Synthesis and pharmacological characterization of nicotinic acetylcholine receptor properties of (+)- and (-)-pyrido-[3,4-b]homotropanes

Article abstract of DOI:10.1021/jm060122n

(±)-Pyrido[3,4-b]homotropane [(±)-1] is a conformationally rigid analogue of nicotine (2) or nornicotine (3) that showed high affinity for nicotinic acetylcholine receptors. Even though the synthesis and potent activity of this highly interesting compound

Full text of DOI:10.1021/jm060122n

3244
J. Med. Chem. 2006, 49, 3244-3250
Synthesis and Pharmacological Characterization of Nicotinic Acetylcholine Receptor Properties
of (+)- and (-)-Pyrido-[3,4-b]homotropanes
F. Ivy Carroll,*,† Xingding Hu,† Herna´n A. Navarro,† Jeffrey Deschamps,‡ Galya R. Abdrakhmanova,§ M. Imad Damaj,§ and
Billy R. Martin§
Organic and Medicinal Chemistry, Research Triangle Institute, P.O. Box 12194, Research Triangle Park, North Carolina 27709, Laboratory
for the Structure of Matter, NaVal Research Laboratory, 4555 OVerlook AVenue, Washington, DC 20375-5341, and Department of
Pharmacology and Toxicology, Medical College of Virginia Commonwealth UniVersity, Richmond, Virginia 23298
ReceiVed February 3, 2006
(()-Pyrido[3,4-b]homotropane [(()-1] is a conformationally rigid analogue of nicotine (2) or nornicotine
(3) that showed high affinity for nicotinic acetylcholine receptors. Even though the synthesis and potent
activity of this highly interesting compound was originally reported in 1986 (Kanne, D. B.; Ashworth, D.
J.; Cheng, M. T.; Mutter, L. C.; Abood, L. G. Synthesis of the first highly potent bridged nicotinoid.
9-Azabicylo[4.2.l]nona[2,3-c]pyridine (pyrido[3,4-b]homotropane). J. Am. Chem. Soc. 1986, 108, 7864-
7865), the individual optical isomers have not been prepared and studied. In this study, we report the synthesis
of (+)- and (-)-1 and show that (+)-1 has Ki ) 1.29 nM at the R4â2* nAChR and has over 260 times
higher affinity than (-)-1. Single-crystal X-ray analysis of an intermediate used to prepare the isomers
established the absolute stereochemistry as (1S,6S)-(+)-1 and (1R,6R)-(-)-1. Surprisingly, both isomers
failed to produce antinociception in the mouse tail-flick and hot-plate assays, engender nicotine-like responding
in rat drug discrimination, or alter current amplitude in R4â2- and R3â4-containing cells. However, (-)-1
antagonized nicotine-induced antinociception with an ED50 of 0.07 µg/kg in the tail-flick assay. The reason
for this unusual pharmacology is unknown, but it is possible that (-)-1 is acting at a non-epibatidine-
sensitive receptor subtype to antagonize nicotine’s effects in the tail-flick assay.
There is a continuing interest concerning the pharmacophores
for the R4â2 and R7 nicotinic acetylcholine receptors (nAChRs),
the two major subtypes present in the brain. Compounds that
interact with these receptors are of interest because of their
potential therapeutic utility in the treatment of central nervous
system (CNS) disorders including Parkinson’s disease, Alzhei-
mer’s disease, schizophrenia, attention-deficit hyperactivity
disorder (ADHD), Tourette’s syndrome, smoking cessation,
epilepsy, and depression.1,2 In the late 1980s, Kanne and Abood
reported that racemic pyrido-[3,4-b]homotropane (1, PHT), a
conformationally rigid analogue of nicotine (2), or nornicotine
(3) possessed high nAChR activity.3,4 Since this initial report
the nAChR activity of a number of conformationally restricted
analogues of nicotine (2) or nornicotine (3) have been reported.
With the exception of natural product epibatidine (4) and some
of its analogues, none of these compounds has provided highly
useful information about the active pharmacophore of 1. In this
study we report the synthesis and pharmacological properties
of (+)- and (-)-1. The (+)-1 isomer shows 260 times higher
Importantly, (R)-(+)-methylbenzylamine was used in place of
benzylamine to generate diastereoisomers that could be separated
and then converted to (+)- and (-)-1 (Scheme 1). Heating a
solution of 9-oxabicyclo[6.1.0]non-4-ene (5) and (R)-(+)-
methylbenzylamine in methanol at 120 °C for 24 h in a sealed
tube gave trans-8-[(R)-phenylethylamino]cyclooct-4-enol as a
diastereoisomeric mixture of 6 and 7, which were separated by
affinity than the (-)-1 in binding to the R4â2 nAChR.
chromatography. Compounds 6 and 7 had optical rotation of
[R]25 +105 and -20, respectively. A single-crystal X-ray
Surprisingly, both isomers failed to produce antinociception in
D
the mouse tail-flick and hot-plate assays, engender nicotine-
like responding in rat drug discrimination, or alter current
amplitude in R4â2- and R3â4-containing cells. However, (-)-1
antagonized nicotine-induced antinociception with particularly
high potency in the tail-flick test. It failed to antagonize the
other pharmacological effects of nicotine.
analysis of 6 showed that it was (1S,8S)-trans-8-[(R)-phenyl-
ethylamine]cyclooct-4-enol (Figure 1). Aminomercuration of 6
and 7 with 1 equiv of mercuric acetate in aqueous tetrahydro-
furan at 0 °C followed by demercuration with sodium borohy-
dride yielded (1S,2S,6S)- and (1R,2R,6R)-9-[(R)-phenylethyl]-
9-azabicyclo[4.2.1]nonan-2-ol (8a and 8b, respectively) in 61%
The synthesis of (+)- and (-)-1 was carried out using a
and 60% yield, respectively, along with small amounts of 9a
or 9b. Swern (Moffott-Swern) oxidation of 8a or 8b using
oxalyl chloride and dimethyl sulfoxide in methylene chloride
gave (1S,6S)- and (1R,6R)-[(R)-phenylethyl]ketones (10a and
10b, respectively) in 85% yield each. Allylation of 10a or 10b
with allyl bromide via the boron enolate formed with potassium
bis(trimethylsilyl)amide and triethylboron in tetrahydrofuran
procedure similar to that reported by Kanne and Abood.3
* Corresponding author. Phone: (919) 541-6679. Fax: (919) 541-8868.
E-mail: fic@rti.org.
† Research Triangle Institute.
‡ Naval Research Laboratory.
§ Medical College of Virginia Commonwealth University.
