). The residue obtained after workup was purified
by flash chromatography over silica gel (20 g), eluting with
EtOAc/petroleum ether (50:50) to furnish a clear oil (0.40 g,
78%). The oil was converted to the tartrate salt with 0.24 g
of tartaric acid. Mp: 120-122 °C. FAB-MS (3-NBA matrix):
pseudomolecular ion at m/ e 506 (MH+, 100). 1H NMR (D2O):
δ 7.47 (d, J ) 8.4 Hz, 2H, C(2′,6′)-H), 7.16 (d, J ) 8.4 Hz, 2H,
C(3′,5′)-H), 7.01-6.97 (m, 1H, C(4′′)-H), 6.90 (dd, J ) 7.8 Hz,
7.2 Hz, 2H, C(3′′,5′′)-H), 6.76 (dd, J ) 6.9 Hz, 1.5 Hz, 2H,
C(2′′,6′′)-H), 5.30-5.20 (m, 1H, C(3)-H), 4.90, 4.79 (d, J ) 12.3
Hz, 1.0 Hz, 12.0 Hz, 1.0 Hz, OCH2), 4.34 (s, 2H, tartaric acid),
4.09-4.02 (m, 1H, C(1)-H), 3.95-3.88 (m, 1H, C(5)-H), 3.47-
3.40 (m, 1H, C(2)-H), 2.38-2.12 (m, 4H, C(4,7)-H2), 2.00-1.92
(m, 2H, C(6)-H2) ppm. Anal. (C23H24NO4I‚C4H6O6) C, H, N, I.

2â-Substituted Analogues of 4′-Iodococaine
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2387
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
b icyclo[3.2.1]oct a n e-2â-(3′-p h en yl-1′,2′,4′-oxa d ia zol-5′-
yl) (11). To a suspension of 15 (0.6 g, 1 mmol) in 8 mL of
CH2Cl2 was added dropwise a solution of oxalyl chloride (0.25
mL, 3 mmol) in 3 mL of CH2Cl2. After gas evolution ceased,
the mixture was stirred for 1.5 h and evaporated to dryness
in vacuo. A solution of the benzamidoxime (0.21 g, 2 mmol)
in 8 mL of dry pyridine was added to the acid chloride (0.40 g,
1 mmol) in 6 mL of CHCl3 and the mixture heated to reflux
for 2 h. The reaction mixture was diluted with 5 mL of H2O,
made basic with 3 N NaOH solution, and extracted with CH2-
Cl2 (3 × 5 mL). The combined organic extract was dried over
MgSO4, purified by flash chromatography over silica gel (12
g), and eluted with EtOAc/petroleum ether (50:50) to obtain a
yellowish oil that solidified on standing (0.20 g, 38%). The
solid was converted to the HCl salt. Mp: 221-222 °C. FAB-
MS (3-NBA matrix): pseudomolecular ion at m/ e 516 (MH+,
100). 1H NMR (CDCl3): δ 8.09 (d, J ) 8.1 Hz, 2H, C(2′,6′)-H),
7.74 (d, J ) 8.7 Hz, 2H, C(3′,5′)-H), 7.68 (d, J ) 8.7 Hz, 2H,
C(3′′,5′′)-H), 7.53-7.46 (m, 3H, C(2′′,4′′,6′′)-H), 5.59-5.49 (m,
1H, C(3)-H), 3.84-3.78 (m, 1H, C(1)-H), 3.74-3.68 (m, 1H,
C(5)-H), 3.40-3.33 (m, 1H, C(2)-H), 2.38-2.24 (m, 2H, C(4)-
H2), 2.21 (s, 3H, NCH3), 2.10-2.00 (m, 2H, C(7)-H2), 1.94-
1.81 (m, 2H, C(6)-H2) ppm. Anal. (C23H22N3O3I‚C4H6O6) C,
H, N, I.
