Pharmacology & Pharmacy, 2011, 2, 94-99
doi:10.4236/pp.2011.22012 Published Online April 2011 (http://www.SciRP.org/journal/pp)
Synthesis and Study of Anti Parkinsonism Activity of
8-Azabicyclo [3.2.1] Octane Analogs
Saurav M. Verma
Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra. Ranchi, India.
Received January 2
nd
, 2011; revised February 16
th
, 2011; accepted March 8
th
, 2011.
ABSTRACT
Parkinson’s disease (PD) is a common neurodegenerative condition associated with the degeneration of dopaminergic
neurons in the zona compacta of the substantia nigra. 3D QSAR study of
8-azabicyclo [3.2.1] octane analogs which
serves as the pathfinder for the design of novel molecule for anti Parkinsonism. Five compounds of 8-azabicyclo [3.2.1]
octane analogs are synthesized and the anti Parkinsonism activity and brain dopamine level were studied on albino mice.
The anti Parkinsonian activity was determined by the effect of test compound A-E on drug induced catatonia using the
method of Morpurgo.
Atropine as well as compounds B and E significantly reduced the catatonic responses and tremors
induced by chlorpromazine. The level of dopamine was measured after the administration of atropine and the test
compounds in brain of mice. The study reveals that the compounds B and E have exhibited significant activity over
atropine.
Keywords: 8-Azabicyclo [3.2.1] Octane, Parkinsonism, Dopamine, Catatonia
1. Introduction
Parkinson’s disease (PD) is the second most common
neurodegenerative disease [1]. It was first described by
Parkinson and is characterized by four features, namely
slowness of movement (bradykinesia), muscular rigidity,
resting tremor and impairment of postural balance lead-
ing to disturbances of gait and falling. The disease occurs
in all ethnic groups and in both sexes. It generally com-
mences in the middle and late age and leads to progres-
sive disability with increasing age. It has been estimated
that about 1% of the population of the age group of 45
years or below suffer from Parkinson’s disease. In a
population of those who are 60 years and above, about
10% suffer, and half of the populations belonging to age
group of 85 years and above have this abnormality [2,3].
In Parkinson’s disease there are decreased levels of
striatal dopamine (1) and this has been found
to be due to
the loss of neurons in substantia nigra pars compacta that
provides dopaminergic innervations to the striatum [4].
At present five distinct dopamine receptors are known.
These five dopamine receptors have been divided into
two groups on the basis of their pharmacological and
structural properties. The D
1
and D
5
receptors have a
long carboxyl terminal and belong to pharmacologically
defined D
1
class of receptors. The D
2
, D
3
and D
4
recep-
tors have a large third intracellular loop and belong to D
2
class [4].
Drugs that are generally used in treatment of Parkin-
son’s disease can be classified into five categories and
that include: Drugs that replace dopamine, the monoam-
ine oxidase inhibitor, Dopamine Receptor Agonists, Drugs
that inhibit dopamine reuptake, Antimuscarinic agents.
The fifth classes of compounds include antimuscarinic
agents, atropine (2) and benztropine (3). Muscarinic ace-
tylcholine receptors exert an excitatory effect and also
presynaptic inhibitory effect on dopaminergic nerve ter-
minals. Suppression of these effects, thus, makes up for
lack of dopamine (1). The antimuscarinic agents dimin-
ish the tremor more than the rigidity or hypokinesia.
They also have side effects like dry mouth, constipation,
and urinary retention [5,6].
OH
OH
NH
2
NCH
3
O
O
OH
O
N
CH
3
(1) (2) (3)
3D-QSAR models of Comparative Molecular Field
Analysis (CoMFA) and Comparative Molecular Similari-

Synthesis and Study of Anti Parkinsonism Activity of 8-Azabicyclo [3.2.1] Octane Analogs
95
ties Indices Analysis (CoMSIA) of 8-azabicyclo [3.2.1]
octane (potent muscarinic receptor blocker) was per-
formed [7]. Results indicate that the CoMFA and CoM-
SIA models could be reliable model which may be used in
the design of novel muscarinic antagonists as leads. The
3D-QSAR models of 8-azabicyclo [3.2.1] octane open
the way to design the novel molecules for antimuscarinic
and anti Parkinsonism.