10.1021/jm060122n CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/03/2006

Properties of (()-Pyrido-[3,4-b]homotropanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3245
Scheme 1a
aluminum hydride reduction of 12a or 12b in methylene chloride
afforded the (1S,6S)- and (1R,6R)-aldehydes 13a and 13b in
76% and 78% yield, respectively. Ozonolysis of 13a or 13b in
methylene chloride containing 1 equiv of trifluoroacetic acid
followed by a dimethyl sulfide workup furnished a dialdehyde
that was not isolated but treated with hydroxylamine hydro-
chloride in acetic acid at 105 °C to yield (1S,6S)- and (1R,6R)-
9-[(R)-phenylethyl]pyrido[3,4-b]homotropanes 14a and 14b in
28% and 26% overall yield, respectively. Subjection of 14a and
14b to transfer hydrogenation using ammonium formate and
10% palladium on carbon catalyst in methanol yielded the
desired (1S,6S)-1 and (1R,6R)-1 in 77% and 78% yield,
respectively. The hydrochloride salts of (-)-1 and (+)-1
possessed optical rotations of -48.3° and +48.5°, respectively.
A racemic sample of pyrido[3,4-b]homotropane was synthe-
sized using a procedure similar to that reported by Kanne and
Abood.3 The proton and carbon-13 NMR spectra of (()-, (+)-,
and (-)-1 as well as those of their hydrochloride salts were
identical.
Biology
The Ki values for the inhibition of [3H]epibatidine (4) binding
at the R4â2* nAChR in male rat cerebral cortex for the (+)-
and (-)-pyrido-[3,4-b]homotropanes (+)- and (-)-1, for nico-
tine (2), and (+)- and (-)-epibatidine are listed in Table 1. The
binding assays were conducted and the Ki values calculated as
previously described.5 Compounds (+)- and (-)-1 were also
evaluated for percent inhibition at 10 µM of binding to R7
nAChR using [125I) iodoMLA and methods previously reported.5
Both compounds showed less than 50% inhibition at 10 µM.
The above compounds were evaluated in two acute pain
models, the tail-flick and the hot-plate tests, and the results are
listed in the Table 1.6 In the tail-flick method of D’Amour and
Smith,7 the tail is exposed to a heat lamp and the amount of
time taken for the animal to move (flick) its tail away from the
heat is recorded. A control response (2-4 s) was determined
for each mouse before treatment, and a test latency was
determined after drug administration. The method used for the
hot-plate test is a modification of those described by Eddy and
Leimbach8 and Atwell and Jacobson.9 Mice were placed into a
10-cm wide glass cylinder on a hot plate (Thermojust apparatus)
maintained at 55.0 °C. Two control latencies at least 10 min
apart were determined for each mouse. The normal latency
(reaction time) was 8-12 s. The reaction time was scored when
the animal jumped or licked its paws. The mice were tested 5
min after sc injections of nicotinic ligands for the dose-response
evaluation. Antinociceptive response was calculated as percent-
age of maximum possible effect (% MPE, where %MPE ) [(test
- control)/(maximum latency - control) × 100]).
a Reagents: (a) (R)-C6H5CH(CH3)NH2, CH3OH, sealed tube 120 °C; (b)
Hg(OAc)2, THF/H2O, 0 °C, 5 h; (c) NaBH4, 3 M NaOH; (d) (COCl)2,
(CH3)2SO, CH2Cl2, -78 to 25 °C; (e) KN[Si(CH3)3]2, Et3B, THF, -78 °C;
(f) CH2dCHCH2Br, -78 to 25 °C, 24 h; (g) TosMic, t-BuOK, DME/
CH3OH; (h) DIBAl-H, CH2Cl2, 0-25 °C; (i) O3, CH2Cl2, CF3CO2H (1
equiv), -78 °C; (j) (CH3)2S, -78 to 25 °C; (k) H2NOH‚HCl, AcOH, 105
°C, 40 min; (l) HCO2NH4, CH3OH, 10% Pd/C.
To measure the effect of analogues on spontaneous activity,
mice were placed into individual Omnitech photocell activity
cages (28 cm × 16.5 cm) 5 min after sc administration of either
0.9% saline or epibatidine analogues. Interruptions of the
photocell beams (two banks of eight cells each) were then
recorded for the next 10 min. Data were expressed as number
of photocell interruptions. Rectal temperature was measured by
a thermistor probe (inserted 24 mm) and digital thermometer
(Yellow Springs Instrument Co., Yellow Springs, OH). Readings
were taken just before and at different times after the sc injection
of either saline or epibatidine analogues. The difference in rectal
temperature before and after treatment was calculated for each
mouse. The ambient temperature of the laboratory varied from
21 to 24 °C from day to day.
Figure 1. Structure of compound 6 showing labeling of the non-
hydrogen atoms. Displacement ellipsoids are at the 50% probability
level.
afforded (1S,6S)- or (1R,6R)-3-allyl-[(R)-phenyethyl]ketones
(11a or 11b, respectively) in 77% and 82% yield, respectively.
Conversion of 11a and 11b to the nitriles 12a or 12b in 77%
and 79% yield, respectively, was accomplished using tosylmeth-
yl isocyanide (TosMic) and potassium tert-butoxide in a mixture
of ethylene glycol dimethyl ether and methanol. Diisobutyl-
Finally, these compounds were evaluated in rat nicotine drug
discrimination. Rats were trained and tested in standard operant

3246 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Carroll et al.
Table 1. Radioligand Binding and Pharmacological Data for (()-, (+)-, and (-)-1, (+)- and (-)-Nicotine, and (+)- and (-)-Epibatidine
AD50 (µg/kg)
R4â2* [3H]epibatidine ED50 mg/kg
ED50 mg/kg
hot-plate
ED50 mg/kg
hypothermia spontaneous activity tail-flick
ED50 mg/kg
compd
X
(Ki, nM)a
tail-flick
hot-plate
body temp
(S)-(-)-nicotine
1.50 ( 0.30
1.3
(0.5-1.8)
8.0
(4.1-8.7)
0.0006
0.65
(0.25-0.85)
3.9
(3.1-4.5)
0.004
1
0.5
(0.15-0.78)
2.9
(2.1-5.4)
0.001
(2)
(0.6-2.1)
7.6
(4.3-8.5)
0.004
(R)-(+)-nicotine
(2)
(+)-epibatidine
(4)
(-)-epibatidine
(4)
(()-1
35 ( 3
0.026 ( 0.002
0.018 ( 0.001
6.1 ( 1.4
0.006
0.004
0.004
0.001
(0.0005-0.005)
2.6
(0.001-0.01) (0.001-0.008) (0.002-0.008)
H
H
H
12% 10
8% at 1
2% at 1
2 at 10
8% at 1
2% at 1
1.6
(0.5-2.5)
2.9
(1.3-4.2)
-0.1 °C at 5*
5.0
1000
(1.2-4.1)
(0.1-10)
(600-2100)
(+)-1
(-)-1
1.29 ( 0.18
350 ( 160
2.0
0% at 1000 5% at 1000 0% at 1000
(1.3-2.9)
10% at 5
0.07
0.8
0% at 1000
(0.05-0.1) (0.18-2.3)
a The Ki’s with mean and 95% CI are as follows: (S)-nicotine, 1.5 (0.6-3.4); (R)-(+)-nicotine, 35 (24-55); (+)-epibatidine, 0.026 (0.018-0.035);
(-)-epibatidine, 0.18 (0.007-0.027); (()-1, 6.1 (2.4-11.8); (+)-1, 1.29 (0.7-1.9); (-)-1, 346 (94-670).
