Synthesis and biological evaluation at nicotinic acetylcholine receptors of N-arylalkyl- and N-aryl-7-azabicyclo[2.2.1]heptanes

Article abstract of DOI:10.1021/jm0103561

A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted 7-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal nicotinic acetylcholine receptors. The in vitro binding affinities (K_i) of the 7-azabicyclo[2.2.1]heptane derivatives were measured by inhibition of [³H]cytisine binding to rat brain tissue, The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]heptane (5b, K_i = 98 nM). The chloro analogue (5a, K_i = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in both hotplate and tail-flick tests when administered subcutaneously. However, when compounds 1 and 5a,b were administered intrathecally, all produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.

Full text of DOI:10.1021/jm0103561

J . Med. Chem. 2002, 45, 3041-3047
3041
Syn th esis a n d Biologica l Eva lu a tion a t Nicotin ic Acetylch olin e Recep tor s of
N-Ar yla lk yl- a n d N-Ar yl-7-Aza bicyclo[2.2.1]h ep ta n es
†
†
†
‡
‡
‡
J ie Cheng, Chunming Zhang, Edwin D. Stevens, Sari Izenwasser, Dean Wade, Shaoyi Chen,
§
,†
Dennis Paul, and Mark L. Trudell*
Department of Chemistry, University of New Orleans, New Orleans, Louisiana 70148, Department of Neurology,
University of Miami School of Medicine, Miami, Florida 33136, and Department of Pharmacology,
Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112
Received J uly 30, 2001
A new series of N-arylalkyl-substituted 7-azabicyclo[2.2.1]heptanes and N-aryl-substituted
7
-azabicyclo[2.2.1]heptanes were synthesized and evaluated as potential ligands for neuronal
nicotinic acetylcholine receptors. The in vitro binding affinities (K ) of the 7-azabicyclo[2.2.1]-
heptane derivatives were measured by inhibition of [ H]cytisine binding to rat brain tissue.
i
3
The most potent ligand of the series was found to be N-(3-pyridylmethyl)-7-azabicyclo[2.2.1]-
heptane (5b, K
i
) 98 nM). The chloro analogue (5a , K ) 245 nM) 5a and epibatidine (1)
i
produced dose-dependent analgesia in both hotplate and tail-flick tests when administered
subcutaneously. However, when compounds 1 and 5a ,b were administered intrathecally, all
produced analgesia in the tail-flick test but only 5a produced analgesia in the hotplate test.
In tr od u ction
To date, numerous structure-activity studies based
upon the novel structure of epibatidine have been
Since the natural product (-)-epibatidine (1) was first
isolated from the skin of the Ecuadorian poison frog,
performed in search of nontoxic, nonnarcotic, analgesic
8-19
agents.
The azetidine derivative ABT-594 (3) was
1
Epipedobates tricolor, by Daly and co-workers, its
recently identified as a potent nAChR analgesic with
remarkable biological activity2 and unique 7-azabicyclo-
-4
15,27-29
reduced toxicity.
The structural differences be-
[2.2.1]heptane ring system have led to numerous inves-
tween 1, 2, and 3 suggest that further elucidation of
the structure-activity relationships of nAChRs is war-
ranted for the development of new analgesic agents with
reduced side effects and/or toxicity. In an effort to
explore the structure-activity relationships of epibati-
dine and the importance of the 7-azabicyclo[2.2.1]-
heptane ring system as a scaffold for molecular recog-
nition of at nAChRs, a series of novel N-arylalkyl- and
N-aryl-7-azabicyclo[2.2.1]heptanes were prepared. Herein,
we report the synthesis and in vitro and in vivo
evaluation of congeners of epibatidine.
tigations of the synthesis and biological activity of 1 as
well as structurally related analogues.5
-19
Extensive
pharmacological evaluations have demonstrated that 1
is a highly potent agonist at several central nervous
system nicotinic acetylcholine receptor (nAChR) sub-
types, including R4â2 and R7 subtypes, as well as at
nAChRs in peripheral autonomic ganglia and skeletal
muscle.4 The binding affinity of 1 at nAChRs is several
orders of magnitude greater than nicotine (2), and the
remarkable analgesic activity of epibatidine is 200 times
,15
1
more potent than morphine. The analgesic properties
of 1 are thought to be mediated through R4â2 subtype
nAChRs,20 and in mice, this effect is thought to be
mediated primarily by spinal nAChRs.21,22 However, the
therapeutic potential of epibatidine is limited due to its
acute toxicity at doses only slightly higher than its
effective analgesic dose.2
Ch em istr y
Multigram quantities of 7-azabicyclo[2.2.1]heptane
hydrochloride (4) were readily prepared by a short and
highly efficient synthetic sequence recently developed
3
0,31
in our laboratories.