2. Chemistry
Synthesis of 9-Methyl-4-oxo-3, 9 diazabicyclo [4.2.1]
nonane-3-carbothiohydrazide derivatives shown in Sche-
me-I. [8-11]
9-Methyl-4-oxo-3, 9 diazabicyclo [4.2.1]
nonane-3-carbothiohydrazide (4) (2.28 g) was taken in
absolute alcohol (25 ml) and treated with glacial acetic
acid (1 ml) and benzaldehyde (1.06 ml) or 2-chloroben-
zaldehyde (1.405 g). After refluxing the reaction mixture
for 24 hrs it was kept in refrigerator when the thiosemi-
carbazone (6) and (7) precipitated out.
N
N
NH
NH
2
S
O
H
3
C
N
N
NH
N
S
O
H
3
C
R
a, b, c,
refluxing for 24 hrs
(4) (6, 7)
Scheme 1. a = absolute alcohol, b = glacial acetic acid, c =
benzaldehyde (for 6) or 2-chlorobenzaldehyde (for 7) and R
= H (6), Cl (7)
Synthesis of 3-benzenesulphonyl-9-methyl-3, 9-diaza-
bicyclo [4.2.1] nonane hydrochloride derivatives shown
in Scheme 2. [8-11]
To a solution of 9-methyl-3, 9-di-
azabicyclo [4.2.1] nonane (5) (0.42g) in dry pyridine was
added benzenesulphonyl chloride (0.6 ml) or p-toluene
sulphonyl chloride (0.8 g) or p-chlorobenzene sulphonyl
chloride and the reaction mixture heated on a water bath
for 30 min. The contents of the flask were poured into ice
cold water (10 ml), basified with potassium carbonate,
and extracted with chloroform (3 × 10 ml). After work-
ing up the chloroform extract in the usual manner, an oily
residue (0.65 g) was obtained. This was converted to the
hydrochloride and crystallized from acetone.
3. Results and Discussion
The Pharmacological studies of the compounds 6 (A), 7
(B), 8 (C), 9 (D), 10 (E) were carried out for the anti-
parkinsonian activity.
3.1. Antiparkinsonian Activity
The antiparkinsonian activity was determined by the
NH
N
H
3
C
N
N
H
3
C
R
S
O
O
heated on water
bath for 30 min
1. a, b
2. c, d, e
(5) (8, 9, 10)
Scheme 2. a = benzenesulfonyl chloride (for 8), p-toluene-
sulphonylchloride (for 9), p-chlorobenzenesulphonyl chlo-
ride (for 10), b = dry pyridine, c = potassium carbonate, d =
chloroform, e = HCl, R = H (8), CH
3
(9), Cl (10).
effect of Test Compound A-E on drug induced catatonia
using the method of Morpurgo [12-14].
Albino mice, weighing 25-30 g maintained on a 12 hrs
light and dark cycle and ad libitum food and water were
throughout used. The catatonia was induced by chlor-
promazine at a dose level of 5 mg/kg body weight intra
peritoneal (IP). Atropine was administered at a dose level
of 2 mg/kg body weight IP. The Test Compounds were
administered at a dose level of 200 g/100 g body weight.
All drugs were dissolved in distilled water or saline in
concentrations with which the IP administration of 1
ml/100g of mice could be kept constant. Each Test
Compound was administered to four animals. The cata-
tonia was induced with chlorpromazine and the Atropine
was used as standard anticatatonic. The score for severity
of catatonic response was recorded as follows:
Stage 1: Normal movement when placed on the table,
score = 0;
Stage 2: Movement only when touched or pushed,
score = 0.5;
Stage 3: Animal placed on the table with front paws
set alternately on a 3 cm high block fails to correct the
posture in 10 seconds, score = 0.5 for each paw with a
total of 1 for this stage.
Stage 4: Animal fails to remove the paw when front
paws are placed alternately on a 9 cm block, score = 1 for
each paw and a total score of 2 for this stage.
Thus for a single animal the maximum possible score
could be 3.5 revealing total catatonia. The results are
tabulated in Table 1. The results clearly indicate that
atropine as well as Compounds B and E significantly
reduced the catatonic responses and tremors induced by
chlorpromazine. In order to confirm this further, the lev-
els of dopamine were measured after the administration
of atropine, Test Compounds B and E in the brain of mice.
