Synthesis and Pharmacological Properties of 1-(6-Aminohexylamino)-1-Phenylcyclohexyl Dihydrochloride (IEM-2062) as Compared with Memantine

Article abstract of DOI:10.1007/s11094-019-01950-z

1-(6-Aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062) had significantly greater antihypoxic, anticonvulsant, antidepressant, and analgesic activity than memantine and similar antiparkinsonism activity as memantine; it had low toxicity and was safer for use. IEM-2062 produced significant pharmacological effects in the dose range 0.3 – 3 mg/kg.

Full text of DOI:10.1007/s11094-019-01950-z

DOI 10.1007/s11094-019-01950-z
Pharmaceutical Chemistry Journal, Vol. 53, No. 1, April, 2019 (Russian Original Vol. 53, No. 1, January, 2019)
SYNTHESIS AND PHARMACOLOGICAL PROPERTIES
OF 1-(6-AMINOHEXYLAMINO)-1-PHENYLCYCLOHEXYL
DIHYDROCHLORIDE (IEM-2062) AS COMPARED
WITH MEMANTINE
1
V. E. Gmiro, S. E. Serdyuk, and O. S. Veselkina
1
2
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 53, No. 1, pp. 30 – 35, January, 2019.
Original article submitted March 23, 2017.
1
-(6-Aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062) had significantly greater antihy-
poxic, anticonvulsant, antidepressant, and analgesic activity than memantine and similar antiparkinsonism ac-
tivity as memantine; it had low toxicity and was safer for use. IEM-2062 produced significant pharmacologi-
cal effects in the dose range 0.3 – 3 mg/kg.
Keywords: memantine, IEM-2062, parkinsonism, convulsions, analgesia.
1
-Aminoadamantane (amantadine) and 3,5-dimethyl-1-
activity in models of acute corasol convulsions and has a
therapeutic index 814 times greater than that of memantine
and, thus, is safer for use than memantine [14].
aminoadamantane (memantine) have found wide use in the
treatment of cerebral ischemia, nonischemic acute and
chronic neurodegenerative diseases of the central nervous
system, Alzheimer’s disease, and Parkinson’s disease [1 – 7].
In recent years, memantine has been proposed for the treat-
ment of neuropathic pain and melancholic depression
We modified the dicationic structure of IEM-1913 by re-
placing the tetramethylene chain between the nitrogen atoms
with a hexamethylene chain and the adamantane-containing
cationic group by a 1-phenylcyclohexane-containing cationic
group. This led to the first combined-type glutamate blocker
with high levels of both NMDA- and AMPA-blocking activ-
ity. in in vitro experiments on rat hippocampal slices, IC50
values (the concentration inducing 50% inhibitory effects on
[
8 – 10].
A serious drawback of amantadine and memantine is the
lack of strong therapeutic activity, such that the largest possi-
ble doses are needed; another is the significant neurotoxic
action at doses 3 – 5 times greater than the therapeutic. These
compounds have low therapeutic indexes and are members
of the category of drugs with low therapeutic ratios
the ion channels of glutamate receptors) were 0.24 mM for
NMDA receptors and 1.7 mM for AMPA receptors [15]. The
literature contains no information on the pharmacological
properties of IEM-2012 in vivo. The high combined activi-
ties of IEM-2062 in in vitro experiments raises the need for
studies of its pharmacological activity and safety with the
aim of evaluating the clinical potential of this drug.
[
11 – 13].
We have previously shown that the adamantane-contain-
ing glutamate blocker IEM-1913, which has a dicationic
molecular structure (in contrast to the monocationic structure
of memantine) and induces combined blockade of NMDA
Me
(
N-methyl-D-aspartate) and AMPA (a-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid) receptors, is 1.5 times
more active than memantine in terms of its anticonvulsant
NH
NH-(CH ) -NH
.
.
2 6 2
HCI
.
2
NH-(CH
.
2
)
4
- N. H
HCI
2
HCI
HCI
HCI
Me
Memantine
1
Institute of Experimental Medicine, 12 Academician Pavlov Street,
IEM-1913
IEM-2062
1
97376 St. Petersburg, Russia; e-mail: gmiro2119@gmail.com
ZAO Vertex Pharmaceutical Company, 27A 24th Line, Vasilevskii Ostrov,
99106 St. Petersburg, Russia.
2
In this report we describe the synthesis and pharmaco-
logical studies of 1-(6-aminohexylamino)-1-phenylcyclo-
1
29
0
091-150X/19/5301-0029 © 2019 Springer Science+Business Media, LLC