-azabicyclo[2.2.1]heptane derivatives 5 were synthe-
With 4 in hand, the N-arylalkyl-
3-26
7
sized in a straightforward fashion (Table 1). A mixture
of 4 and the corresponding arylmethyl chlorides was
refluxed in a mixture of triethylamine and ethanol for
1
8-24 h. This furnished the desired N-arylmethyl-7-
azabicyclo[2.2.1]heptane derivatives (5a ,e-g) in 51-
9% yield. The homologues 5c,d were prepared in a
7
similar fashion from the 3-pyridylalkyl mesylates 6a ,b,
respectively. The derivative 5b was obtained in 95%
yield from 5a by hydrogenolysis over 10% palladium on
carbon.
The series of N-aryl-7-azabicyclo[2.2.1]heptane de-
rivatives 7 were prepared by palladium-catalyzed ami-
nation of heteroaryl halides with 4 employing the
bisimidazolium salt 8 (DiIPr‚HCl) as a ligand precursor
*
To whom correspondence should be addressed. Tel.: (504)280-
7
337. Fax: (504)280-6860. E-mail: mtrudell @uno.edu.
†
University of New Orleans.
University of Miami School of Medicine.
Louisiana State University Health Sciences Center.
‡
for formation of the palladium-bisimdazol-2-ylidene
§
30,32
complex to catalyze the C-N bond formation.
A wide
1
0.1021/jm0103561 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/04/2002

3
042 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Cheng et al.
Ta ble 2. N-Aryl-7-azabicyclo[3.3.1]heptane Derivatives (7)a
Ta ble 1. N-Arylalkyl-7-azabicyclo[2.2.1]heptane Derivatives (5)
a
Isolated yield. b Prepared from 5a by hydrogenolysis over 10%
Pd/C.
variety of heterocylic halides underwent the amination
reaction and furnished the desired N-aryl-7-azabicyclo-
[2.2.1]heptane derivatives in moderate to good yields
(
36-71%, Table 2). It is noteworthy that under these
a
See ref 30 for synthetic details.
conditions, the 2-chloro-5-iodopyridine gave a predomi-
nant coupling product at the 2-position to yield 7e as
the major product.
3
3
Ta ble 3. Inhibition of [ H]Cytisine Binding and [ H]Dopamine
Release at R4â2 Subtype NAChRs in Rat Brain
binding affinity
dopamine release
Resu lts a n d Discu ssion
Ki (nM)a
a
compd
EC50 (nM)
(
(
(
(
-)-epibatidine (1)
()-epibatidine
+)-epibatidine
-)-cytisine
0.079 ( 0.016
0.14 ( 0.02
0.16 ( 0.03
4.2 ( 0.5
0.2 ( 0.1
0.4 ( 0.3
1.3 ( 1.3
8.8 ( 4.4
7.3 ( 2.6
The binding affinities of the N-arylalkyl-7-azabicyclo-
[
2.2.1]heptanes (5a -g) and N-aryl-7-azabicyclo[2.2.1]-
heptanes (7a -h ), summarized in Table 3, were deter-
3
mined by the inhibition of [ H]cytisine binding in
(S)-nicotine (2)
(R)-nicotine
5
5
5
5
8.0 ( 4.5
homogenates of rat striatum. There are a variety of
nACHRs subtypes that exist in the central nervous
system; however, the R4â2 subtype is the predominant
nAChR in rat striatum tissue.15 Therefore, the binding
affinities reported in Table 3 correspond to the R4â2
subtype affinity of epibatidine and related compounds.
As shown in Table 3, both the N-arylalkyl- and the
N-aryl-7-azabicyclo[2.2.1]heptane derivatives 5 and 7
exhibited significantly lower binding affinities when
compared to (-)-, (()-, and (+)-epibatidine. The N-
arylalkyl derivatives 5a -e were found to possess higher
binding affinity than the N-aryl derivatives 7a -h .
87 ( 45
b
a
b
c
d
245 ( 35
79 ( 38
1.4 ( 0.3
b
98 ( 9
b
2230 ( 275
27 200 ( 200
31 300 ( 800
<50%c
b
8140 ( 880
b
5e
b
5
5
7
f
b
c
g
<50%
a -h b
<50%c
a
All values are the mean ( SEM of three experiments per-
formed in triplicate. b Tested as the oxalate salt. c Percent inhibi-
tion at highest dose tested (100 µM).
[2.2.1]heptane derivatives 5a -g, the N-(3-pyridylm-
ethyl)-7-azabicyclo[2.2.1]heptane (5b) exhibited the most
potent binding affinity of the series. The derivative 5b
(Ki ) 98 nM) was found to be equipotent with (R)-
nicotine (Ki ) 87 nM) and only 10-fold less potent than
3
Compounds 5f,g and 7a -h did not fully inhibit [ H]-
cytisine binding at the highest dose tested (100 µM);
hence, the binding affinities are reported as the percent
inhibition at 100 µM. Among all N-arylalkyl-7-azabicyclo-

N-Arylalkyl- and N-Aryl-7-Azabicyclo[2.2.1]heptanes
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3043
Ta ble 4. ED50 Values of Subcutaneously Administered 1 and
a
5
a ,b for Tail-Flick and Hotplate Analgesia
tail-flick ED50
hotplate ED50
compd
(mg/kg) [95% CI]
(mg/kg) [95% CI]
1
0.000 46
0.000 72
[0.000 30-0.0017]
12.23
[1.26-118.9]
5.36
[
0.000 232-0.000 92]
5
5
a
11.1
[
2.42-51.3]
b
12.4
[4.40 - 34.9]
[2.68-10.3]
a
ED50 values were determined using nonlinear regression
analysis.