Table 2. In Vitro Agonist/Antagonist Activity of Test Compounds at
conditioning chambers (Lafayette Instruments Co., Lafayette,
the Expressed R4â2 and R3â4 nAChRs
IN) as recently described.10 Briefly, rats were trained to press
effect at R4â2 nAChR
effect at R3â4 nAChR
one lever following administration of 0.4 mg/kg nicotine and
to press another lever after injection with saline, each according
to a fixed ratio 10 schedule of food reinforcement. Following
successful acquisition of the discrimination, stimulus substitution
tests with test compounds were conducted during 15-min test
sessions. During test sessions, responses on either lever delivered
reinforcement according to a fixed ratio 10 schedule. To be
tested, rats must have completed the first FR and made at least
80% of all responses on the injection-appropriate lever on the
preceding day’s training session.
compd
(10 µM)
% of ACh
% remaining
% of ACh
% remaining
responsea
ACh responseb
responsea
ACh responseb
(+)-1
(-)-1
28 ( 5
0
117 ( 3
89 ( 3
13 ( 2
0.9 ( 0.2
101 ( 5
93 ( 3
a Percent agonist activity of 10 µM test compound relative to that of
ACh at its EC50 concentration (20 µM ACh for R4â2 nAChR and 100 µM
ACh for R3â4 nAChR). b Percent antagonist activity of 10 µM test
compound against the ACh EC50 concentration. Results are presented as
means ( SEM (n ) 3-4). Whole-cell currents were recorded at a holding
potential of -80 mV.
ED50 values with 95% confidence limits for behavioral data
were calculated by unweighted least-squares linear regression
as described by Tallarida and Murray.11
The effects of (+)- and (-)-1 on the function of nicotinic
receptors were evaluated using patch-clamp technique in the
whole-cell configuration in recombinant R3â4 and R4â2 neu-
ronal nAChRs. Cell lines were generously provided Dr. R. Lukas
from Barrow Neurological Institute (human R4â2 in SH-EP1
cells) and Dr. K. Kellar from Georgetown University (rat R3â4
in HEK 293 cells).
Abood3,4 synthesis, we were able to obtain a separable mixture
of 6 and 7 (see Scheme 1). Subjection of 6 and 7 to a sequence
of improved steps similar to that of Kanne and Abood led to
overall good yield of the final described individual isomers
(1S,6S)-(+)-1 and (1R,6R)-(-)-1.
In this study, using [3H]epibatidine (4) to label R4â2*
nAChRs in rat brain we found that (()-, (+)-, and (-)-1
possessed Ki’s of 6.1, 1.3, and 346 nM, respectively. Thus,
(1R,2R)-(+)-1 has a 266 times higher affinity than (1S,2S)-(-
)-1. This contrasts sharply with natural (S)-(-)-nicotine (2),
which is only 23 times more potent than (R)-(+)-nicotine (2),
and (+)-epibatidine (4), which is 0.7 times less potent than (-)-
epibatidine (4). Both (+)-1 and (-)-1 inhibited binding of the
selective R7 nAChR ligand [125I] iodoMLA by less than 50%
at 10 µM, and they had very low affinity for the subtype.
To assess in vitro function (+)-1 and (-)-1 were tested for
both agonist and antagonist activity in R4â2 or R3â4 nAChRs.
Prior to examination of the test compound activity, whole-cell
currents were elicited by pulse application (200 ms) of ACh, at
the concentration close to its EC50 value for each nAChR
subtype.12,13 When (+)- and (-)-1 were tested alone at 10 µM,
(-)-1 did not activate currents in R4â2 or R3â4 nAChR-
expressing cells (Table 2), while some low agonist activity was
induced by (+)-1 in both nAChR subtypes being more
pronounced in R4â2 than in R3â4 nAChRs (28 ( 5% vs 13 (
2%, respectively, of ACh (EC50)-induced peak current). Detailed
examination of the agonist effect of (+)-1 on R4â2 nAChRs
revealed that the compound behaved as a weak partial agonist
with an intrinsic activity of 17 ( 0.7% versus a full agonist
ACh (1 mM) and EC50 of 5.5 µM. In addition, ACh (EC50)-
induced currents mediated by R4â2 and R3â4 nAChRs were
not inhibited in the presence of (+)- or (-)-1 at the 1-10 µM
concentration range. When (+)-1 concentration was increased
Results and Discussion
Kanne, Abood, and co-workers3,4 synthesized (()-pyrido[3,4-
b]homotropane [(()-1] as a rigid analogue of anatoxin-a (15)
and nornicotine (3). Compound (()-1 had an IC50 value of 5
nM compared to 7 nM for (()-nicotine and 80 nM for (()-
nornicotine using [3H]nicotine-labeled R4â2 nAChRs in rat
brain. These workers also reported that (+)-nicotine, which can
be viewed as resulting from N-methylation of (+)-nornicotine,
was over 10 times more potent than (+)-nornicotine. However,
they found that N-methyl analogue 16 was 200 times less potent
than (()-1.
Even though this highly interesting conformationally rigid
analogue of nornicotine and nicotine was originally reported in
1986,3,4 the individual isomers had not been reported and
studied. By replacing benzylamine with (R)-(+)-methylbenzyl-
amine in the first step of the originally reported Kanne and

Properties of (()-Pyrido-[3,4-b]homotropanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3247
Table 3. Agonist/Antagonist Activity of Test Compounds in Nicotine
Rat Discrimination
a paradox in that it has little affinity for the epibatidine-binding
site, fails to activate or block either R4â2 and R3â4 receptors,
yet it is highly effective in blocking nicotine-induced antinoci-
ception. These observations underscore previous findings that
indicate receptor subtypes other than R4â2 participate in
antinociceptive effects in the tail-flick procedure. The failure
of (-)-1 to alter ACh-induced currents in R4â2-containing cells
argues against allosteric modulation. On the other hand, it is
possible that (-)-1 is acting at a non-epibatidine-sensitive
receptor subtype to antagonize nicotine’s effects in the tail-flick
procedure. If such a receptor subtype exists, then it appears to
play a weaker role in antinociception measured by the hot-plate
test. There are several possible explanations for the apparent
lack of correlation between affinity/activity at R4â2 and R3â4
nAChR subtypes and its in vivo efficacy. One is that (-)-1
antagonized nicotine-induced antinociception in the tail-flick by
binding to other nAChRs subtypes such as R7 nicotinic
receptors. However, we showed that (-)-1 does not compete
with high-affinity R7 subtypes ruling out such possibility.
