Derivatives of pinane amino acids as new anticonvulsants

Full text of DOI:10.1134/S0012500808100029

ISSN 0012-5008, Doklady Chemistry, 2008, Vol. 422, Part 2, pp. 248–250. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © T.G. Tolstikova, E.A. Morozova, A.V. Pavlova, A.V. Bolkunov, M.P. Dolgikh, E.A. Koneva, K.P. Volcho, N.F. Salakhutdinov, G.A. Tolstikov, 2008,
published in Doklady Akademii Nauk, 2008, Vol. 422, No. 4, pp. 490–492.
CHEMISTRY
Derivatives of Pinane Amino Acids
as New Anticonvulsants
T. G. Tolstikova, E. A. Morozova, A. V. Pavlova, A. V. Bolkunov,
M. P. Dolgikh, E. A. Koneva, K. P. Volcho, N. F. Salakhutdinov,
and Academician G. A. Tolstikov
Received April 10, 2008
DOI: 10.1134/S0012500808100029
Epileptic seizures occurring in different life periods fore, the interest of researchers in the search for more
effective anticonvulsants without side effects is
unabated [2–5].
affect about 3% of the world population [1]. The aim of
drug therapy for epilepsy is to effectively control con-
vulsions and ultimately maintain a good quality of life.
According to [1, 2], pharmaceuticals used to control
Among the compounds with anticonvulsant activity
are amino acids structurally related to γ-aminobutyric
seizures are ineffective in about 25% of patients. There- acid I (GABA), including amino acids II–IV [6, 7].
COOH
COOH
COOH
NH2
COOH
F
NH2
NH2
NH2
IV
F
I
II
III
We have shown that the derivatives of pinane amino and (–)-V are β-amino acids. Another important feature of
acids obtained from optically active (+)- and (–)-α- compounds V–VII is that they have a rigid structure,
pinenes can serve as parent compounds for a new series of which can affect the selectivity of their binding to targets
anticonvulsants. As distinct from compounds I–IV, which and increases the effect of absolute stereochemistry of the
are γ-amino acids, the proposed pinane amino acids (+)- compounds on their biological activity.
COOEt
NH2
COOH
NH2
COOEt
NH2
COOEt
NH2
(–)-V
(+)-V
(–)-VI
(+)-VI
NH2
OH
(–)-VII
(–)-V were prepared by refluxing corresponding amino
esters (+)- and (–)-VI in aqueous dioxane for 20 h
according to the procedure described in [10].
Compounds VI and VII of high optical purity (at
least 99.5%) were obtained from (+)- and (–)-α-
pinenes by procedures [8, 9], and amino acids (+)- and
Pharmacological study was carried out on outbred
white mice with a weight of 20–22 g. Standard tests
were used to study the anticonvulsant activity of com-
Vorozhtsov Institute of Organic Chemistry,
Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
248