natural (S)-nicotine (Ki ) 8 nM). The des-chloro ana-
logue 5b was 2-fold more potent than the 6-chloro
analogue 5a (Ki ) 245 nM). This result is opposite of
that observed for 1 and 3.15,27,29 Even though these
compounds have much lower affinities for nAChRs as
compared to epibatidine, the affinities still fall within
a useful range. Epibatidine has an exceptionally high
affinity, both in producing nicotinic agonist effects and
in producing side effects, and this contributes greatly
to the problems with its clinical usefulness.
F igu r e 1. Reduction of body temperature produced by sub-
cutaneous epibatidine (1) and 5a ,b. Groups of mice (n g 10)
were injected sc with the indicated dose of 1 and 5a ,b, and
rectal temperature was assessed immediately before tail-flick
testing. Data are expressed as mean ( SEM.
To determine the potential for functional agonist
activity at nAChRs, selected compounds were examined
3
33-35
in [ H]dopamine release studies.
As shown in Table
3
, the nAChR agonists epibatidine, cytisine, and nicotine
were potent dopamine-releasing agents. Of the epiba-
tidine analogues tested, 5b was found to be equipotent
with (()-epibatidine and was 3-4-fold more potent than
(-)-nicotine (2) and (-)-cytisine. Unexpectedly, the
chloro analogue 5a was 50-fold less potent than 5b,
while the extended tethered derivative 5d was over
F igu r e 2. Tail-flick analgesia produced by intrathecal 1 and
6
000-times less potent. All of the compounds produced
5
a ,b. Groups of mice (n g 10) were injected ip with the
approximately 100% efficacy (based on the stimulation
of dopamine release by nicotine) except for compound
indicated dose of 1 and 5a ,b and tested for tail-flick analgesia
10 min later. Data are expressed as mean ( SEM.
5
b, which was only 50% efficacious at the highest
concentration tested (100 µM). There was a significant
2
2
correlation (r ) 1 if the original values are used, r )
.804 if log values of binding Ki and release EC50 are
0
used) between binding and dopamine release. While we
tried to use conditions that would prefer the R4â2 site,
it is not possible to know which nicotinic receptor
subtype is involved in the release of dopamine in these
studies. Further studies aimed at elucidating the spe-
cific nicotinic sites to which these compounds bind will
help us to better understand the mechanisms involved
in these functions.
Compounds 5a ,b were further characterized in vivo
for analgesic agonist activity. Accordingly, the analgesic
effects of subcutaneously and intrathecally administered
F igu r e 3. Hotplate analgesia produced by intrathecal 1 and
5
a ,b. Groups of mice (n g 10) were injected it with the
1
and analogues 5a ,b were assessed using the tail-flick
indicated dose of 1 and 5a ,b and tested for hotplate analgesia
immediately after tail-flick testing. Data are expressed as
mean ( SEM. Only compound 5a produced significant anal-
gesia. At a dose of 32 ng, 1 produced hyperalgesia.
3
6-38
and hotplate assays.
It has been reported that
nicotinic agonists also induce a reduction in body
3
9
temperature. The thermoregulatory effects of these
drugs following subcutaneous administration activity
were also determined. Like 1, compounds 5a ,b, when
injected subcutaneously, produced dose-dependent an-
algesia in both the tail-flick and the hotplate tests (Table
the hotplate assay. Spinally administered 1 produced
hyperalgesia (an increased sensitivity to painful stimuli)
in the hotplate assay (Figure 3), similar to that seen in
rats.. At the highest doses (10 and 32 µg), compounds
20
4
). Over the same dose range, all three drugs produced
a dose-dependent reduction in body temperature (Figure
). However, at a dose of 32 µg/kg, both compounds 5a ,b
5
a ,b produced signs of spinal seizures. Thus, the safety
1
of compounds 5a ,b is less than or equal to that of
epibatidine. Others have stressed the importance of
spinal nAChRs in the mediation of the analgesia
caused fatal seizures before the animals could be tested.
In contrast, when administered spinally, all three
drugs produced analgesia in the tail-flick assay (Figure
2
0-22
produced by nicotinic agonists.