3.45-3.39 (m, 1H, C(1)-H), 3.30-3.23 (m, 1H, C(5)-H), 2.34-
2.219 (m, 1H, C(2)-H), 2.15 (s, 3H, NCH3), 2.14-1.89 (m, 4H,
C(4,7)-H2), 1.61-1.45 (m, 2H, C(6)-H2), 0.85 (s, 9H, C(CH3)3),
0.05 (s, 6H, OSi(CH3)2) ppm.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-[1R-(exo,exo)]-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e-2â-eth en e (21). Butyllithium
(21.5 mL, 20 mmol) was added dropwise to a stirred suspension
of methyltriphenylphosphonium bromide (7.20 g, 20 mmol) in
50 mL of dry THF cooled in ice. After 1 h at room temperature,
the solution was recooled in ice, 20 (4.90 g, 17 mmol) dissolved
in 30 mL of THF was added dropwise, and the reaction mixture
was stirred at room temperature for 16 h. The salts were
removed by filtration over Celite, and the resulting solution
was diluted with water and extracted with ether (3 × 20 mL).
The ethereal extract was dried over MgSO4 and concentrated
under reduced pressure, and the residue obtained was purified
by flash chromatography over silica gel (80 g) and eluted with
EtOAc/petroleum ether (30:70) to obtain an oil (2.68 g, 55%).
1H NMR (CDCl3): δ 6.26-6.12 (m, 1H, CHdCH2), 5.11-4.99
(m, 2H, CHdCH2), 3.99-3.80 (m, 1H, C(3)-H), 3.18-3.10 (m,
1H, C(1)-H), 3.10-3.03 (m, 1H, C(5)-H), 2.37-2.29 (m, 1H,
C(2)-H), 2.19 (s, 3H, NCH3), 2.12-1.97 (m, 2H, C(4)-H2), 1.97-
1.50 (m, 4H, C(6,7)-H2), 0.87 (s, 9H, C(CH3)3), 0.03 (s, 6H, OSi-
(CH3)2) ppm.
3-Hyd r oxy-[1R-(exo,exo)]-8-m eth yl-8-a za bicyclo[3.2.1]-
octa n e-2â-eth en e (22). To 21 (2.0 g, 7 mmol) was added 30
mL of 75% acetic acid in water, and the mixture was stirred
for 3 h. The solution was neutralized to pH 7 with concen-
trated NH4OH and extracted with CH3Cl (3 × 20 mL). The
organic extracts were dried over Na2SO4, and the residue
obtained after concentration by rotary evaporation was puri-
fied by flash chromatography on silica gel (40 g) using EtOAc/
petroleum ether (50:50) as the eluent to furnish an oil (0.59 g,
50%). 1H NMR (CDCl3): δ 6.25-6.12 (m, 1H, CHdCH2), 5.11-
4.98 (m, 2H, CHdCH2), 4.19-4.00 (m, 1H, C(3)-H), 3.18-3.12
(m, 1H, C(1)-H), 3.08-3.02 (m, 1H, C(5)-H), 2.35-2.27 (m, 1H,
C(2)-H), 2.00 (s, 3H, NCH3), 2.10-1.95 (m, 2H, C(4)-H2), 1.96-
1.48 (m, 4H, C(6,7)-H2) ppm.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-[1R-(exo,exo)]-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e-2â-ca r boxylic Acid Meth yl
Ester (18). To a solution of tert-butyldimethylsilyl chloride
(4.50 g, 30 mmol) and imidazole (3.40 g, 50 mmol) in 7 mL of
DMF was added ecgonine methyl ester 17 (4.0 g, 20 mmol) in
2 mL of DMF. The solution was heated to 75 °C for 1 h and
stirred at room temperature for 18 h. The solution was poured
into 15 mL of H2O and extracted with CH2Cl2 (3 × 20 mL).
