Synthesis and biological evaluation of N 1,N 2-bis-[4-(t-amino)-2-butynyl]phthalamides as oxotremorine and acetylcholine antagonists

Article abstract of DOI:10.1007/s00044-012-0147-2

A series of N ¹,N ²-bis-[4-(t-amino)-2-butynyl] phthalamides have been synthesized and investigated for the blocking of the motor effect of oxotremorine in intact mice and for their antagonistic activity towards acetylcholine on isol

Full text of DOI:10.1007/s00044-012-0147-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:1597–1603
DOI 10.1007/s00044-012-0147-2
ORIGINAL RESEARCH
Synthesis and biological evaluation of N1,N2-bis-[4-(t-amino)-
2-butynyl]phthalamides as oxotremorine and acetylcholine
antagonists
•
Zuhair Muhi-eldeen Elham Al-Kaissi
•
Hanan Ghantous
Received: 25 January 2012 / Accepted: 5 June 2012 / Published online: 29 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A series of N1,N2-bis-[4-(t-amino)-2-butynyl]
phthalamides have been synthesized and investigated for
the blocking of the motor effect of oxotremorine in intact
mice and for their antagonistic activity towards acetyl-
choline on isolated guinea pig ileum preparations. All
N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides showed more
selectivity as oxotremorine antagonists than atropine and
less potent than atropine on peripheral cholinergic antag-
onistic activity.
opposed to peripheral cholinergic effects (Inch et al.,
1973). The observations of Parkinson-like effect exerted by
tremorine and more intense by oxotremorine have initiated
intensive research on antiparkinsonian agents, in particular
from their central cholinergic role in reducing tremor
(Muhi-Eldeen et al., 1980). Several series of acetylenic
compounds which are structurally related to oxotremorine
with specific structural changes to afford the antagonistic
activity have been synthesized. These include amides,
esters, cyclic imides (Muhi-Eldeen et al., 1980; Ringdhal
et el., 1979a; Karlen, 1970; Schulte and Rucker, 1970;
Muhi-Eldeen et al., 1982; Dahlbom et al., 1974; Ringdhal
et el., 1979b; Eicholzer and Orgen, 1977). Previously we
have synthesized in our laboratories a series of N-[4-(t-
amino)-2-butynyl]phthalimides (Muhi-Eldeen et al., 1980),
and investigated for their oxotremorine and peripheral
acetylcholine antagonistic activity. All compounds except
one showed oxotremorine antagonistic activity and all
showed peripheral acetylcholine antagonistic activity as
compared to atropine (Muhi-Eldeen et al., 1980). In
reviewing the above mentioned structural modifications,
we were interested in inserting two aminoacetylenic moiety
in amide form namely N1,N2-bis-aminoacetylenic phthal-
amides 13–16 to verify whether the presences of bis-am-
inoacetylenic moiety in phthalamide may yield a more
effective oxotremorine antagonists as seen in tacrine dimer
in treatment of Alzheimer (Scutara et al., 2011), and in
bivalent bendamustine and melphalan in cancer treatment
(Bolognesi et al., 2007). The new aminoacetylenic phthal-
amides were generated through the hydrazinolysis of cor-
responding N-[4-(t-amino)-2-butynyl]phthalimides 5–8 as
illustrated in the experimental part. The IR, 1HNMR,
13CNMR and elemental analysis were consistent with the
assigned structures. All synthesized compounds showed
greater selectivity as oxotremorine antagonist than peripheral
Keywords Acetylcholine antagonist ꢀ
Aminoacetylenic derivatives ꢀ
Aminoacetylenic phthalamides derivatives ꢀ
Oxotremorine antagonist
Introduction
Tremorine 1, and oxotremorine 2, were very active mus-
carinic agent when tested in vivo or in isolated organs and
comparable to acetylcholine in potency (Cho et al., 1962).
They are relatively specific in producing central, as
Z. Muhi-eldeen (&)
Department of Medicinal Chemistry and Pharmacognosy,
Faculty of Pharmacy, Petra University, Amman, Jordan
e-mail: eldeenz@hotmail.com
E. Al-Kaissi
Department of Pharmaceutics and Biotechnology,
Faculty of Pharmacy, Petra University, Amman, Jordan
e-mail: kaielham@hotmail.com
H. Ghantous
Department of Medicinal Chemistry, Faculty of Pharmacy,
University of Baghdad, Baghdad, Iraq
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Med Chem Res (2013) 22:1597–1603
N1,N2-bis-[4-(t-amino)-2-butynyl] phthalamides 13–16
cholinergic antagonistic activity except compound 15 in
which the cyclic amine is 2,6-dimethylpiperidine was
inactive as oxotremorine antagonist.