3.2. Determination of Brain Dopamine Level in
Mice
The method of estimation of dopamine was based on

Synthesis and Study of Anti Parkinsonism Activity of 8-Azabicyclo [3.2.1] Octane Analogs
96
Table 1. Degree of catatonic responses on mice of Atropine
and Test Compounds A to E.
Group Degree of Catatonic Response
15 min 30 min 45 min
1 Control
1.0
1.0
0.5
1.0
2.0
2.0
2.0
1.0
3.5
3.5
3.5
2.0
Mean (S.D) 0.875(0.25)1.75(0.5) 3.125(0.75)
2 Atropine*
0.0
0.5
0.0
0.5
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
Mean (S.D) 0.25(0.288)0.0(0.0) 0.0(0.0)
3 A**
0.5
0.5
0.5
1.0
1.0
1.0
1.5
1.5
3.0
2.0
1.5
2.0
Mean (S.D) 0.625(0.25)1.25(0.288) 2.125(0.629)
4 B*
0.0
0.5
0.0
0.5
0.0
0.5
0.5
0.0
0.0
0.5
0.0
0.0
Mean (S.D) 0.25(0.288)0.25(0.288) 0.125(0.25)
5 C**
1.0
1.0
0.5
0.5
1.5
1.5
1.0
1.0
2.0
3.0
1.5
2.0
Mean (S.D) 0.75(0.288)1.375(0.25) 2.125(0.629)
6
D**
1.0
1.0
1.0
1.0
1.5
1.5
1.0
1.5
2.0
2.0
1.5
2.0
Mean (S.D) 1.0 (0.0) 1.375(0.25) 2.125(0.629)
7 E*
0.0
0.0
0.0
0.5
0.0
0.0
0.5
0.0
0.0
0.0
0.0
0.0
Mean (S.D) 0.125(0.25)0.125(0.25) 0.0(0.0)
Value in parenthesis indicates standard deviation; *p < 0.01, **p > 0.05
when compared to control (Dunnett’s Multiple Comparison test); *p < 0.05,
**p > 0.05 when compared to control (Paired t-Test)
development of fluorescence by chemical reaction. The
catecholamine was oxidized to the fluorescent hydroxyl
indole derivative. The iodine was used to oxidize the
amine. The fluorescence was measured when the reaction
mixture irradiated with ultraviolet light [15-17].
Adult inbreed albino mice of either sex weighing be-
tween 30 - 35 g were used for the experiments. They
were divided into four groups each containing four mice.
Two groups, group 3 and 4 were treated with the two test
drugs (B and E) and group 2 was treated with atropine.
One group, group 1 which was treated with vehicle was
used as control.
The mice were sacrificed by cervical decapitation after
half an hour of intraperitoneal injection of the drug/At-
ropine/vehicle. The brain of mice was removed quickly
and chilled immediately to less than 0˚C in a beaker con-
taining a weighed mixture of ice and calcium chloride
and were weighed again.
3.2.1. Extraction of Dopamine
This is essentially the method described by Kent Shel-
lenberger and J. H. Gordon and developed for estimation
of dopamine [15,16].
Perchloric acid (0.4 N) for use in tissue extraction was
prepared by adding sodium metabisulfite (1.0 gm) and
ethylene diamine tetra acetate-disodium salt (EDTA, 0.5
gm), to each liter of diluted acid.
The brain samples were homogenized in 2.5 ml of the
0.4 N perchloric acid reagent using Teflon tissue ho-
mogenizer. The homogenates are left to stand in ice for
10 min and then centrifuged at 14 000 rpm for 15 min at
0˚C in refrigerated centrifuge. The supernatant was trans-
ferred to another test tube and brain samples were re-
homogenized in 2.0 ml perchloric acid reagent. Follow-
ing the second centrifugation, the supernatants were
pooled and adjusted to 5 ml.