The combined organic extract was dried over MgSO4 and
concentrated in vacuo to obtain a liquid that was passed over
silica gel and eluted with EtOAc/petroleum ether (50:50) to
obtain a clear liquid (5.40 g, 98%). 1H NMR (CDCl3): δ 3.99-
3.90 (m, 1H, C(3)-H), 3.70 (s, 3H, OCH3), 3.43-3.36 (m, 1H,
C(1)-H), 3.27-3.20 (m, 1H, C(5)-H), 2.75-2.70 (m, 1H, C(2)-
H), 2.21 (s, 3H, NCH3), 2.18-2.00 (m, 2H, C(4)-H2), 1.68-1.60
(m, 2H, C(7)-H2), 1.52-1.45 (m, 2H, C(6)-H2), 0.86 (s, 9H,
C(CH3)3), 0.05 (s, 6H, OSi(CH3)2) ppm.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-[1R-(exo,exo)]-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e-2â-h yd r oxym eth a n e (19). To
18 (5.40 g, 17 mmol) in 50 mL of dry toluene and cooled to 0
°C in ice/salt bath was added a 1 M solution of diisobutylalu-
minum hydride, Dibal-H (34 mL, 34 mmol), in hexanes, and
the mixture was stirred for 1 h. The reaction mixture was
quenched with 50 mL of saturated Rochelle salt solution and
the slurry stirred for 0.5 h, diluted with water, and extracted
with CHCl3 (4 × 20 mL). The combined organic extract was
dried over MgSO4 and concentrated in vacuo. The resulting
oil was purified by flash chromatography over silica gel (60 g)
using EtOAc as the eluent to obtain a yellowish oil (5.0 g,
100%). 1H NMR (CDCl3): δ 4.08-4.00 (m, 1H, C(3)-H), 3.89
(dd, J ) 9.0 Hz, 2H, CH2O), 3.39-3.35 (m, 1H, C(1)-H), 3.20-
3.14 (m, 1H, C(5)-H), 2.20 (s, 3H, NCH3), 2.14-2.05 (m, 1H,
C(2)-H), 1.77-1.68 (m, 2H, C(4)-H2), 1.65-1.49 (m, 4H, C(7,6)-
H2), 0.89 (s, 9H, C(CH3)3), 0.05 (s, 6H, OSi(CH3)2) ppm.
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2â-eth en e (12). To 22 (0.5 g, 3 mmol)
dissolved in 10 mL of dry benzene was added Et3N (1.36 g, 13
mmol) followed by 4′-iodobenzoyl chloride (1.07 g, 4 mmol)
dissolved in 10 mL of benzene dropwise under N2. The
resulting mixture was stirred at 45 °C for 90 min and kept at
room temperature overnight. The mixture was transferred to
a separatory funnel with 50 mL of CHCl3 and washed with
5% Na2CO3 solution (4 × 20 mL). The organic extract was
dried over MgSO4 and concentrated in vacuo to obtain a light
yellowish oil that was purified by flash chromatography over
silica gel (20 g), eluting with EtOAc/petroleum ether (50:50)
to obtain a colorless oil (0.58 g, 97%). The oil was converted
to the tartrate salt with tartaric acid (0.50 g) to obtain 0.80 g
of salt. Mp: 206-207 °C. 1H NMR (D2O): δ 7.67 (d, J ) 8.7
Hz, 2H, C(2′,6′)-H), 7.46 (d, J ) 8.4 Hz, 2H, C(3′,5′)-H), 5.98-
5.86 (m, 1H, CHdCH2), 5.29-5.17 (m, 2H, CHdCH2, C(3)-H),
4.31 (s, 2H, tartaric acid), 3.88-3.81 (m, 2H, C(1,5)-H), 3.15-
3.08 (m, 1H, C(2)-H), 2.60 (s, 3H, NCH3), 2.32-2.16 (m, 2H,
C(4)-H2), 2.16-1.19 (m, 4H, C(7,6)-H2) ppm. Anal. (C17H20
NO2I‚C4H6O6) C, H, N, I.
-
3-Hyd r oxy-[1R-(exo,exo)]-8-m eth yl-8-a za bicyclo[3.2.1]-
octa n e-2â-eth a n e (23). To a solution of 22 (0.20 g, 1 mmol)
in 20 mL of cyclohexane was added 20 mg of 5% Pt/C. The
flask was evacuated under a vacuum and fitted to a balloon
filled with hydrogen gas. The mixture was stirred at room
temperature overnight. The reaction mixture was filtered over
Celite, and the filtrate was evaporated to dryness to obtain a
colorless oil (0.20 g, 100%). 1H NMR (CDCl3): δ 4.00-3.92
(m, 1H, C(3)-H), 3.85-3.70 (m, 2H, C(1,5)-H), 3.35-3.10 (m,
1H, C(2)-H), 2.82 (s, 3H, NCH3), 2.52-2.30 (m, 4H, C(4,7)-
H2), 2.26-2.15 (m, 2H, C(6)-H2), 1.88-1.62 (m, 2H, CH2CH3),
1.00 (t, J ) 7.5 Hz, 3H, CH2CH3) ppm.