In these studies,
2
), whereas only compound 5a produced analgesia in
analgesic models using spinal reflexes were used. The

3
044 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Cheng et al.
hotplate assay requires the mouse to make a coordi-
nated response (licking of the hind paw) involving
supraspinal circuitry. The finding that 1 and compound
Exp er im en ta l Section
All chemicals and reagents not otherwise noted were
purchased from Aldrich Chemical Co. Tetrahydrofuran (THF)
and 1,2-dimethoxyethane (DME) were dried by distillation
from Na and benzophenone. The spectral data for all com-
pounds are reported for the free base. The free base was then
converted into the oxalate salt to give a hygroscopic solid used
for microanalysis and biological testing. Microanalysis for C,
H, and N was performed by Atlantic Microlabs, Inc., Norcross,
5
b produced hotplate analgesia when injected subcu-
taneously, but not when injected intrathecally, is evi-
dence that hotplate analgesia is not mediated by spinal
nAChRs.
The structure-activity relationships of the N-substi-
tuted 7-azabicyclo[2.2.1]heptanes offer some interesting
insights into the neuronal nAChR pharmacophore. The
low binding affinities of compounds 7a -h can be at-
tributed to the reduced basicity of the bridging nitrogen
atom of the 7-azabicyclo[2.2.1]heptane moiety due to the
electron-withdrawing effects of the aryl groups. Even
the structural isomer of des-chloro-epibatidine, 7b, did
1
13
GA. H and C nuclear magnetic resonance (NMR) spectra
were recorded on a Varian Multiprobe 400 MHz spectrometer.
Melting points were recorded on a Hoover Mel-Temp ap-
paratus and are uncorrected.
P r ep a r a tion of 5a ,e-g (Gen er a l P r oced u r e). A solution
of the corresponding aryl-alkyl halide (1.5 mmol), triethy-
lamine (2 mmol, 280 µL), and 7-azabicyclo[2.2.1]heptane
hydrochloride (1 mmol, 133 mg) in ethanol (8 mL) was refluxed
and monitored by thin-layer chromatography (TLC). After 18-
24 h, the solvent was removed under reduced pressure, the
residue was dissolved in dichloromethane (20 mL), and water
3
not fully inhibited [ H]cytisine binding at the highest
does tested (100 µM). This is consistent with pharma-
cophore models that require a basic tertiary nitrogen
for protonation forming an onium site on the molecule.
Similar to 1 and 2, the attachment of the alicyclic amine
residue to the 3-position of the pyridine ring exhibited
the optimal effect on binding affinity (5b > 5e > 5f).
2 3
(10 mL) was added. Saturated aqueous Na CO solution was
carefully added to adjust the pH to 10-11. The organic layer
was removed, and the water layer was then extracted with
dichloromethane (3 × 20 mL). The combined organic layers
were dried (K CO ) and evaporated under reduced pressure.
2
3
The resulting residue was purified by chromatography (CH
Cl /MeOH/Et N, 80:2:1) to afford the corresponding amine.
N -[(2-Ch lor o-5-p yr id yl)m e t h yl]-7-a za b icyclo[2.2.1]-
2
-
It is apparent from the structure-activity studies of
this relatively homogeneous series of compounds that
the N-N distance between the onium-nitrogen (N7) and
the hydrogen bond acceptor nitrogen (pyridyl-N) has
some relevance for high affinity binding at neuronal
R4â2 nAChRs. From X-ray crystallographic studies
2
3
1
h ep ta n e (5a ). Colorless oil (56%). H NMR (CDCl
3
): δ 8.30
(
d, J ) 2.4 Hz, 1H), 7.70 (dd, J ) 8.0, 2.0 Hz, 1H), 7.25 (d, J
)
8.0 Hz, 1H), 7.35 (d, J ) 7.2 Hz, 1H), 3.52 (s, 2H), 3.21-
(quintet, J ) 2.4 Hz, 2H), 1.73 (d, J ) 7.2 Hz, 4H), 1.31 (d, J
4
0
41
13
(
4.737 Å) and computational studies (4.71 Å), the
) 7.6 Hz, 4H). C NMR (CDCl
1
1
3
): δ 150.1, 149.7, 139.5, 134.6,
24.2, 59.5 (2), 48.6, 28.5 (4). IR (NaCl, thin film): 3405, 1568,
N-N distance of 5b was found to be consistent with the
optimal N-N distances proposed in the Sheridan nAChR
phamacophore model.42 The analogues 5c,d , which
-
1
+
458, 1102, 827 cm . MS (CI): m/z 223 (MH , 100) 187 (30);
2 2 4
Cl‚C H O ‚
mp 156-158 °C (oxalate salt). Anal. (C12
.25H O) C, H, N.
N-(2-P yr id ylm et h yl)-7-a za b icyclo[2.2.1]h ep t a n e (5e).