A mixture of N-[4-(t-amino)-2-butynyl]phthalimide (0.025
mol) hydrazine hydrate (0.03 mol) and ethanol 95 % (60 ml)
were refluxed for 1.5 h. The mixture was allowed to cool and
(4 ml) of concentrated hydrochloric acid was added drop
wise, stirred for 1.5 h, and filtered, the precipitate was
washed with (30 ml) of water and filtered through section on
Celite. The solvent was removed under reduced pressure
afforded a mixture of two products, the corresponding
hydrochloride salt of aminoacetylene amine and [N1,N2-bis-
[4-(t-amino)-2-butynyl]phthalamide. The free amine was
generated through treatment of HCl salt with (K2Co3/ether).
The ether was dried with anhydrous MgSO4 and concentrated
in vacuum affording the corresponding [4-(t-(amino)-2-
butynyI]amine 9–12, the boiling points of the aminoacety-
lenic amines are listed in (Table 1), 1R(neat,cm-1).
3500–3300 (broad, NH2, Stretch), 2850–2800 (CH2,
Stretch), 2120 (C:C, Stretch), 1420, 1330 (CH2, bending);
1HNMR (DMSO-d6)d, 1.8–1.6(m, CH2 of cyclic protons),
2.6 (t, –CH2–N-cyclic amine), 2.85 (m, 2H, NH2–CH2–C:),
4.0–4.5(m, 2H, NH2–C).
N
N
1-[4-(1-pyrrolidinyl)-2-butynyl]pyrrolidine
Tremonine
5.6 + 0.02 Ao
O
3.0 Ao
N
N
3.5 + 0.02 Ao
1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone
N1,N2-bis-[4-(t-amino)-2-butynyl] phthalamides 13
Oxotremonine
The title compound was prepared according to the general
procedure for the synthesis of N1,N2-bis-[4-(t-amino)-
2-butynyl]phthalamides Scheme 1. The yield %, mp,
and elemental analysis were shown in (Table 2). IR
(KBr,Cm-1): 3200–3150 (NH, stretch), 2950–2845 (ArH,
stretch), 2230 (C:C, stretch), 1665 (C=O, stretch, amide),
1612, 1458 (Ar, C=C, stretch), 1030, 948 (Ar, C=C,
Materials and method
Chemical methods
Melting points were measured using Fischer–Johns melting
point apparatus. Infrared spectra (IR) were recorded on a
Nicolet Impact-400 FT-IR spectrophotometer. 1H-NMR
was recorded with the aid of Bruker-DPX300 MHz spec-
trometers. Elemental analysis was performed in the labo-
ratories of Dr. Bernhardt, Mulheim, Germany. The results
obtained had a maximum deviation of 0.04 % from the
theoretical value.
1
11
0
bending). HNMR (DMSO-d6): d, 1.53 (m, 2H, CH2 ),
0
0
1.59 (m, 4H, 10CH2–10 CH2), 1.64 (m, 4H, CH2–9 CH2),
3.39 (t, 2H, J = 2.4 Hz, 8CH2–N), 3.66 (t, CH2,
9
5
3
0
J = 2.4 Hz, CH2 ), 7.4 (d, 1H, J = 4.2 Hz, Ar H), 7.8 (d,
1H, J = 4.2 Hz, Ar1H). 11CNMR (DMSO-d6): d, 24.3
0
0
(13C), 25.8 (10,10 C), 27.1 (9,9 C), 52.9 (8C), 66.6 (5C), 74.2
(7C), 79.3 (6C), 123.8 (3C), 131.9 (1C), 135.2 (2C), 167.0
(4C).
N-propargylphthalimide 4
N1,N2-bis-[4-(2-methyl-1-piperidinyl)-
2-butynyl]phthalamide 14
This compound was prepared in 65 % yield according to
the method described in the literature of Cho et al., 1962
mp 150–151 °C.