3-[(ter t-Bu tyld im eth ylsilyl)oxy]-[1R-(exo,exo)]-8-m eth -
yl-8-a za bicyclo[3.2.1]octa n e-2â-for m a ld eh yd e (20). Ox-
alyl chloride (2.21 g, 17 mmol) was dissolved in 20 mL of
CH2Cl2 and the solution cooled to -78 °C in dry ice/acetone
bath. DMSO (2.66 g, 34 mmol) in 10 mL of CH2Cl2 was added,
and after 5 min, the alcohol 19 (5.0 g, 17 mmol) in 50 mL of
CH2Cl2 was added dropwise. Stirring continued for 30 min.
The reaction was quenched with Et3N (8.60 g, 85 mmol) and
the resulting solution allowed to warm to room temperature.
Water was added, and the mixture was extracted with CH2-
Cl2 (3 × 20 mL). The organic extract was dried over MgSO4
and concentrated in vacuo, keeping the temperature under 40
°C. The unstable aldehyde (4.90 g, 99%) was used in the next
step without any further purification. 1H NMR (CDCl3): δ
9.99 (d, J ) 3.3 Hz, 1H, CHO), 4.12-4.05 (m, 1H, C(3)-H),
3-[(4′-Iod oben zoyl)oxy]-[1R-(exo,exo)]-8-m eth yl-8-a za -
bicyclo[3.2.1]octa n e-2â-eth a n e (13). To 23 (0.2 g, 1 mmol)
dissolved in 10 mL of dry benzene was added Et3N (0.10 g, 1

2388 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13
Avor et al.
mmol) followed by a dropwise addition of 4′-iodobenzoyl
chloride (0.35 g, 1 mmol) dissolved in 10 mL of benzene under
N2. The resulting mixture was stirred at 45 °C for 90 min
and kept at room temperature overnight. The mixture was
transferred to a separatory funnel with 20 mL of CHCl3 and
washed with 5% Na2CO3 solution (4 × 5 mL). The organic
extract was dried over MgSO4 and concentrated in vacuo to
obtain an oil that was purified by flash chromatography over
silica gel (10 g), eluting with EtOAc/petroleum ether (40:60)
to obtain a light yellowish oil (0.25 g, 71%). The oil was
converted to the tartrate salt with tartaric acid (0.19 g) to
obtain 0.34 g of salt. Mp: 207-208 °C. 1H NMR (D2O): δ
7.91 (d, J ) 8.4 Hz, 2H, C(2′,6′)-H), 7.76 (d, J ) 8.7 Hz, 2H,
C(3′,5′)-H), 5.52-5.45 (m, 1H, C(3)-H), 4.41 (s, 2H, tartaric
acid), 4.05-3.96 (m, 2H, C(1,5)-H), 3.34-3.00 (m, 1H, C(2)-
H), 2.84 (s, 3H, NCH3), 2.54-2.32 (m, 4H, C(4,7)-H2), 2.28-
2.18 (m, 2H, C(6)-H2), 1.88-1.60 (m, 2H, CH2CH3), 1.03 (t, J
) 7.5 Hz, 3H, CH2CH3) ppm. Anal. (C17H22NO2I‚C4H6O6) C,
H, N, I.
incubated for 2 h in an ice bath and terminated by rapid
filtration through Whatman GF/B glass fiber filters presoaked
for 30 min in 0.05% polylysine solution. Membranes were
rapidly washed three times with ice-cold buffer. Nonspecific
binding of was defined by the presence of 100 µM (-)-cocaine.