Another explanation is that (-)-1 binds to a receptor population
different from epibatidine. In the binding assays, we are limited
to the subtype binding profile of [3H] epibatidine, and our tissue
homogenate contains predominantly the R4â2 nAChR subtypes.
Thus, (-)-1 may have an nAChR subtype binding profile
different from epibatidine. Finally, compounds may have
differential binding affinity to the various conformations of
nicotinic receptors (desensitized or inactive state for example)
or simply bind to nonnicotinic receptors. It is worth mentioning
that the other nAChR ligands characterized by high binding
affinity to native R4â2* receptors and low efficacies at nAChRs
possess interesting in vivo profiles, yet their mechanism of action
is not fully understood. Future exploration of this novel nicotine
modulator will be required in order to understand its pharma-
cological properties.
agonist effectsa
antagonist effectsb
compd
(dose mg/kg)
% nicotine lever response
% nicotine lever
responding
responding
rate
vehicle
2.7 ( 1.2
98.3 ( 0.7c
17 ( 7.7
1.0 ( 0.2
1.0 ( 0.1
0.4 ( 0.1c
0.2 ( 0.1c
1.1 ( 0.2
(S)-(-)-nicotine (0.4)
(()-1 (3)
84 ( 16
(+)-1 (0.56)
(-)-1 (3)
44.5 ( 9.5c
23.8 ( 16
97 ( 0.25d
84 ( 9.5
a Following successful acquisition of the discrimination, stimulus
substitution tests with test compounds were conducted during 15-min test
sessions 10 min after sc injection. b Antagonist testing was conducted by
pretreating rats with the target dose followed 10 min later with 0.4 mg/kg
of (-)-nicotine. c P < 0.05 from vehicle. d For antagonist studies with (+)-
1, the compound was given at 0.3 mg/kg.
up to 40 µM in the experiments on R4â2 nAChRs, the
compound inhibited ACh-induced currents in average by 10%.
Even though (+)-1 has a Ki essentially identical to that of
(S)-(-)-nicotine (2), its pharmacological profile differs from that
of (S)-(-)-nicotine. It depressed spontaneous activity and
produced hypothermia, although it was less potent than (S)-(-
)-nicotine. However, these effects were not blocked by the
nicotinic antagonist mecamylamine. On the basis of these
findings, it is highly likely that the effects of (+)-1 on
spontaneous activity and body temperature are not produced
through actions at nAChRs. Compound (+)-1 failed to produce
antinociception in either tail-flick or hot-plate assays at 1 mg/
kg, a dose that (S)-(-)-nicotine produces robust antinociception.
The inability of (+)-1 to produce antinociceptive effects is not
likely a biodispositional problem, since an intrathecal injection
of (+)-1 at a dose of 10 µg/mouse was also ineffective in the
tail-flick test (data not shown). In contrast to nicotine, which
fully substituted for itself (Table 3), (()-1 and (+)-1 failed to
fully substitute for nicotine (0.4 mg/kg) in rat drug discrimina-
tion. At a slightly higher dose (1 mg/kg), (+)-1 produced lethal
effects in the two rats to which it was administered. Higher
dose were therefore not tested. Moreover, (+)-1 decreased
overall response rates compared to vehicle (p > 0.05; Table
3). In addition, (()-1 and its isomers given at the highest inactive
dose failed to significantly block nicotine discrimination.
Not surprising (-)-1 with the Ki of 346 nM was inactive in
all four mouse behavioral assays. It was also inactive when given
intrathecally (10 µg/mouse) in the tail-flick test. It failed to
generate nicotine-like responding in rat drug discrimination and
did not block the nicotine cue. Surprisingly, (-)-1 was highly
potent in antagonizing nicotine-induced antinociception in the
tail-flick test (AD50 ) 0.07 µg/kg). Compound (-)-1 also
antagonized the antinociceptive effects of nicotine in the hot-
plate test, showing an AD50 of 0.8 µg/kg. Compound (-)-1 did
not antagonize nicotine effects of body temperature.
The enantiomers of 1 represent intriguing probes for nicotinic
receptors for several reasons. Certainly, the enantioselectivity
exhibited by (+)- and (-)-1 far exceeds that of previously
reported nicotinic ligands such as nicotine and epibatidine and
serves as a guide for gaining greater insight into the receptor
pharmacophore. While (+)-1 retains the ability to bind to the
epibatidine-binding site (assumed to be an R4â2 subtype), it
lacks sufficient intrinsic efficacy to activate either R4â2 and
R3â4 receptors to a sufficient degree to produce the full
spectrum of nicotine pharmacological effects. In addition, it
failed to antagonize several of nicotine’s behavioral effects and
in vitro receptor activation. It is possible that (+)-1 is involved
in a different mechanism of nicotinic receptor modulation not
detected in our experimental models. However, (-)-1 represents
Experimental Section
1H and 13C NMR spectra were recorded on a 300 MHz (Bruker
AVANCE 300) or 500 MHz (Varian 500) spectrometer. Chemical
shift data for the proton resonances were reported in parts per
million (δ) relative to internal (CH3)4Si (δ 0.0). Melting points were
determined on a Bristoline apparatus. All optical rotations were
determined at the sodium D line using a Rudolph Research Autopol
III polarimeter (1 dm cell). Thin-layer chromatography was carried
out on EMD silica gel 60 TLC plates. Visualization was ac-
complished under UV or in an iodine chamber. Microanalyses were
carried out by Atlantic Microlab Inc. The compounds were purified
by flash chromatography on silica gel 60 (230-400 mesh) or
RediSep columns by running CombiFlash Companion Isco system.
All moisture-sensitive reactions were performed under a positive
pressure of nitrogen.
Trans-8-[(R)-Phenylethylamino]cyclooct-4-enol (6 and 7). A
solution of 9-oxabicyclo[6.1.0]non-4-ene (5, 30.60 g, 0.246 mol)
and (R)-(+)-methylbenzylamine (50.8 mL, 0.394 mol) in methanol
(12 mL) was placed in a sealed tube and was stirred at 120 °C for
72 h, then cooled to room temperature. The CH3OH and excess
methylbenzylamine were evaporated under reduced pressure. Re-
crystallization of the residue in hexane followed by flash chroma-
tography [silica, 100% EtOAc followed by CH2Cl2/CH3OH (9:1)]
of the resulting concentrated filtrate afforded overall 20.12 g (33%)
of (+)-6 as white crystals and 20.57 g (34%) of (-)-7 as a colorless
viscous oil.
(1S,8S)-(+)-trans-8-[(R)-Phenylethylamino)cyclooct-4-enol (6).