Compound 14 was prepared according to the procedure
listed for compounds 13–16. The yield %, mp, and ele-
mental analysis were shown in (Table 2). IR (KBr,Cm-1):
3200–3150 (NH, stretch), 2900–2820 (ArH, stretch), 2220
(C:C, stretch), 1670 (C=O, stretch, amide), 1620, 14560
(Ar, C=C, stretch), 1030, 948 (Ar, C=C, bending). 1HNMR
N-[4-(t-amino)-2-butynyl]phthalimides 5–8
These compounds were prepared in 65–86 % yield as
described in reference (Muhi-Eldeen et al., 1980), mp
(85–86 °C), (105–107 °C), (132–134 °C), (75–77 °C). The
IR, 1HNMR spectra and elemental analysis were consistent
with the assigned structures.
(DMSO-d6): d, 1.12 (d, 3H, J = 4.2 Hz, 12CH3), 1.5 (m,
0
6H, 10CH2–10 CH2–11CH2), 1.64(m, 2H, 9CH), 1.64 (m,
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Med Chem Res (2013) 22:1597–1603
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Table 1 Physical data for 4-tert-amino-2-butynylamines (9–12)
Cyclic amine
Comp. no.
R2
R2
n*
Yield (%)
Formula
B.P. (°C) (mmHg)
Piperidine
9
10
11
12
H
H
1
1
1
3
78
61
43
40
C9H14N2
C10H18N2
C11H20N2
75–77 (0.7)
78–79 (0.7)
79–81 (0.7)
81–82 (0.7)
2-Methyl-piperidine
2,6-Dimethyl piperidine
Perhydro-Azocine
CH3
CH3
H
H
CH3
H
C11H20N2
* n Number of carbon
The synthesis N 1,N 2-bis-[4-(t-amino)-2-butynyl]phthalamides
Scheme 1 The synthesis
N1,N2-bis-[4-(t-amino)-2-
butynyl]phthalamides
O
C
N
CH2
C
CH2
NH
NH
CH2
C
C
CH2
N
O
N 1,N 2-bis-[4-(1-piperidinyl)-2-butynyl]phthalamide (13)
H3C
O
C
N
CH2
CH2
CH2
C
NH
NH
H3C
C
CH2
C
N
O
N 1,N 2-bis-[4-(2-methyl-1-piperidinyl)-2-butynyl]phthalamide (14)
H3C
O
C
N
CH2
CH2
C
NH
NH
H3C
H3C
CH2
C
CH2
C
N
O
H3C
N 1,N 2-bis-[4-(2,6-dimethyl-1-piperidinyl)-2-butynyl]phthalamide (15)
O
C
N
(CH2)3
CH2
CH2
C
NH
NH
CH2
C
CH2
C
N
(CH2)3
O
N 1,N 2-bis-[4-(perhydro-1-azapinyl)-2-butynyl]phthalamide (16)
0
0
0
0
1H, 9 CH), 3.05 (t, 8CH2, J = 2.4 Hz), 3.66 (t, 2H,
(12C), 20 (11 C), 24 (11C), 26.2 (10 C), 27.4 (10C), 43.8(9 C),
52.9 (8C), 54.5 (5C), 78.2 (7C), 79.5 (6C), 123.8 (3C), 131.9
(1C), 135.2 (2C), 167.2 (4C).