DERIVATIVES OF PINANE AMINO ACIDS AS NEW ANTICONVULSANTS
249
Table 1. Interaction of compounds V–VII with corasol
The anticonvulsant activity in both models mark-
edly decreases when passing from amino ester (–)-VI
to its hydrogenated derivative, amino alcohol (–)-VII,
while amino acid (–)-V increases animal death in both
tests, showing an opposite effect.
The absolute configuration of the compounds under
study is very important. In contrast to compound (–)-
VI, its enantiomer, amino ester (+)-VI, potentiates the
corasol effect by increasing convulsion development.
At the same time, compound (+)-VI, like amino ester
(−)-VI, decreases the development of convulsions
induced by nicotine.
As distinct from the pair of amino ester (–)-VI and
amino acid (–)-V, which have an opposite effect in both
tests, amino ester (+)-VI and amino acid (+)-V display
the same properties in the corasol toxicity and nicotine
toxicity tests, but compound (+)-V has a more pro-
nounced effect in both tests.
In the L-Dopa interaction tests, characterizing the
indirect effect on the dopaminergic (adrenergic) sys-
tem, compounds V–VII at a 10 mg/kg dosage have no
reliable effect on this neuromediator system.
and nicotine
Animal death in group, %
compound
(10 mg/kg)
and corasol
(90 mg/kg)
compound
(10 mg/kg)
andnicotine
(20 mg/kg)
Com-
pound
corasol,
90 mg/kg
(control)
nicotine,
20 mg/kg
(control)
(–)-V
(+)-V
(–)-VI
(+)-VI
(–)-VII
50
50
30
50
30
62.5
100
10
62.5
37.5
40
87.5
12.5
10
75
37.5
40
25
20
20
pounds V–VII: convulsion induced by a central genesis
stimulant, corasol (90 mg/kg of body weight, intraperi-
toneal injection), and by an N-cholinomimetic, nicotine
(20 mg/kg of body weight, intraperitoneal injection);
the open field test; and a test with a dopamine precur-
sor, L-Dopa (200 mg/kg of body weight, intraperitoneal
injection), characterizing the effect on the dopaminer-
gic (adrenergic) system. In the open field test and the
L-Dopa interaction test, the effect was estimated from
the change in the number of different kinds of motion
and the overall emotional state of animals. The locomo-
tor activity was monitored automatically using a Coul-
bourn Instruments TruScan system (United States).
The study of the effect of α-pinene derivatives V–
VII on the behavioral reactions of mice in the open field
test showed that compounds (–)-VI and (–)-VII have
no reliable effect on the locomotor activity in compari-
son with the control (Table 2). Compounds (–)-V, (+)-V,
and (+)-VI reliably decrease the distance and speed of
motion, exhibiting a slight sedative activity.
The acute toxicity of compound (–)-VI was deter-
mined on a single intragastric administration by the
Kerber method.
Acute toxicity on a single intragastric administra-
tion was determined for compound (–)-VI, which has
the highest anticonvulsant activity. On the basis of the
data, amino ester (–)-VI can be classified with moder-
ately toxic substances of Toxicity Class III (LD50 is
higher than 1000 mg/kg, which is 8.1 times lower than
median lethal dose of phenobarbital, the administration
mode being the same [2]).
It is seen from Table 1 that amino ester (–)-VI in a
10 mg/kg dosage shows a significant anticonvulsant
activity in the corasol toxicity and nicotine toxicity
tests, possibly due to the effect of this compound on
neuromediator (GABAergic and N-cholinergic) sys-
tems involved in regulation of the convulsive response.
For comparison, ED50 of phenobarbital used as an anti-
Thus, we found for the first time that pinane amino
acids and their derivatives exert a considerable effect on
convulsant in the corasol toxicity test is 72 mg/kg [11]. neuromediator systems, the type of the functional oxy-
Table 2. Effect of compounds V–VII on locomotor activity in mice
Overall locomotor activity Locomotor activity,
Motion distance,
cm
Motion speed,
cm/s
Compound
(number of acts)
s
(–)-V
Control
11.6 0.9
10.5 1.3
105.8 1.1
106.0 1.5
272.6 17.6*
354.4 11.9
2.2 0.2*
2.9 0.1
(+)-V
(+)-VI
Control
12.8 1.0**
12.1 1.2**
9.5 1.1
102.4 1.9
105.6 1.4
108.6 1.1
277.0 20.0**
263.4 26.2**
373.1 19.5
2.3 0.2**
2.2 0.2**
3.1 0.2
(–)-VI
(–)-VII
Control
11.1 1.0
10.0 0.8
12.3 1.7
104.1 1.1
107.4 1.4
103.4 2.7
309.9 22.9
376.4 35.3
302.3 23.7
2.6 0.2
3.1 0.3
2.5 0.2
Note: Reliability as compared with the control group: * P < 0.01 and ** P < 0.05.
DOKLADY CHEMISTRY Vol. 422 Part 2 2008

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TOLSTIKOVA et al.
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these compounds playing an important role.
We established that amino ester (–)-VI has high
anticonvulsant activity in vivo in the corasol toxicity
and nicotine toxicity tests and LD50 higher than
1000 mg/kg and, at the studied dosage, exerts a slight
sedative effect on locomotor activity. Taking into
account the above data and the fact that compound
(−)-VI can be prepared in two stages from the
widespread monoterpene α-pinene, amino ester (–)-VI
may be considered as a parent compound for the devel-
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DOKLADY CHEMISTRY Vol. 422 Part 2 2008