1
[R]25 +104.5 (c 1.38, CHCl3); mp 91-92 °C; H NMR (CDCl3)
D
δ 7.15-7.38 (m, 5H), 5.35-5.60 (m, 2H), 3.92 (q, J ) 6.6 Hz,
1H), 3.31 (dt, J ) 3.0, 6.6 Hz, 1H), 3.29 (s, 1H), 2.20-2.45 (m,
2H), 1.90-2.15 (m, 6H), 1.36 (d, J ) 6.6 Hz, 3H), 1.30 (m, 1H),
1.09 (m, 1H); 13C NMR (CDCl3) δ 144.42, 130.41, 128.48, 127.96,

3248 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Carroll et al.
127.19, 126.96, 71.52, 57.65, 56.24, 34.52, 32.46, 24.76, 23.01,
60.65, 42.52, 35.41, 30.88, 27.21, 22.62, 20.08; MS (APCI) m/z
(M+ + 1) calcd 244.3, obsd 244.5.
22.93; MS (ESI) m/z (M+ + 1) calcd 246.4, obsd 246.5.
(1S,6S)-3-Allyl-9-[(R)-phenylethyl)-9-azabicyclo[4.2.1]nonan-
2-one (11a). To a cooled (-78 °C) solution of potassium bis-
(trimethylsilyl)amide (95%, 3.54 g, 0.017 mol) in THF (25 mL)
under nitrogen was added 10a (3.16 g, 0.013 mol) dissolved in
THF (20 mL) dropwise. The resulting solution was allowed to stir
at -78 °C for an additional 10 min before 1.0 M triethylboron
(16.9 mL, 16.9 mmol) was added dropwise over 10 min, then allyl
bromide (99%, 1.47 mL, 16.9 mmol) was added all at once. The
mixture was stirred at -78 °C for 30 min, then warmed to room
temperature and stirred at room temperature for 24 h. Water (30
mL) was added, and the mixture was extracted with ether (3 × 30
mL). The combined organic phases were washed with brine, dried
(MgSO4), filtered, and evaporated. Flash chromatography [silica,
EtOAc/hexanes (1:4)] of the residue afforded 2.47 g (77%) of 11a
as a light yellow, viscous oil along with 0.42 g of 10a recovered.
1H NMR (CDCl3) δ 7.15-7.40 (m, 5H), 5.77 (m, 1H), 5.02 (dd, J
) 0.6, 12.6 Hz, 2H), 3.84 (q, J ) 6.6 Hz, 1H), 3.62 (dd, J ) 0.9,
9.6 Hz, 2H), 3.12 (m, 1H), 2.46 (m, 1H), 1.42-2.20 (m, 9H), 1.36
(d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3) δ 218.50, 145.56, 137.21,
128.69, 127.29, 127.25, 116.44, 70.76, 60.50, 59.94, 48.89, 35.33,
35.04, 31.23, 27.67, 26.03, 22.74; MS (APCI) m/z (M+ + 1) calcd
284.4, obsd 284.6.
(1R,8R)-(-)-trans-8-[(R)-Phenylethylamino]cyclooct-4-enol (7).
[R]25D -20.1 (c 3.36, CHCl3); 1H NMR (CDCl3) δ 7.16-7.38 (m,
5H), 5.60-5.75 (m, 1H), 5.44 (m, 1H), 3.74 (q, J ) 6.6 Hz, 1H),
3.31 (dt, J ) 3.0, 7.5 Hz, 1H), 2.58 (m, 1H), 2.10-2.40 (m, 5H),
1.95 (m, 1H), 1.74 (m, 1H), 1.20-1.50 (m, 6H); 13C NMR (CDCl3)
δ 145.55, 130.78, 128.71, 128.24, 127.44, 126.56, 71.76, 58.81,
57.87, 34.98, 33.47, 23.50, 23.12, 22.87; MS (ESI) m/z (M+ + 1)
calcd 245.4, obsd 245.6.
(1S,2S,6S)-(+)-9-[(R)-Phenylethyl]-9-azabicyclo[4.2.1]nonan-
2-ol (8a). To a solution of mercuric acetate (98%, 3.32 g, 0.01
mol) in THF (30 mL) and water (30 mL) at 0 °C was added (1S,8S)-
(+)-trans-8-[(R)-phenylethylamino]cyclooct-4-enol (6) (2.45 g, 0.01
mol) in THF (20 mL). The mixture was stirred at 0 °C for 5 h, and
then 3 M NaOH (10.0 mL) was added followed by sodium
borohydride (99%, 390 mg, 10.2 mmol) in 3 M NaOH (10.0 mL).
After stirring for 30 min while warming to room temperature, the
solution was diluted with brine, and the THF layer was separated.
The aqueous layer was extracted with ether (2 × 40 mL). The
combined organic phases were washed with brine, dried (MgSO4),
filtered, and evaporated. Flash chromatography [silica, CH2Cl2/CH3-
OH (10:1)] of the residue afforded 1.49 g (61%) of 8a as a colorless
viscous oil along with 0.23 g (7.6%) of 9a as a side product. [R]25
D
(1R,6R)-3-Allyl-9-[(R)-phenylethyl]-9-azabicyclo[4.2.1]nonan-
2-one (11b). Compound 11b was prepared from 10b in 82% yield
in a manner analogous to that described for 11a as a light yellow,
viscous oil: 1H NMR (CDCl3) δ 7.15-7.40 (m, 5H), 5.75 (m, 1H),
4.98-5.20 (m, 2H), 3.85 (m, 1H), 3.65 (q, J ) 6.6 Hz, 1H), 3.50
(m, 1H), 2.70-3.00 (m, 2H), 2.47 (m, 1H), 1.40-2.25 (m, 8H),
1.34 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3) δ 216.95, 145.63,
136.72, 128.62, 127.28, 127.19, 116.47, 71.70, 62.08, 62.00, 52.01,
1
+20.5 (c 1.05, CHCl3); H NMR (CDCl3) δ 7.10-7.40 (m, 5H),
3.65-3.80 (m, 2H), 3.47 (t, J ) 8.1 Hz, 1H), 3.25 (t, J ) 6.2 Hz,
1H), 2.05 (m, 1H), 1.71-1.90 (m, 3H), 1.48-1.70 (m, 4H), 1.36-
1.47(m, 2H), 1.20-1.35 (m, 4H); 13C NMR (CDCl3) δ 146.93,
128.30, 127.31, 126.75, 73.65, 66.15, 61.26, 57.37, 36.39, 33.51,
33.17, 22.98, 22.64, 20.30; MS (ESI) m/z (M+ + 1) calcd 246.4,
obsd 246.5.
(1R,2R,6R)-9-[(R)-Phenylethyl]-9-azabicyclo[4.2.1]nonan-2-
ol (8b). Compound 8b, a colorless viscous oil, was prepared from
(1R,8R)-(-)-7 in 60% yield in a manner analogous to that of 8a,
35.98, 31.46, 30.78, 27.43, 23.19, 22.81; MS (APCI) m/z (M+
1) calcd 284.4, obsd 284.6.