J = 2.4 Hz, CH2), 7.4 (d, 1H, J = 4.2 Hz, Ar3H) 7.8 (d,
1H, J = 4.2 Hz, Ar1H). 13CNMR (DMSO-d6): d, 20.0
5
123

1600
Med Chem Res (2013) 22:1597–1603
Scheme 1 continued
O
O
N-
Na+
CH
CH2
C
+
N
CH2
CH
C
Br
O
O
(3)
(2)
(1)
O
C
O
N
O
H
H
( ) NH NH / H O
1
2
2
2
CH2
CH2
(CH2)n
C
N
C
2
( ) HCl
(3) K2CO3 / ether
(CH2)n
HN
(4 - 8)
O
O
C
N
(CH2)n
CH2
CH2
C
NH
NH
H2N
CH2
C
CH2
(CH2)n
C
N
+
CH2
C
CH2
C
N
(CH2)n
(9 - 12)
(13 - 16)
Scheme of synthesis
where n= 1,3
Table 2 Physical data for N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides (13–16)
Cyclic amine
Comp. no. R1
R2
n* Yield (%) Formula
mp* (°C) Calc (%)
Found (%)
C
H
N
C
H
N
Piperidine
13
14
H
H
H
1
I
14.0
14.1
16.6
14.7
C26H34N4O2 140–142 71.65 7.85 12.91 71.63 7.82 12.92
C28H38N4O2 151–152 72.31 8.22 12.12 72.30 8.23 12.15
C30H42N4O2 158–160 73.64 8.57 11.42 73.66 8.60 11.43
2-Methyl-Piperidine
CH3
2,6-Dimethyl Piperidine 15**
Perhydro-azocine 16
CH3 CH3
1
3
H
H
C30H42N4O2 132–134 73.64 8.57 11.42 73.61 8.60 11.43
* All derivatives were recrystallized from methanol; Microanalyses were performed in the laboratories of Dr. Bernhardt, Mulheim, Germany
** The 2,6-dimethyl in 11 and 15 are cis(diequatorial)
N1,N2-bis-[4-(2,6-dimethyl-1-piperidinyl)-
2-butynyl]phthalamide 15
1
1100, 10485, 940 (Ar, C=C, bending). HNMR (DMSO-
d6): d, 1.14 (d, 3H, J = 4.4 Hz, 12CH3), 1.14 (d, 3H,
0
0
J = 4.2 Hz, 0 12 CH3), 1.5 (m, 6H, 10CH2–11CH2–10 CH2),
0
1.8 (m, 2H, 9 CH–9 CH), 3.4 (t, 2H, J = 2.4 Hz, 8CH2), 3.68
The title compound (15) was prepared according to the
method describe for compounds 13–16. The yield %, mp,
and elemental analysis were described in (Table 2). IR
(KBr,Cm-1): 3180–3150 (NH, stretch, amide), 3030–29301
(ArH, stretch), 2250 (C:C, stretch), 1660–1640 (C=O,
stretch, amide), 1612, 14565, 1390 (Ar, C=C, stretch),
(t, 2H, J = 2.4 Hz, CH2), 7.4 (d, 1H, J = 4.2 Hz, Ar3H)
5
7.8 (d, 1H, J = 4.2 Hz, Ar1H). 13CNMR (DMSO-d6): d,
0
0
0
22.02 (12C), 24.03 (11 C), 25.8 (10,10 C), 27.1 (9,9 C), 52.9
8C), 66.6 (5C), 74.2 (7C), 79.3 (6C), 128.8 (3C), 131.9 (1C),
135.2 (2C), 167.0 (4C).
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Med Chem Res (2013) 22:1597–1603
1601
N1,N2-bis-[4-(perhydro-1-azapinyl)-
2-butynyl]phthalamide 16
dissolved in 0.1 N HCl on the same day of the biological
evaluation. Contractions of the ileum were recorded on a
physiograph using an isotonic lever exerting I gm tension.
From the results obtained, a graphic estimate was made of
the concentrations. For non-competitive antagonist, the
effective concentration was recorded as that which reduces
the maximum response to acetylcholine by 50 % and the
PD2 value which is defined as the non-competitive antag-
onist which reduces the maximum response to one half was
estimated (Arunlanksana and Schild, 1959).
The title compound was synthesized according to the general
procedure for the preparation of N1,N2-bis-[4-(t-amino)-
2-butynyl]phthalamides. The yield %, mp, and elemental
analysis were shown in (Table 2). IR (KBr,Cm-1): 3210–
2950 (NH, stretch), 2924, 2831 (Ar, C=C, stretch), 2220
(C:C, stretch), 1662, 1640 (C=O, stretch, amide), 840, 794,
1
717 (Ar, C=C, stretch, bending). HNMR (DMSO-d6): d,
0
1.2–1.4 (m, 10H, 10CH2–10 CH2–11CH2–12CH2–13CH2), 1.6
PD2 ¼ ꢁ log B50
0
(m, 4H, 9CH2–9 CH2), 3.03 (t, 2H, J = 2.4 Hz, 8CH2), 3.66
5
(t, 2H, J = 2.4 Hz, CH2 ), 7.4 (d, 1H, J = 4.2 Hz, Ar H),
3
0
7.8 (d, 1H, J = 4.2 Hz, Ar1H). 13CNMR0(DMSO-d6): d, 26.8
Results and discussion
0
(11C,12C,13C), 27.4 (10,10 C), 28.15 (9,9 C), 47.7 (8C), 54.7
(7C), 78.5 (6C), 80.8 (6C), 123.8 (3C), 131.9 (1C), 135.1 (2C),
167.2 (4C).