3.2.2. Estimation of Dopamine
The reagents were prepared and estimation of dopamine
in mice brain was carried out. Phosphate buffer -EDTA
solution was prepared by adding 9.0 gm of disodium
EDTA to 1.0 liter of 0.1 M phosphate buffer and adjust-
ing the pH to 7.0 with 5.0 N NaOH. The phosphate
buffer is made with 4.27 gm Na
2
HPO
4
(anhydrous) and
9.32 gm KH
2
PO
4
per liter. Iodine reagent was prepared
by dissolving 2.0 gm of potassium iodide and 0.5 gm
iodine in 40.0 ml of distilled water.
Alkaline sodium sulfite solution 2.5% w/v was pre-
pared by diluting 1.0 ml of a solution containing 250 mg
sodium sulfite, to 10 ml of 5.0 N NaOH. 1 ml of the ali-
quot of the perchloric acid elute was brought to pH 6.5 ±
0.2 with 1.0 ml of 0.1 M phosphate buffer-EDTA solu-
tion. 0.2 ml iodine reagent was added, and mixed and
kept for exactly 2 min. After this 0.4 ml of alkaline so-
dium sulfite solution was added and kept for another 2
min. It was acidified to pH 4.4 - 4.8 with 0.4 ml of gla-
cial acetic acid and heated in an oven maintained at
100˚C for 40 min to develop the fluorescence. Next, the
tubes were taken out from the oven and placed in an ice
bath for cooling. The fluorescence was measured at the
activation wavelength of 300 nm and emission wave-

Synthesis and Study of Anti Parkinsonism Activity of 8-Azabicyclo [3.2.1] Octane Analogs
97
length of 335 nm using spectrofluorophotometer (RF
1603-PC, Shimadzu, Japan). The standard plot was pre-
pared by taking appropriate concentrations of dopamine
and the same depicted in Figure 1. Dopamine levels in
the brain of mice treated with atropine and test com-
pounds B and E were calculated using the standard plot.
Out of these, Compound E showed significantly higher
brain dopamine level, this was followed by Compound B
and Atropine (2) (Table 2).
4. Experimental
4.1. General
The melting points reported are uncorrected. The spectral
data was obtained from Sophisticated Analytical Instru-
mentation Facility, Central Drug Research Institute,
Lucknow, Orchid Chemicals and Pharmaceuticals, Chen-
nai, Ranbaxy Research Laboratory, Gurgaon and Central
Instrumentation Facility at B.I.T. Mesra. The purity of
compounds was ascertained by running the samples on
TLC.
4.2. Synthesis
4.2.1. 9-methyl-4-oxo-n-(phenylmethylene)–3,
9-diazabicyclo [4.2.1]
nonane-3-carbothiohydrazide (6)
9-Methyl-4-oxo-3,9 diazabicyclo [4.2.1] nonane-3-car-
bothiohydrazide (4) (2.28 g) was taken in absolute alcohol
(25 ml) and treated with glacial acetic acid (1 ml) and ben-
zaldehyde (1.06 ml). After refluxing the reaction mixture
Table 2. Levels of dopamine in mice brain after administra-
tion of atropine, test compounds b and e.
Group Compounds
Dopamine level
(ng/gm of brain weight)
1 Vehicle treated (control) 254.97 (3.56)*
2 Atropine (2) treated** 284.84 (3.15)*
3 Compound B(7) treated** 295.44 (2.01)*
4 Compound E (10) treated**314.32 (1.24)*
*Values in parentheses indicate standard deviation (n = 4); ** p < 0.01 when
compared to control (Paired t-test).
Figure 1. Standard curve of dopamine.
for 24 hrs it was kept in refrigerator when the thiosemi-
carbazone (6) precipitated out. Mp: 203
o
C; yield 1.4 g
(44.3%); I.R. :1692 cm
–1
(C═O stretch); 1106 cm
–1
(C═S
stretch); 1404 cm
–1
(C═N stretch); 1258 cm
–1
(C—N
stretch); 746 cm
–1
(aromatic C—H bending);
1
HNMR (δ,
ppm): δ = 1.643 ppm, (3H, singlet, N—CH
3
); δ = 7.990
ppm, (1H, singlet, aldehydic proton ═C—H); δ = 2.076
ppm, (1H, multiplet, bridgehead proton —CH—); δ =
7.019 ppm, (1H, singlet, amine proton —NH); δ = 4.155
ppm, (2H, quartet, axial methylene proton —CH
2
—) ; δ
= 7.161 ppm, (3H, triplet, aromatic proton- meta, para );
δ = 2.837 ppm, (2H, triplet, equatorial methylene proton
—CH
2
—); δ = 7.629 ppm, (1H, doublet, aromatic proton
-ortho position). FAB-MS (m/z): M
+1
peak at 317.0.