H
15
N
2
0
2
4
1
possessed significantly longer N-N distances than 5b,
4
3
approaching that of the potent ligands cytisine and
1
Colorless oil (79%). H NMR (CDCl ): δ 8.29 (d, J ) 4.8 Hz,
3
epibatidine,44 exhibited low binding affinities. The
1H), 7.42 (dt, J ) 7.6, 1.6 Hz, 1H), 7.34 (d, J ) 7.6 Hz, 1H),
6.93-6.89 (m, 1H), 3.52 (s, 2H), 3.13 (quintet, J ) 2.4 Hz, 2H),
4
1
compound 5e with a shortened N-N distance of 3.4 Å
also exhibited diminished binding affinity. However, the
1
3
1
.67-1.64 (m, 4H), 1.12 (d, J ) 7.2 Hz, 4H). C NMR
4
1
(CDCl
(
3
): δ 149.4, 137.3, 135.5, 124.7, 123.1, 61.4 (2), 53.0, 27.9
isomer 5f (5.1 Å), which also possesses a N-N distance
within the idealized range of several nAChR pharma-
4). IR (NaCl, thin film): 3392, 1639, 1596, 1472, 879, 762
-1
+
+
cm . MS (CI): m/z 189 (MH , 100), 188 (M , 70); mp 104-
06 °C (oxalate salt). Anal. (C12 ‚C ‚0.25H O) C, H,
N.
4
2-45
cophore models,
exhibited very low affinity at
1
H
16
N
2
2
H
2
O
4
2
nAChRs. It has been noted that N-N distance is not
sufficient to provide a pharmacophore model that can
accurately predict the binding affinities and activity for
N-(4-P yr id ylm et h yl)-7-a za b icyclo[2.2.1]h ep t a n e (5f).
1
Colorless oil (69%). H NMR (CDCl ): δ 8.49 (d, J ) 5.6 Hz,
3
a diverse set of nAChR ligands;4
4,45
2H), 7.31 (d, J ) 5.2 Hz, 2H), 3.57 (s, 2H), 3.26 (s, 2H), 1.90
it appears that
1
3
(
(
d, J ) 7.2 Hz, 4H), 1.33 (d, J ) 7.2 Hz, 4H). C NMR
CDCl ): δ 157.9, 150.8 (2), 124.8 (2), 62.3, 59.9 (2), 27.6 (4).
within this series of compounds, an optimal N-N
nd iAs tC a hn Rc es .of ≈4.7 Å is required for potent binding at R4â2
3
-1
IR (NaCl, thin film): 3407, 2920, 2852, 1639, 1463 cm . MS
(
1
+
+
CI): m/z 189 (MH , 100), 200 (M+2H , 20), 98 (65); mp 122-
24 °C (oxalate salt). Anal. (C12 ‚C ) C, H, N.
N-(2-Qu in olin ylm eth yl)-7-azabicyclo[2.2.1]h eptan e (5g).
H
16
N
2
2 2 4
H O
Con clu sion
1
Pink oil (77%). H NMR (CDCl ): δ 8.12 (d, J ) 8.4 Hz, 1H),
8.02 (d, J ) 8.4 Hz, 1H), 7.79-7.76 (m, 2H), 7.67 (t, J ) 8.0
Hz, 1H), 7.48 (t, J ) 7.2 Hz, 1H), 3.88 (s, 2H), 3.31 (t, J ) 2.0
Hz, 2H), 1.87 (d, J ) 6.8 Hz, 4H), 1.33 (d, J ) 7.2 Hz, 4H).
NMR (CDCl
1
1
3
From a series of novel epibatidine analogues, two new
nAChR agonists have been identified. The N-(3-pyridyl-
methyl)-7-azabicyclo[2.2.1]heptane (5b) and the corre-
sponding 6′-chloro derivative 5a were found to elicit
moderately potent nicotinic agonist activity via occupa-
tion of R4â2 subtype nAChRs. In addition, like epiba-
tidine, these novel nAChR agonists produced dose-
dependent analgesic activity when administered sub-
cutaneously in both tail-flick and hotplate tests. How-
ever, 5a exhibited anomalous activity in spinally ad-
ministered hotplate tests, producing analgesic effects,
while 1 and 5b did not. The structure-activity relation-
ships of these structurally simple epibatidine analogues
should be useful in the further studies aimed at the
elucidation of nAChR pharmacophore.
1
3
C
3
): δ 147.8, 136.5, 129.5, 129.2 (2), 127.7, 127.6,
26.1, 121.0, 60.2 (2), 54.8, 28.8 (4). IR (NaCl, thin film): 3397,
-
1
+
601, 1503, 830 cm . MS (CI): m/z 239 (MH , 100), 240
+
(
M+2H , 30); mp 162-164 °C (oxalate salt, pink). Anal.
‚C ) C, H, N.