The Mannich reaction of N-propargylphthalimide 4 with
paraformaldehyde and various selected cyclic amines in
peroxide-free dioxan in the presence of catalytic amount of
cuprous chloride yielded 65-86 % of N-[4-(t-amino)-
2-butynyl]phthalimides 5–8. Reaction of compounds 5–8
with hydrazine hydrate followed by the addition of
hydrochloric acid yielded two products, the hydrochloride
salts of 4-tert-amino-2-butynylamines. The free base 9–12
(Table 1) was generated through treatment with potassium
carbonate (ether) in 40-60 % yield. The second products
were the N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides
13–16 (Table 2). The elemental analysis, IR, H1NMR and
13CNMR were consistent with assigned structures as shown
in the experimental part.
The new N1,N2-bis-[4-(t-amino)-2-butynyl]phthala-
mides (Table 3) were tested for their blocking action on the
motor effects of oxotremorine in intact mice and for their
antagonistic activity towards acetylcholine on isolated
guinea pig ileal preparations. The methods used were
described in the experimental part. The pharmacological
results are summarized in (Table 3) and include atropine as
a reference compound. Three of the aminoacetylenic
phthalamide derivatives 13, 14, 16 antagonize the tremor-
genic effects of oxotremorine, they were more potent than
atropine in their central effects. Compound 15 in which the
cyclic amine is 2,6-dimethylpiperidine was inactive as
oxotremorine antagonist.
Pharmacology
Male mice, averaging 20–25 g, were used throughout the
experiments. Distilled water was used for reagent prepa-
ration; oxotremorine was purchased from Fluka AG,
Chemische Fabrik, Switzerland.
Each test compound was administered intraperitoneally
in geometrically spaced doses to groups of five mice in
volume not exceeding 10 ml/kg. After 15–20 min oxotre-
morine was injected intraperitoneally in a dose of 40
0lg/kg. 15–20 min later the intensity of the motor effects
was graded visually by a three point system previously
described (Eicholzer and Ogren, 1977).
The tremorolytic dose was estimated by visual interpo-
lation as the dose in mol/kg., which reduced the mean
tremor response by one point relative to a control group
receiving oxotremorine only.
Guinea pigs of either sex, weighing 350–550 g were
sacrificed by a sharp blow on the head.
Terminal portions (2- to 3-cm long) of the ileum were
removed in close proximity to the ileo-cecal junction, and
cleared of their contents by gently flushing with warm
Krebs solution. Two of such segments were mounted in
separate 50 ml jacketed muscle chambers, containing
Krebs solution at 37 °C and bubbled with a mixture of
oxygen (95 %) and CO2 (5 %). After mounting, the tissue
was allowed to stabilize for 1 h prior to the addition of test
compounds. Cumulative dose response curves were
obtained using acetylcholine only.
These observation were in agreement with our previous
finding with the inactivity of N-[4-(2,6-dimethylpiperidino)-
2-butynyl]phthalimides 7 (Table 4). The inactivity may be
attributed to the steric factors around the basic nitrogen in
phthalimide and phthalamide derivatives. Furthermore, the
aminoacetylenic phthalamides were more potent than the
aminoacetylenic phthalimides as oxotremorine antagonist,
this may be attributed to either bis-aminoacetylenic func-
tional groups or due to the N1,N2-bis-aminoacetylenic moi-
ety are appropriately located in phthalamide to block
oxotremorine activity. All compounds listed in (Table 3)
The test compound was added after 15-min intervals at
the lowest concentration and then after another 15 min, a
dose response curve of acetylcholine was obtained in the
presence of test compound. This procedure was repeated
after at least three concentrations of the test compound
increasing the ratio 1/3, 1/10, 1/30. All compounds were
123

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Med Chem Res (2013) 22:1597–1603
Table 3 Pharmacological data for N1,N2-bis-[4-(t-amino)-2-butynyl]phthalamides (13–16)
Compound no.