4.2.2. 9-methyl-4-oxo-n-(2-chlorophenyl) methylene 3,
9-diazabicyclo [4.2.1]
nonane-3-carbothiohydrazide (7)
9-Methyl-4-oxo-3,9diazabicyclo[4.2.1]nonane-3-carbothi
ohydrazide (4) (2.28 g) was taken in absolute alcohol (25
ml) and treated with 1 ml of glacial acetic acid and
2-chlorobenzaldehyde (1.405 g). The reaction mixture
was next processed in the same fashion as 9-methyl-
4-oxo-N-(phenyl-methylene)-3,9 diazabicyclo [4.2.1]
nonane-3-carbothiohydrazide (7). mp: (260˚C); yield 1.8
g (51.3%); I.R.: 1635 cm
–1
(C═O stretch in tertiary am-
ide); 1127 cm
–1
(C═S stretch); 1446 cm
–1
(C═N stretch);
1250 cm
–1
(C—N stretch); 757 cm
–1
(aromatic C—H
bending);
1
HNMR (δ, ppm): δ = 2.048 ppm, (3H, singlet,
N—CH
3
); δ = 1.385 ppm, (2H, sextet, equatorial me-
thylene —CH
2
); δ = 4.130 ppm, (2H,quartet, methylene
proton —CH
2
—); δ = 4.448 ppm, (2H, sextet, axial me-
thylene proton —CH
2
—); δ = 7.335 ppm, (1H,quartet,
aromatic proton- meta, para); δ = 7.283 ppm, (1H, singlet,
amino proton —NH—); δ = 8.153 ppm, (1H, singlet,
aldehydic proton ═C—H ); δ = 8.511 ppm, (1H, doublet,
aromatic proton -ortho position). FAB-MS (m/z): M
+1
peak at 352.9.
4.2.3. 3-benzenesulphonyl-9-Methyl-3,
9-diazabicyclo- [4.2.1] nonane (8)
hydrochloride
To a solution of 9-methyl-3, 9-diazabicyclo [4.2.1]
nonane (5) (0.42g) in dry pyridine was added benzene-
sulphonyl chloride (0.6 ml) and the reaction mixture
heated on a water bath for 30 min. The contents of the
flask were poured into ice cold water (10 ml), basified
with potassium carbonate, and extracted with chloroform
(3 × 10 ml). After working up the chloroform extract in
the usual manner, an oily residue (0.65 g) was obtained.
This was converted to the hydrochloride and crystallized
from acetone. yield 0.32 g (34.4 %); mp 223-225˚C; I.R.:
1342 cm
–1
, 1163 cm
–1
(sulfonamides); 750 cm
–1
(mono
substituted aromatic C—H bending); 1285 cm
–1
(C—N

Synthesis and Study of Anti Parkinsonism Activity of 8-Azabicyclo [3.2.1] Octane Analogs
98
strecth);
1
HNMR (δ, ppm): δ = 1.215 ppm (3H, singlet,
N—CH
3
proton); δ = 7.717 ppm (1H, doublet, aromatic
–meta proton); δ = 7.513 ppm (1H, doublet, aromatic –
ortho proton); δ = 1.941 ppm (2H, triplet, —CH
2
— axial
proton; at C
1
and C
2
); δ = 1.812 ppm (2H,triplet,
—CH
2
— equatorial proton; at C
1
and C
2
); δ = 4.1537
ppm (1H, doublet, —CH
2
— axial proton; at C
7
); δ =
3.630 ppm (1H, doublet, —CH
2
— equatorial proton, at
C
7
); δ = 2.035 ppm (1H, quartet, —CH— proton at
bridge junction); δ = 2.269 ppm (1H, quartet, —CH—
proton at bridge junction); δ = 4.137 ppm (1H, doublet,
—CH
2
— axial proton at C
4
); δ = 3.906 ppm (1H, doublet,
—CH— proton at C
4.