N-(3-P yr id ylm eth yl)-7-a za bicyclo[2.2.1]h ep ta n e (5b). A
mixture of 5a (115 mg, 0.52 mmol) and 10%Pd-C (10wt %,
2 mg) was added to methanol (10 mL). The mixture was
(C
16
H
18
N
2
2 2 4
H O
1
hydrogenated (1 atm) overnight. The catalyst was removed by
filtration, and the solvent was evaporated under reduced
pressure. The residue was chromatographed (CH
2 2
Cl /MeOH/
1
Et N, 80:2:1) to give 5b (280 mg, 95%) as a colorless oil. H
3
NMR (CDCl ): δ 8.56 (d, J ) 2.0 Hz, 1H), 8.48 (dd, J ) 5.2,
3
2.0 Hz, 2H), 7.73 (d, J ) 8.0 Hz, 1H), 7.26-7.23 (m, 2H), 3.53

N-Arylalkyl- and N-Aryl-7-Azabicyclo[2.2.1]heptanes
s, 2H), 3.21 (quintet, J ) 2.4 Hz, 2H), 1.78 (d, J ) 6.8 Hz,
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 3045
5 mM KCl, 1 mM MgCl , and 2.5 mM CaCl , pH adjusted to
(
2
2
4
1
3
H), 1.31 (d, J ) 7.2 Hz, 4H). 13C NMR (CDCl
3
): δ 150.2, 148.7,
7.4). The tissue was homogenized for 30 s with a polytron
(setting 4) and centrifuged at 35 000g for 10 min at 4 °C. The
supernatant was discarded, and the resultant pellet was
resuspended in fresh buffer. The membrane suspension was
then added to tubes containing increasing concentrations of
the drug being tested, with each concentration done in
triplicate. Additional triplicate samples were incubated with
36.6 (2), 123.6, 59.6 (2), 49.5, 28.5 (4). IR (NaCl, thin film):
392, 1648, 1517 cm-1. MS (CI): m/z 189 (MH , 100), 98 (35);
+
mp 166-168 °C (oxalate salt). Anal. (C12
.25H O) C, H, N.
N-[2-(3-P yr id yleth yl)]-7-a za bicyclo[2.2.1]h ep ta n e (5c)
a n d N-(3-p yr id ylp r op yl)-7-a za bicyclo[2.2.1]h ep ta n e (5d )
Rep r esen ta tive P r oced u r e). Compound 4 (200 mg, 1.5
mmol) was added to a solution of the corresponding 3-pyridy-
lalkylmesylate (6a ,b) (1 mmol) and Et N (3 mmol) in dimeth-
H
16
N
2
‚C
2 2 4
H O ‚
0
2
3
(
[ H]cytisine in the presence of 1 mM (-)-nicotine for determi-
nation of nonspecific binding. The tubes were quickly vortexed
3
3
and incubated on ice for 5 min before adding [ H]cytisine to
ylformamide (DMF) (5 mL) at room temperature. The mixture
was heated to 120 °C for 24 h. The solution was allowed to
cool to room temperature and concentrated under reduced
each tube at a concentration of 3.5 nM per tube. The final
volume in the tubes was 0.5 mL. The tubes were again quickly
vortexed and were then incubated at 2 °C for 90 min. The
assay was terminated by the addition of 3 mL of ice-cold Tris
buffer and filtration with a Brandel Cell Harvester through
GF/B glass fiber filters that had been soaked overnight in 0.5%
polyethylenimine in water to reduce nonspecific binding. Two
additional 3 mL washes were carried out, and the filters were
transferred to scintillation vials containing 0.5 mL of absolute
ethanol and 2.75 mL of Beckman Ready Value scintillation
cocktail. The vials were counted 24 h later at an efficiency of
approximately 25%. Under these conditions, the affinity of (-)-
cytisine is 4.2 ( 0.5 nM.
2 2
pressure. The residue was poured in a saturated Na CO
solution (10 mL) and extracted with dichloromethane (4 × 10
mL). The solvent was removed under reduced pressure, and
the residue was then purified by flash chromatography (CH
Cl /MeOH,/Et N, 80:20:1) to give the corresponding free base.
N-[2-(3-P yr id yleth yl)]-7-a za bicyclo[2.2.1]h ep ta n e (5c).
2
-
2
3
1
Colorless oil (46%). H NMR (CDCl ): δ 8.43 (d, J ) 2.0 Hz,
3
1
1
2
H), 8.39 (dd, J ) 4.8, 1.6 Hz, 1H), 7.49 (dt, J ) 7.6, 2 Hz,
H), 7.15 (dd, J ) 7.2, 4.4 Hz, 1H), 3.28 (quintet, J ) 2.4 Hz,
H), 2.76 (t, J ) 8.0 Hz, 2H), 2.55 (t, J ) 8.0 Hz, 2H), 1.70
(
(
2
2
dd, J ) 8.8, 2.4 Hz, 4H), 1.25 (d, J ) 7.2 Hz, 4H). 13C NMR
Dop a m in e Relea se Assa ys. Dopamine release was mea-
CDCl
3
): δ 150.2, 147.6, 136.2, 136.0, 123.3, 59.4 (2), 49.5, 33.5,
31,32
sured essentially as described previously.
Male Sprague-
-
1
8.4 (4). IR (NaCl, thin film): 3407, 1548 cm . MS (CI): m/z
Dawley rats (350-500 g, Hilltop, Scottdale, PA) were killed
by decapitation, and their brains were removed to an ice-cooled
dish for dissection of the striatum. The tissue was weighed
and chopped into 250 µm slices on a Sorvall TC2 tissue slicer
with two successive cuts at an angle of 90°. The strips of tissue
were suspended in oxygenated modified Krebs-HEPES buffer
(MKB) consisting of 127 mM NaCl, 5 mM KCl, 1.3 mM NaH2-
PO , 1.2 mM MgSO (where indicated), 15 mM HEPES acid,
+
+
03 (MH , 100), 204 (M+2H , 55); mp 136-138 °C (oxalate
‚C ) C, H, N.