In vitro dose (mol/kg) in mice
required to produce
oxotremorine blockadea
Concentration (mol/L) to
antagonize acetylcholine
on isolated guinea pig ileumb
Acetylcholine antagonism
on isolated guinea
pig ileum (PD2)c
13
8.0 9 10-6
4.2 9 10-7
Inactive
3.2 9 10-8
2.8 9 10-6
1.6 9 10-6
1.2 9 10-6
3.0 9 10-6
5.0 9 10-6
3.7 9 10-9
5.6
5.7
5.8
5.9
8.4
14
15
16
Atropine
a
Dose of the test compound required to block the dose of oxotremorine (400 lg/kg) inducing a predetermined tremor in mice
Concentration of the test compound required to reduce the maximum response to acetylcholine by 50 %
The value of the antagonist, which reduces the maximum response of acetylcholine to one half
b
c
Table 4 Pharmacological data for compounds N-[4-(t-amino)-2-butynyl]pthalimides (5–8)
Compound* no.
In vivo dose (mol/kg) in mice
required to produce
oxotremorine blockade
Concentration (mol/L)
to antagonize acetylcholine
on isolated guinea pig ileum
Acetylcholine antagonism
on isolated guinea
pig ileum (PD2)
5
7.6 9 10-4
9.6 9 10-6
Inactive
2.4 9 10-6
2.8 9 10-6
1.6 9 10-6
1.2 9 10-6
2.0 9 10-6
8.0 9 10-7
3.7 9 10-9
5.8
5.9
5.7
6.1
8.4
6
7
8
Atropine
* As reported in the study of Cho et al., 1962
Evaluation of N1,N2-bis-(4-t-amino-2-butynyl)phthalamides
antagonistic effect to oxotremorine over peripheral cholin-
ergic effects. The dose response curves obtained on isolated
guinea pig ileal preparations of compounds 13–16 and
atropine are shown in Fig. 1. As the concentration of the
compounds is increased, the curve is shifted to the right and
at the highest concentration used a reduction in the maximum
response was observed, the negative logarithm of the molar
concentration of the antagonist that caused 50 % reduction
of the maximum response due to agonist is estimated
(Table 3). It is evidence from (Table 3) that introduction of
one methyl group around the basic nitrogen in compound 14
or increase the size of the cyclic amine to azocine in 16
resulted in an increase in the tremorolytic and peripheral
antagonistic activity to acetylcholine, may indicate that the
higher hydrophobic factors in the absence of steric factors
around the basic nitrogen may enhance the tremolytic and
peripheral acetylcholine antagonistic activity. Further work
is necessary to confirm the various points suggested in this
article.
A
B
C
D
E
F
G
H
I
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
J
K
0.3 0.6 0.9 2.2
5
10
20
40
80 120 160
Dose of each compound (ug)
Fig. 1 Effect of compounds 13-16 and atropine on acetylcholine
dose–response curves in guinea pig ileum A Mean control in the
presence of 2 lg of compound 13. B Mean control in the presence of
6 lg of compound 13. C Mean control in the presence of 20 lg of
compound 13. D Mean control in the presence of 2 lg of compound
14. E Mean control in the presence of 6 lg of compound 14. F Mean
control in the presence of 20 lg of compound 14. G Mean control in
the presence of 6 lg of compound 15. H Mean control in the presence
of 20 lg of compound 15. I Mean control in the presence of 20 lg of
compound 16. J Mean control in the presence of 20 lg of atropine.
K Mean control in the presence of 60 lg of atropine
possessed a competitive antagonistic effect to acetylcholine
at low concentration but behaved as non-competitive
antagonists at higher concentration. Compounds 13–16 were
less active than atropine as peripheral cholinergic antago-
nists, this in line with our objective to have specific central
Conclusion
In conclusion, the new series of bis-aminoacetylenic
phthalamides showed more potent selective central oxo-
tremorine antagonistic activity and lower peripheral
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Inch TD, Green DM, Thompson PB (1973) The central and peripheral
activities of anti-acetylcholine drug, some concepts of practical
relevance. J Pharm Pharmacol 25:359–370
Karlen B (1970) Chemical and biological studies of tremorine,
oxotremorine and oxotremorine antagonists. Acta Pharm Suec
7:169–200
acetylcholine activity than atropine. Further investigation
in progress to find out more selective compounds to be
more effective in treatment Parkinson’s disease.
Muhi-Eldeen ZA, Shubber A, Musa N, Muhammed A, Khayat A,
Ghantous H (1980) Synthesis and biological evaluation of N-(4-
t-amino-2-butynyloxy) and N-(4-t-amino-2-butynyl)phthalimides.
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