+
(1S,6S)-3-Allyl-9-[(R)-phenylethyl]-9-azabicyclo[4.2.1]nonane-
2-carbonitrile (12a). To a stirred, cooled (0 °C) solution of 11a
(2.83 g, 0.01 mol) and tosylmethyl isocyanide (3.90 g, 20.0 mmol)
in ethylene glycol dimethyl ether (DME) (50 mL) and methanol
(0.82 mL) was added potassium tert-butoxide (95%, 5.90 g, 0.05
mol) all at once. The resulting solution was heated to 50 °C and
stirred for 36 h. The mixture was then cooled in an ice bath, and
2 N HCl was added until a pH of 8 was obtained. Most of the
DME was evaporated under reduced pressure, and the mixture was
extracted with ether (3 × 30 mL). The combined organic phases
were washed with brine, dried (MgSO4), filtered, and evaporated.
Flash chromatography (silica, 100% CH2Cl2) of the residue afforded
2.28 g (77%) of 12a as a light yellow oil: 1H NMR (CDCl3) δ
7.15-7.45 (m, 5H), 5.65-5.85 (m, 1H), 4.90-5.20 (m, 2H), 3.40-
3.95 (m, 3H), 1.82-2.50 (m, 6H), 1.20-1.70 (m, 9H); MS (APCI)
m/z (M+ + 1) calcd 295.4, obsd 295.3.
(1R,6R)-3-Allyl-9-[(R)-phenylethyl]-9-azabicyclo[4.2.1]nonane-
2-carbonitrile (12b). Compound 12b, which was prepared from
11b in 79% yield in a manner analogous to that of 12a, is a light
yellow oil: 1H NMR (CDCl3) δ 7.10-7.40 (m, 5H), 5.75 (m, 1H),
5.00-5.20 (m, 2H), 3.55-4.00 (m, 2H), 3.18-3.40 (m, 1H), 2.00-
2.50 (m, 5H), 1.55-1.95 (m, 2H), 1.25-1.53 (m, 8H); MS (APCI)
m/z (M+ + 1) calcd 295.4, obsd 295.3.
(1S,6S)-3-Allyl-9-[(R)-phenylethyl]-9-azabicyclo[4.2.1]nonane-
2-carbaldehyde (13a). To a stirred, cooled (0 °C) solution of 12a
(2.94 g, 0.01 mol) in anhydrous CH2Cl2 (20 mL) was added
dropwise 1.0 M diisobutylaluminum hydride (12.0 mL, 12.0 mmol)
in CH2Cl2. The mixture was stirred at 0 °C for 2 h and then warmed
to room temperature and stirred for 3 h. The mixture was again
cooled to 0 °C, and water (10 mL) and 2 N HCl (0.5 mL) were
added. The mixture was stirred at room temperature for 1 h, then
filtered through Celite and thoroughly washed with CH2Cl2. The
filtrate was extracted with CH2Cl2 (3 × 30 mL), and the combined
organic phases were washed with brine, dried (Na2SO4), filtered,
and evaporated. Flash chromatography [silica, EtOAc/hexanes (1:
4)] of the residue provided 2.26 g (76%) of 13a as viscous, light
yellow oil: 1H NMR (CDCl3) δ 9.23 (s, 1H), 7.15-7.40 (m, 5H),
along with 9.2% of 9b as a side product. [R]25 -9.2 (c 1.16,
D
1
CHCl3); H NMR (CDCl3) δ 7.10-7.40 (m, 5H), 3.68-3.83 (m,
2H), 3.47 (t, J ) 6.3 Hz, 1H), 3.25 (t, J ) 8.4 Hz, 1H), 1.95-2.05
(m, 2H), 1.25-1.92 (m, 11H), 1.10-1.25 (m, 1H); 13C NMR
(CDCl3) δ 146.92, 128.23, 127.22, 126.62, 74.11, 64.48, 61.33,
59.12, 35.93, 33.17, 23.26, 22.85, 20.42; MS (APCI) m/z (M+ +1)
calcd 246.4, obsd 246.5.
(1S,6S)-9-[(R)-Phenylethyl]-9-azabicyclo[4.2.1]nonan-2-one
(10a). To a cooled (-78 °C) solution of oxalyl chloride (4.5 mL,
9.0 mmol, 2 M in CH2Cl2) in CH2Cl2 (15 mL) under nitrogen was
added dimethyl sulfoxide (1.28 mL, 18.0 mmol) dropwise. The
resulting solution was allowed to stir at -78 °C for an additional
10 min before the addition of 8a (1.47 g, 0.006 mol) dissolved in
methylene chloride (10 mL). The mixture was stirred at -78 °C
for 30 min, and then triethylamine (5.0 mL, 36 mmol) was added.
The mixture was stirred overnight while warming up to room
temperature. Water (20 mL) was added, and the mixture was
extracted with CH2Cl2 (3 × 25 mL). The combined organic phases
were washed with brine, dried (Na2SO4), filtered, and evaporated.
Flash chromatography [silica, EtOAc/hexanes (1:4)] of the residue
afforded 1.24 g (85%) of 10a as a light yellow, viscous oil: [R]25
D
1
+107 (c 0.48, CHCl3); H NMR (CDCl3) δ 7.12-7.40 (m, 5H),
3.93 (q, J ) 6.6 Hz, 1H), 3.73 (dd, J ) 1.8, 9.9 Hz, 1H), 3.52 (m,
1H), 2.82 (dt, J ) 3.6, 14 Hz, 1H), 2.40 (dd, J ) 5.7, 15 Hz, 1H),
2.10-2.30 (m, 1H), 1.45-1.98 (m, 7H), 1.34 (d, J ) 6.6 Hz, 3H);
13C NMR (CDCl3) δ 218.30, 145.48, 128.55, 127.13, 127.09, 70.18,
59.64, 59.37, 43.10, 34.15, 30.16, 27.90, 22.75, 20.00; MS (APCI)
m/z (M+ + 1) calcd 244.3, obsd 244.5.
(1R,6R)-9-[(R)-Phenylethyl]-9-azabicyclo[4.2.1]nonan-2-one
(10b). Compound 10b, which was prepared from 8b in 85% yield
in a manner analogous to that of 10a, is a light yellow, viscous oil:
[R]25D -20.7 (c 1.45, CHCl3); 1H NMR (CDCl3) δ 7.12-7.40 (m,
5H), 3.80 (q, J ) 6.6 Hz, 1H), 3.55-3.73 (m, 2H), 3.01 (dt, J )
2.7, 13.7 Hz, 1H), 2.32 (dd, J ) 5.7, 14.4 Hz, 1H), 2.07-2.24 (m,
1H), 1.45-1.95 (m, 7H), 1.34 (d, J ) 6.6 Hz, 3H); 13C NMR
(CDCl3) δ 218.31, 145.61, 128.46, 127.17, 127.10, 69.94, 61.56,

Properties of (()-Pyrido-[3,4-b]homotropanes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3249
5.65-6.18 (m, 1H), 4.95-5.25 (m, 2H), 3.40-3.70 (m, 2H), 1.20-
2.40 (m, 16H); 13C NMR (CDCl3) δ 205.38, 145.54, 136.66, 128.35,
127.85, 127.13, 116.98, 64.32, 62.27, 61.55, 60.73, 40.81, 37.58,
36.37, 34.68, 28.71, 27.36, 20.75; MS (APCI) m/z (M+ + 1) calcd
298.4, obsd 298.5.