Binding potency for the norepinephrine transporter was
determined by displacement of [3H]nisoxetine according to the
method of Tejani-Butt39 as modified by Bennett et al.40
Membranes were freshly prepared after homogenization (Poly-
tron, setting 6, 20 s) of a whole brain minus cerebellum in 30
volumes of ice-cold 50 mM Tris-HCl buffer, pH 7.4, containing
120 mM NaCl and 5 mM KCl and centrifuged. The mem-
branes were resuspended in an ice-cold nisoxetine buffer (50
mM Tris-HCl, pH 7.4, containing 300 mM NaCl and 5 mM
KCl). To each assay tube was added 750 µL of membrane
solution, 0.7 nM [3H] nisoxetine, and additional buffer contain-
ing the test compounds to a final volume of 1 mL. Tubes were
incubated at 25 °C for 40 min, and the reaction was terminated
by rapid filtration through Whatman GF/B filters presoaked
for 1 h in Tris-HCl buffer containing 0.1% bovine serum
albumin with three washes of ice-cold buffer. Desipramine (1
µM) was used to define nonspecific binding.
Affinity of analogues at the serotonin transporter was
determined by displacement of [3H]paroxetine binding from
freshly prepared cortical membranes as assayed by Habert et
al.41 Cortices dissected on ice were homogenized (Polytron,
setting 6, 20 s) in 10 volumes (vol:wt) of 50 mM Tris-HCl
buffer, pH 7.4, containing 120 mM NaCl and 5 mM KCl and
centrifuged twice at 48000g for 10 min. Fresh buffer was used
to resuspend the membrane pellet from each centrifugation.
The incubation mixture contained 50 mg of membranes
(original wet weight) in 1500 µL of buffer, 0.4 nM [3H]-
paroxetine (100 µL), 300 µL of buffer, and various test
compound concentrations (100 µL) in a total volume of 2 mL.
The tubes were incubated at 25 °C for 60 min. The reaction
was termined by rapid filtration (Brandel) through Whatman
GF/B glass filters presoaked in Tris-HCl buffer containing
0.1% bovine serum albumin for at least an hour. Membranes
were then rapidly washed three times with an ice-cold buffer.
Nonspecific binding was determined in the presence of 10 µM
fluoxetine.
3-[(2′-H yd r oxy-4′-iod ob en zoyl)oxy]-[1R-(exo,exo)]-8-
m eth yl-8-a za bicyclo[3.2.1]octa n e-2-ca r boxylic Acid Iso-
p r op yl Ester (14). To ecgonine HCl (24, 0.50 g, 2 mmol) was
added 20 mL of 2-propanol, and the mixture was warmed to
obtain a solution that was saturated with HCl gas and stirred
at room temperature for 12 h. The solution was neutralized
with 20% NH4OH and extracted with CHCl3 (3 × 10 mL). The
combined organic extract was concentrated in vacuo and
passed through a silica gel plug eluted with petroleum ether/
EtOAc (50:50) to obtain an oil (0.50 g, 82%). The oil (0.30 g,
1 mmol) was dissolved in 5 mL of dry benzene, and Et3N (0.50
mL) was added followed by 4-iodosalicyloyl chloride21 (0.28 g,
1 mmol) in 1 mL of dry benzene. After 24 h, the reaction
mixture was transferred to a separatory funnel, water (2.0 mL)
was added, and the organic layer was separated. The organic
layer was then washed with 5% aqueous Na2CO3 solution (2
× 2 mL) and dried over MgSO4. After solvent removal, the
crude product was purified over silica gel (20 g) and eluted
with EtOAc/MeOH (50:50) to obtain an oil (0.10 g, 21%) which
was converted to the tartrate salt. Mp: 153-155 °C. EIMS
(70 eV, DIP): 473 (M+). 1H NMR (D2O): δ 7.39 (d, J ) 8.4
Hz, 2H, C(3′,5′)-H), 7.25 (d, J ) 8.7 Hz, 1H, C(6′)-H), 5.48-
5.40 (m, 1H, C(3)-H), 4.83-4.66 (m, 1H, CH(CH3)2), 4.64 (s,
2H, tartaric acid), 4.10-4.04 (m, 1H, C(1)-H), 4.00-3.90 (m,
1H, C(5)-H), 3.54-3.40 (m, 1H, C(2)-H), 2.74 (s, 3H, NCH3),
2.36-3.24 (m, 4H, C(4,7)-H2), 2.09-2.06 (m, 2H, C(6)-H2), 0.97
9d, J ) 6.3 Hz, 3H, CH(CH3)2), 0.70 (d, J ) 6.3 Hz, 3H, CH-
(CH3)2) ppm. Anal. (C19H24NO5I‚HCl‚0.5H2O) C, H, N, I.