N-[3-(3-P yr idylpr opyl)]-7-azabicyclo[2.2.1]h eptan e (5d).
salt). Anal. (C13
H
18
N
2
2 2 4
H O
1
Colorless oil (34%). H NMR (CDCl
3
): δ 8.42 (brs, 1H), 8.40
(
brs, 1H), 7.50 (d, J ) 8.0 Hz, 1H), 7.19 (dd, J ) 8, 4.8 Hz,
1
2
(
H), 3.31 (s, 2H), 2.64 (t, J ) 8.0 Hz, 2H), 2.41 (t, J ) 8.0 Hz,
H), 1.86 (quintet, J ) 8.1 Hz, 2H), 1.75-1.73 (m, 4H), 1.29
4
4
1
3
d, J ) 7.6 Hz, 4H). C NMR (CDCl
3
): δ 150.1, 147.7, 137.3,
and 10 mM glucose (adjusted to pH 7.4 with NaOH), which
was presaturated with 95% O /5% CO and warmed to 37 °C.
1
36.0, 123.5, 59.8 (2), 47.0, 31.2, 30.4, 28.3 (4). IR (NaCl, thin
2
2
-
1
film): 3365, 1654, 1580, 714, 606 cm . MS (CI): m/z 217
The tissue was rinsed three times, each in approximately 20
volumes of buffer. The tissue slice suspensions were then
+
+
(
MH , 100), 218 (M+2H , 15); mp 120-122 °C (oxalate salt).
Anal. (C12 Cl‚2C ) C, H, N.
-(3-P yr id yleth yl)m esyla te (6a ). 3-Pyridylacetic acid hy-
drochloride (1.7 g, 10 mmol) was added slowly to a slurry of
LiAlH (1.9 g, 50 mmol) in THF (30 mL) under argon at 0 °C.
H
15
N
2
2
H
2
O
4
incubated in 20 mL of buffer containing [ H]dopamine (final
3
2
concentration 15 nM) and 0.1 mM ascorbic acid at 37 °C for
30 min. The tissue was then washed twice in 20 mL of MKB
and once in MKB containing domperidone, which was included
in all subsequent steps of the experiment to prevent feedback
4
The mixture was refluxed for 24 h and cooled to room
temperature. Methanol (10 mL) was added slowly to decom-
pose the excess hydride, and water (20 mL) was added. The
two layers were separated, and the aqueous layer was ex-
tracted with ether (4 × 25 mL). The combined organic phase
3
inhibition by released [ H]dopamine. The tissue was suspended
a final time in MKB and distributed in 275 µL aliquots
between glass-fiber filter disks into chambers of a BRANDEL
(Gaithersburg, MD) superfusion apparatus. MKB was super-
fused over the tissue at a flow rate of 0.6 mL/min. A low, stable
baseline release, of approximately 1.1%/collection interval of
2 min, was established over a 30 min period. The tissue was
3 4
was washed with 5% NaHCO solution and dried over MgSO .
Evaporation of the solvent followed by chromatography of
the residue (ethyl acetate) gave 0.76 g (62%) of 3-pyridinyl-
1
3
ethanol as a colorless oil. H NMR (CDCl
8
(
3
): δ 8.33 (s, 1H),
then stimulated to release [ H]dopamine by a 2 min exposure
.29 (d, J ) 4 Hz, 1H), 7.54 (dt, J ) 8, 1.2 Hz, 1H), 7.18-7.15
m, 1H), 4.2 (brs, 1H), 3.82 (t, J ) 6.4 Hz, 2H), 2.80 (t, J ) 6.4
Hz, 2H).
A solution of methanesulfonyl chloride (0.44 g, 3.8 mmol)
in dichloromethane (2 mL) was added to a stirred solution of
-pyridylethanol (3.2 mmol, 0.4 g) and Et N (5 mmol) in
dichloromethane (15 mL) at 0-5 °C, and the mixture was
stirred for 6 h. Saturated Na CO solution (20 mL) was added
to the mixture, which was then extracted with dichlo-
romethane (4 × 20 mL). The organic phase was dried (Na
SO ) and concentrated to give the mesylate 6a as a solid (0.56
g) for use without further purification. (>95% pure by
to a test compound (Stimulus 1, S1). The inflow was then
returned to a nonstimulating buffer (interstimulus interval)
for a period of 10 min. The tissue was then stimulated a second
+
time for 2 min with 10 mM K (Stimulus 2, S2). Inflow was
again returned to nonstimulating buffer to allow a return to
baseline release before the final extraction of radioactivity
remaining in the tissue by a 45 min exposure to 0.2 N HCl.