4.2.4. 3-(P-Toluenesulphonyl)-9-Methyl-3, 9
Diazabicyclo [4.2.1] Nonane (9) Hydrochloride
To a solution of 9-methyl-3, 9-diazabicyclo [4.2.1] nonane
(5) (0.42 g) in dry pyridine (10 ml) was added p-toluene-
sulphonylchloride (0.8 g) and heated on a water bath for
30 min. The contents of the flask were next poured into
ice cold water (10 ml), basified with potassium carbonate
and extracted with chloroform (3 × 10 ml). The chloro-
form extract was dried, filtered and evaporated to yield
an oily residue (0.72 g). This was converted to the hy-
drochloride and crystallized from absolute ethanol. yield
0.45 g (45.4%), mp 245-247˚C; I.R.:1339 cm
–1
, 1106
cm
–1
(sulfonamides); 852 cm
–1
(aromatic C—H bending),
1290 cm
–1
(C—N stretch);
1
H NMR: δ = 2.9171 ppm (3H,
singlet, N—CH
3
proton); δ = 7.306 ppm (1H, doublet,
aromatic –meta proton); δ = 7.6124 ppm (1H, doublet,
aromatic – ortho proton); δ = 1.2532 ppm (3H, singlet,
—CH
3
proton); δ = 2.4379 ppm (1H, quentet, —CH—
proton at bridge junction;); δ =3.8151 ppm (1H, doublet,
—CH
2
— axial proton at C
7
); δ = 2.0120 ppm (1H, dou-
blet, —CH
2
— equatorial proton at C
7
); Mass: M
+1
peak
at 294.6.
4.2.5. 3-(4-chlorobenzesulphonyl)-9-methyl-3,
9-diazabicyclo [4.2.1] nonane
(10)hydrochloride
To a solution of 9-methyl-3,9-diazabicyclo[4.2.1]nonane
(5) (0.71 g) in 5 ml dry pyridine was added p-chloro-
benzenesulphonyl chloride (1.05 g). The mixture was
heated on a water bath for 30 min. The contents of flask
were poured into ice-cold water (10 ml), basified with
potassium carbonate and extracted with chloroform (3
x10 ml). After working up the chlorform extract the oily
residue was converted to hydrochloride and crystallized
from absolute ethanol. mp. 132˚C, yield 0.26 g (14.8%);
I.R.: 1329 cm
–1
, 1159 cm
–1
(sulfonamides); 825 cm
–1
(aromatic C—H bending), 1280 cm
1
(C—N stretch);
1
H
NMR: δ = 2.637 ppm (3H, singlet, N—CH
3
proton); δ =
7.2632 ppm (1H, doublet, aromatic – meta proton); δ =
7.33 ppm (1H, doublet, aromatic – ortho proton); δ =
1.6222ppm (2H, triplet, —CH
2
— axial proton; at C
1
and
C
2
); δ = 1.388 ppm (2H,triplet, —CH
2
— equatorial pro-
ton; at C
1
and C
2
); δ = 3.10 ppm (1H, doublet, —CH
2
—
axial proton; at C
7
); δ = 3.0 ppm (1H, doublet, —CH
2
—
equatorial proton, at C
7
); δ = 2.10 ppm (1H, quartet,
—CH— proton at bridge junction); δ = 4.20 ppm (1H,
triplet, —CH
2
— axial proton at C
5
); δ = 3.80 ppm (1H,
multiplet, —CH— proton at bridge junction;); δ = 1.99
ppm (1H, quartet, —CH
2
— proton at C
4
); Mass :M
+1
peak at 315.1.
5. Acknowledgements
This work is acknowledged to our late vice-chancellor of
BIT Mesra, Ranchi, Dr. S. K. Mukharjee, who has given
all the opportunity of software and instruments. Greatly
indebted to Central Drug Research Institute, Lucknow,
India, Orchid Chemicals and Pharmaceuticals, Chennai,
Ranbaxy Research Laboratory, Gurgaon and CIF BIT
Mesra, Ranchi, India for the spectral analysis.
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