Molecu la r Mod elin g. The molecular modeling studies
were performed on an SGI Octane workstation (R10000) using
Spartan 5.0 (Wavefunction, Inc., Irvine, CA) and InsightII97
(Molecular Simulations, San Diego, CA). All structures were
minimized using the built in Semi-Emperical AM1 method in
Spartan and the Delphi module in InsightII97. The lowest
energy conformers were calculated and used in measuring the
distance between the different substituents on the rings and
the nitrogen atoms.
Bin d in g Assa ys. The method of Reith et al.38 was followed.
Whole brains from male Sprague-Dawley rats (Sasco Inc,
Wilmington, MA) were rapidly harvested after decapitation
with a guillotine. The striata was isolated and homogenized
(Polytron, setting 6, 15 s) in ice-cold 0.32 M sucrose solution
(1.5 mL/100 mg of tissue). The homogenizer and blade were
rinsed with twice the volume of 0.32 M sucrose solution and
added to the homogenate. The combined mixture was centri-
fuged at 3300 rpm for 10 min at 4 °C. The resulting
supernatant fraction was subsequently centrifuged at 13800
rpm for 20 min to obtain a pellet, P2, which was homogenized
in ice-cold 35 mM sodium phosphate buffer (obtained by mixing
35 mM NaH2PO4 and 17.5 mM Na2HPO4 to obtain a pH 7.4
at room temperature). Each assay tube contained 130 µL of
buffer or buffer plus 10 µL of unlabeled test compound (1 ×
10-10 to 1 × 10-6 M), [3H]WIN 35,428 in the same buffer (20
µL, 4 nM), and 50 µL of membranes (4 mg/mL) to a total
volume of 200 µL. Assays performed in triplicates were
Filters containing membrane-bound radioligand were added
to vials containing 10 mL of scintillation fluid (EcoLume),
stored overnight, and counted on a Beckman LS3801 scintil-
lation counter. IC50 values were determined from competition
curves of 12 points using the curve-fitting program EBDA
(Biosoft Software, Ferguson, MO). Mean values and standard
errors were calculated from two to three assays for each test
compound.
Locom otor Activity Testin g. C57BL/6J mice (Sasco,
Omaha, NE), 8-weeks-old, were housed on hardwood litter at
constant temperature and humidity with a standard 12 h light/
dark cycle. Animals were allowed to acclimatize for 3 days
before testing. Locomotor activity was determined in an
automated computerized acrylic enclosure, 16 in. × 16 in. ×
15 in. (San Diego Instruments, San Diego, CA) with four
infrared photobeams on each side. The mice were placed in
the testing chamber for 20 min to ensure a steady state level
of activity before testing. Locomotor activity was recorded as
mean ( sem number of light beam breaks by individual mouse
(n ) 6/dose) during a 30 min period after ip injection of saline
(10 mL/kg), cocaine (20 mg/kg), or test compound (20, 40, and
80 mg/kg) in a 10 mL/kg volume. For inhibition studies, mice
were injected ip with saline or test compound; after 10 min,
each mouse was challenged with cocaine (20 mg/kg) and
locomotor activity was monitored for 30 min.
Data was analyzed utilizing Tukey-Kramer Multiple Com-
parison Test. In all cases, a p value of 0.05 was considered
significant.
Ack n ow led gm en t. This work is supported by a
grant from the National Institute on Drug Abuse (DA
08587).

2â-Substituted Analogues of 4′-Iodococaine
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