Hz, 1H), 3.81 (m, 1H), 3.08 (dt, J ) 3.3, 14.4 Hz, 1H), 2.70 (dt,
J ) 3.6, 15.9 Hz, 1H), 2.45 (m, 1H), 2.00-2.20 (m, 2H), 1.73-
1.98 (m, 3H), 1.66 (m, 1H); 13C NMR (CDCl3) δ 149.28, 148.48,
148.13, 143.72, 125.57, 60.80, 58.34, 34.17, 31.99, 31.68, 30.13;
MS (APCI) m/z (M+ + 1) calcd 175.3, obsd 175.6.
(1R,6R)-3-Allyl-9-(1-phenylethyl)-9-azabicyclo[4.2.1]nonane-
2-carbaldehyde (13b). Compound 13b, which was prepared from
12b in 78% yield in a manner analogous to that of 13a, is a light
yellow, viscous oil: 1H NMR (CDCl3) δ 9.46 (s, 1H), 7.15-7.40
(m, 5H), 5.75 (m, 1H), 4.90-5.10 (m, 2H), 3.84 (dd, J ) 2.4, 10.2
Hz, 1H), 3.59 (q, J ) 6.6 Hz, 1H), 3.26 (m, 1H), 2.25-2.45 (m,
2H), 2.10 (m, 1H), 1.32-2.00 (m, 9H), 1.21 (d, J ) 6.6 Hz, 3H);
13C NMR (CDCl3) δ 205.58, 146.44, 136.40, 128.27, 127.12,
126.72, 116.95, 63.85, 62.04, 61.73, 59.48, 40.68, 36.81, 36.40,
34.52, 27.54, 27.21, 23.18; MS (ESI) m/z (M+ + 1) calcd 298.4,
obsd 298.4.
To a stirred solution of (-)-1 free base (62 mg, 0.333 mmol) in
CH2Cl2 (10 mL) and CH3OH (2 mL) at 0 °C was added HCl (1 M
in ether, 1.3 mL) dropwise. The mixture was warmed to room
temperature and stirred at room temperature for 1 h. The solvent
and excess HCl were evaporated and then kept under vacuum
overnight to provide 86 mg (98%) of (-)-1‚2HCl. [R]25 (c 0.85,
D
CH3OH) -48.3; Anal. Calcd for (C11H16Cl2N2): C, H, N.
(1R,6R)-(+)-Pyrido[3,4-b]homotropane [(+)-1] Dihydrochlo-
ride. To a solution of 14b (300 mg, 1.08 mmol) and dry ammonium
formate (1.36 g, 0.022 mol) in absolute methanol (10 mL) was
added dry 10 wt % Pd/C (300 mg). The mixture was stirred at
room temperature under nitrogen for 24 h and then filtered through
Celite and thoroughly washed with methanol. The filtrate was
evaporated under reduced pressure. Flash chromatography [silica,
CH2Cl2/CH3OH/29%NH3‚H2O (90:18:2)] of the resulting residue
(1S,6S)-9-[(R)-Phenylethyl]-pyrido[3,4-b]homotropane (14a).
To a stirred, cooled (0 °C) solution of 13a (2.97 g, 0.01 mol) in
anhydrous CH2Cl2 (20 mL) under nitrogen was added trifluoroacetic
acid (0.80 mL, 10.5 mmol). After stirring at 0 °C for 10 min, the
solution was cooled to -78 °C, and then ozone was bubbled through
the solution over 20-30 min until a light blue color appeared. After
the solution stirred 2 min longer, the ozone was removed. The
excess ozone in the solution was evacuated with nitrogen for about
10 min until the light blue color disappeared. Methyl sulfide (4.4
mL) was added, and the mixture was stirred for 2 h while warming
up to room temperature and stirred 1 h at room temperature. The
solvent was evaporated under reduced pressure, and the residue
was dissolved in 60 °C acetic acid (10 mL), which was added
dropwise to a 105 °C solution of hydroxylamine hydrochloride (3.47
g, 0.05 mol) in acetic acid (25 mL). The mixture was stirred at
105 °C for 30 min under nitrogen; the color of solution changed to
deep brown. The solution was cooled to room temperature and
poured into ice-cold ether (80 mL), basified with 29% ammonium
hydroxide and then saturated K2CO3 to pH 8. The ether layer was
separated, and the aqueous phase was extracted with ether (3 × 50
mL). The combined organic phases were washed with brine, dried
(Na2SO4), filtered, and evaporated. Flash chromatography (silica,
100% EtOAc) of the residue afforded 0.78 g (28%) of 14a as a
light yellow, viscous oil which solidified on standing. [R]25D +46.6
(c 0.77, CHCl3); 1H NMR (CDCl3) δ 8.36 (s, 1H), 8.36 (d, J ) 4.8
Hz, 1H), 7.13-7.33 (m, 5H), 7.10 (d, J ) 4.8 Hz, 1H), 4.49 (dd,
J ) 0.9, 9.3 Hz, 1H), 3.20-3.40 (m, 2H), 3.05 (dt, J ) 3.6, 12.9
Hz, 1H), 2.48-2.72 (m, 2H), 2.11 (m, 1H), 1.65-2.00 (m, 3H),
1.25 (d, J ) 6.3 Hz, 3H), 1.13-1.33 (m, 1H); 13C NMR (CDCl3)
δ 149.9, 149.57, 148.45, 145.68, 139.38, 128.45, 127.20, 126.87,
124.98, 61.38, 58.08, 55.85, 32.18, 31.30, 28.73, 24.87, 23.08; MS
(ESI) m/z (M+ + 1) calcd 279.4, obsd 279.4.
afforded 146 mg (78%) of (+)-1 as a white solid. [R]25 (c 1.34,
D
CHCl3) +38.3; 1H NMR (CDCl3) δ 8.31 (d, J ) 4.8 Hz, 1H), 8.30
(s, 1H), 7.07 (d, J ) 4.8 Hz, 1H), 4.40 (dd, J ) 2.1, 11.1 Hz, 1H),
3.85 (m, 1H), 3.09 (dt, J ) 3.6, 14.4 Hz, 1H), 2.72 (dt, J ) 3.6,
15.9 Hz, 1H), 2.60 (s, 1H), 2.46 (m, 1H), 2.17 (m, 1H), 1.73-1.98
(m, 3H), 1.69 (m, 1H); 13C NMR (CDCl3) δ 149.34, 148.70, 148.29,
143.14, 125.68, 60.78, 58.44, 33.89, 31.97, 31.66, 30.06; MS
(APCI) m/z (M+ + 1) calcd 175.3, obsd 175.3.