Concentration-response curves for the test compounds were
established using five concentrations of each drug. Superfu-
sates were collected at 2 min intervals in scintillation vials,
and the glass-fiber filter disks and tissue were collected into
the final vials. Released radioactivity was determined by liquid
scintillation spectroscopy. Data were expressed as radioactivity
released above baseline during the collection interval as a
fraction of total radioactivity in the tissue at the beginning of
the collection interval (percent fractional release) to allow
visualization of absolute amounts of release. All data were
statistically analyzed as ratios (S1/S2). Data were analyzed
as ratios so that each tissue sample could serve as its own
control. Under the experimental conditions used, the released
3
3
2
3
2
-
4
1
H
NMR). 3-(3-Pyridylpropyl)mesylate (6b) was synthesized in
similar fashion from commercially available 3-pyridyl-1-pro-
panol.
[3
H]Cytisin e Bin d in g Assa y. The binding affinities of 1,
(S)-nicotine (2), (R)-nicotine, the N-arylalkyl-7-azabicyclo-
[2.2.1]heptanes (5a -g), and N-aryl-7-azabicyclo[2.2.1]heptanes
(7a -h ) were determined in homogenates of rat striatum. Rats
were killed by decapitation, and their brains were quickly
removed and dissected on an ice-cold platform removing the
caudate putamen. The tissue was weighed and placed in 30
volumes of ice-cold Tris buffer (50 mM Tris HCl, 120 mM NaCl,
3
1
radioactivity has been shown to be primarily dopamine.
Curves were generated, and EC50 values were determined with
GraphPad Prism software.

3
046 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Cheng et al.
An a lgesia P a r a d igm s. Su bjects. Male CD-1 mice (25-
J . Chem. Soc., Perkin Trans. 1 1999, 10, 675-676. (d) Namyslo,
J . C.; Kaufmann, D. E.; Chemistry in the Ambient Field of the
Alkaloid Epibatidine. Part 3. Asymmetric Synthesis of Both
Enantiomers of N-Protected Epibatidine via Reductive Heck-
Type Heteroarylation. Synlett 1999, 6, 804-808. (e) Palmgren,
A.; Larsson, A. L. E.; B a¨ ckvall, J . E.; Helquist, P. Palladium-
(II)-Catalyzed 1,4-Oxidation of 2-Aryl-1,3-cyclohexadienes. Ap-
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Org. Chem. 1999, 64, 836-842. (f) Barros, M. T.; Maycock, C.
D.; Ventura, M. R. The Effect of DMSO on the Borohydride
Reduction of a Cclohexanone: A Formal Enantioselective Syn-
thesis of (+)-Epibatidine. Tetrahedron Lett. 1999, 40, 557-560.
3
5 g) were used in all analgesia experiments and maintained
on a 12/12 h light/dark cycle with food and water available ad
libitum. Subcutaneous injections (sc) were made on the back
in a volume of 10 mL/kg. Intrathecal (it) injections were made
under light halothane anesthesia (4%) with a 10 µL syringe
fitted to a 30 ga needle with PE10 tubing by lumbar punc-
3
8
ture. The 30 ga needle was inserted sc and then inserted
between two lumbar vertebrae. A flinch of the tail or a leg
was taken as a positive sign of insertion. The injection volume
was 1 µL. Exposure to halothane produced a drop in body
temperature of approximately 2 °C. Therefore, thermoregu-
latory effects were not studied after intrathecal injections.
Da ta An a lysis. For analgesia studies, mean percent effect
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(
)
MPE) was calculated for each mouse using the formula: MPE
1
996, 6, 279-282.
(test latency - baseline latency)/(12 - baseline latency).
(
9) Malpass, J . R.; Hemmings, D. A.; Wallis, A. L. Synthesis of
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ED50 values ( CI95 were determined from dose-response
curves using nonlinear regression analysis.
3
6
Ta il-F lick An a lgesia . Each mouse’s tail was exposed to
a focused light beam, and the latency to move the tail was
measured using a photocell. The mean of two determinations
was taken as the mouse’s tail-flick latency. The mean postdrug
latencies were compared to predrug baseline latencies. A 12 s
maximal latency was used to minimize tissue damage.
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(
3
7
Hotp la te An a lgesia . For animals tested using the hot-
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by placing each animal on a 52 °C hotplate apparatus (IITC,
Inc., Woodland Hills, CA) and measuring the time until the
mouse licked its hind paws or jumped. A maximal latency of
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(
13) Bencherif, M.; Caldwell, W. S.; Dull, G. M.; Lippiello, P. M.
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3
0 s was used to minimize tissue damage.
Th er m or egu lation . Immediately before baseline and postin-
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Cole-Parmer, Vernon Hills, IL).
(
(
(
(
(
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Ack n ow led gm en t. We thank the National Institute
on Drug Abuse (DA12703) for the financial support of
this research.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic data and an ORTEP diagram of 5b and tail-flick and
hotplate analgesia data for subcutaneous adminstration of 1
and 5a ,b. This material is free of charge via the Internet at
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