To a stirred solution of (+)-1 freebase (134 mg, 0.769 mmol) in
CH2Cl2 (20 mL) and CH3OH (4 mL) at 0 °C was added HCl (1 M
in ether, 3.1 mL) dropwise. The mixture was warmed to room
temperature and stirred at room temperature for 1 h. The solvent
and excess HCl were evaporated and then kept under vacuum
overnight to provide 189 mg (99.5% yield) of (+)-1‚2HCl. [R]25
(c 0.76, CH3OH) +48.5; Anal. Calcd (C11H16Cl2N2): C, H, N.
D
Acknowledgment. This research was supported by the
National Institute on Drug Abuse Grant DA12001.
Supporting Information Available: Crystal data, structural
refinement analysis, atomic coordinates, bond lengths, bond angles,
anisotropic displacement parameters, hydrogen coordinates, and
isotropic displacement parameters of 6 and elemental analysis data
for compounds (+)- and (-)-1. This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Lloyd, G. K.; Williams, M. Neuronal nicotinic acetylcholine receptors
as novel drug targets. J. Pharmacol. Exp. Ther. 2000, 292, 461-
467.
(2) Romanelli, M. N.; Gualtieri, F. Cholinergic nicotinic receptors:
competitive ligands, allosteric modulators, and their potential ap-
plications. Med. Res. ReV. 2003, 23, 393-426.
(1R,6R)-9-[(R)-Phenylethyl]pyrido[3,4-b]homotropane (14b).
Compound 14b, which was prepared from 13b in 26% yield in a
manner analogous to that of 14a, is a light yellow, viscous oil which
solidified on standing. [R]25 +93 (c 0.51, CHCl3); 1H NMR
D
(CDCl3) δ 8.29(d, J ) 4.8 Hz, 1H), 7.43 (s, 1H), 7.18-7.33 (m,
3H), 7.02-7.13 (m, 3H), 3.80-3.97 (m, 2H), 3.28 (q, J ) 6.3 Hz,
1H), 3.08 (dt, J ) 3.6, 12.9 Hz, 1H), 2.70 (dt, J ) 3.3, 15.6 Hz,
1H), 2.18-2.48 (m, 2H), 2.11 (t, J ) 12.9 Hz, 1H), 1.68-1.95
(m, 2H), 1.55 (m, 1H), 1.28 (d, J ) 6.3 Hz, 3H); 13C NMR (CDCl3)
δ 150.18, 149.60, 148.34, 145.18, 139.69, 128.45, 127.46, 127.12,
124.58, 61.79, 57.59, 55.76, 32.32, 30.89, 29.17, 24.87, 23.66; MS
(APCI) m/z (M+ + 1) calcd 279.4, obsd 279.6.
(3) Kanne, D. B.; Abood, L. G. Synthesis and biological characterization
of pyridohomotropanes. Structure-activity relationships of confor-
mationally restricted nicotinoids. J. Med. Chem. 1988, 31, 506-509.
(4) Kanne, D. B.; Ashworth, D. J.; Cheng, M. T.; Mutter, L. C.; Abood,
L. G. Synthesis of the first highly potent bridged nicotinoid.
9-Azabicylo[4.2.l]nona[2,3-c]pyridine (Pyrido[3,4-b]homotropane).
J. Am. Chem. Soc. 1986, 108, 7864-7865.
(5) Carroll, F. I.; Lee, J. R.; Navarro, H. A.; Ma, W.; Brieaddy, L. E.;
Abraham, P.; Damaj, M. I.; Martin, B. R. Synthesis, nicotinic
acetylcholine receptor binding, and antinociceptive properties of
2-exo-2-(2′,3′-disubstituted 5′-pyridinyl)-7-azabicyclo[2.2.1]heptanes:
epibatidine analogues. J. Med. Chem. 2002, 45, 4755-4761.
(6) Damaj, M. I.; Glassco, W.; Aceto, M. D.; Martin, B. R. Antinoci-
ceptive and pharmacological effects of metanicotine, a selective
nicotinic agonist. J. Pharmacol. Exp. Ther. 1999, 291, 390-398.
(7) D’Amour, F. E.; Smith, D. L. A method for determining loss of pain
sensation. J. Pharmacol. Exp. Ther. 1941, 72, 74-79.
(1S,6S)-(-)-Pyrido[3,4-b]homotropane[(-)-1] Dihydrochlo-
ride. To a solution of 14a (141 mg, 0.506 mmol) and dry
ammonium formate (638 mg, 10.12 mmol) in absolute methanol
(5 mL) was added dry 10 wt % Pd/C (141 mg). The mixture was
stirred at room temperature under nitrogen for 24 h and then filtered
through Celite and thoroughly washed with methanol. The filtrate
was evaporated under reduced pressure. Flash chromatography
[silica, CH2Cl2/CH3OH/29%NH3‚H2O (90:18:2)] of the resulting
residue afforded 68 mg (77%) of (-)-1 as a white solid. [R]25D (c
(8) Eddy, N. B.; Leimbach, D. Synthetic analgesics: II. Dithienybutenyl-
and benzomorphans. J. Pharmacol. Exp. Ther. 1953, 107, 385-939.
(9) Atwell, L.; Jacobson, A. E. The search for less harmful analgesics.
Lab. Anim. 1978, 7, 42-47.
1
2.90, CHCl3) -38.4; H NMR (CDCl3) δ 8.31 (d, J ) 4.8 Hz,
1H), 8.30 (s, 1H), 7.06 (d, J ) 4.8 Hz, 1H), 4.36 (dd, J ) 2.1, 11.1

3250 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Carroll et al.
(10) Damaj, M. I.; Wiley, J. L.; Martin, B. R.; Papke, R. L. In vivo
characterization of a novel inhibitor of CNS nicotinic receptors. Eur.
J. Pharmacol. 2005, 521, 43-48.
(11) Tallarida, R. J.; Murray, R. B. Manual of Pharmacological Calcula-
tions with Computer Programs; Springer-Verlag: New York, 1987.
(12) Zhang, J.; Xiao, Y.; Abdrakhmanova, G.; Wang, W.; Cleemann, L.;
Kellar, K. J.; Morad, M. Activation and Ca2+ permeation of stably
transfected alpha3/beta4 neuronal nicotinic acetylcholine receptor.
Mol. Pharmacol. 1999, 55, 970-981.
(13) Abdrakhmanova, G.; Damaj, M. I.; Carroll, F. I.; Martin, B. R.
2-Fluoro-3-(4-nitro-phenyl)deschloroepibatidine is a novel potent
competitive antagonist of human neuronal {alpha}4{beta}2 nAChRs.
Mol. Pharmacol., in press.
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