3
0
V. E. Gmiro et al.
Scheme 1
2
Br-(CH ) -Br
2 5
F3C-COOH
CH CN
2
+
NaOH, PhCH NMe CI
2
H SO4
-
1
2
3
CN
3
4
CO
Br-(CH ) -N
2 6
CO
Br , H O, KOH
2
7
2
CO-NH2
NH2
5
6
CO
CO
a) N H .H O
2
4
2
NH-(CH ) -N
2
NH-(CH ) -NH2
2 6
6
b) HCI
HCI
HCI
8
IEM-2062
Scheme 1. Synthesis of 1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062).
2
150°C/20 mm. The yield was 33 g (27.5%), nD 1.5321
5
hexyl dihydrochloride (IEM-2062). The pharmacological ac-
tivity and toxicity of IEM-2062 and reference drug
memantine were studied in tests accepted for assessment of
acute toxicity and antihypoxic, anticonvulsant, antiparkinso-
nism, analgesic, and antidepressant activities.
25
(
published value nD 1.5323 [17]).
-Phenylcyclohexane carboxamide (5). A mixture of
7 g of 1-phenylcyclohexane carbonitrile, 115 ml of trifluo-
1
3
roacetic acid, and 16.4 ml of concentrated H SO was boiled
2
4
for 14 h, cooled, and poured into a beaker containing 140 g
of ice or snow; the mix was filtered and the residue on the fil-
ter was washed with water, taken up in 100 ml of cyclohex-
ane, left for 1 h in a refrigerator at (-5)-(-10)°C, and filtered;
the material on the filter was washed with hexane and dried
at 50 – 60°C at reduced pressure (15 – 20 mmHg). The yield
EXPERIMENTAL CHEMICAL SECTION
IEM-2062 was synthesized as shown in Scheme 1.
The reaction of phenylacetonitrile (1) with 1,5-dibromo-
pentane (2) in the presence of strong base benzyltriethylam-
monium oxide (forms during the reaction from benzyl-
triethylammonium chloride (3) and NaOH) yielded
was 33.7 g (83%) of 1-phenylcyclohexane carboxamide, Tm
8
3 – 85°C (published T 87 – 88°C [17]).
1
-phenylcyclohexane carbonitrile (4), which was converted
by sulfuric acid to 1-phenylcyclohexane carboxamide (5).
Treatment of the latter compound with bromine and alkali
the Hofmann reaction) yield 1-phenylcyclohexylamine (6);
m
1
-Phenylcyclohexylamine (6). A 1-liter three-neck flask
with a mixer and thermometer was loaded with a solution of
00 g of KOH in 0.5 liter of water, cooled to +5°C, and sup-
plemented with 9 ml of Br ; the reaction was mixed for
1
(
alkylation of this with N-(6-bromohexyl)phthalimide (7) and
subsequent treatment of the phthalimide derivative (8) with
hydrazine hydrate gave the target compound 1-(6-aminohe-
xylamino)-1-phenylcyclohexyl dihydrochloride (IEM-2062).
2
5
min at 5°C, after which 33 g of 1-phenylcyclohexane
carboxamide was added; the reaction was mixed at +5°C for
.5 h, when cooling was stopped and the reaction was held
1
for a further 1 h at room temperature; it was then extracted
with three 100-ml portions of ether, the ether extract was
evaporated, and the residue was taken up in 110 ml of con-
1
-Phenylcyclohexane carbonitrile (4) [16]. A 1-liter
three-neck flask with a mixer, cooler, and dropping funnel
was loaded with 94 ml of phenylacetonitrile (benzyl cya-
nide), 113 ml of 1,5-dibromopentane, 12.8 g of benzyltrie-
thylammonium chloride, and 160 ml of benzene. This mix-
ture was supplemented by dropwise addition of a solution
containing 368 g of NaOH in 368 ml of water over 1.5 – 2 h
with mixing keeping the reaction temperature at 80 – 90°C.
The reaction was then mixed at 80-85°C for a further 1.5 h
and washed twice with water (in a separating funnel); the up-
per benzene solution was separated from the lower aqueous
solution and distilled, collecting the 1-phenylcyclohexane
carbonitrile fraction with boiling point Tb = 143 –
centrated HCl and heated to 80 – 110°C. After CO evolution
2
was complete (monitored using an Alifanov flask at the out-
let of the cooler), the mixture was heated to 110°C for a fur-
ther 30 min and evaporated; the residue was supplemented
with 20 g of NaOH in 50 ml of water and extracted with
ether; the ether solution was dried with anhydrous Na SO4
2
and evaporated. The yield was 8.6 g (30%) of 1-phenylcyclo-
hexylamine, T 85 – 95°C/5 mm. The T of the HCl salt was
b
m
246 – 247°C (published Tm of the HCl salt 247 – 248°C
[17]).

Synthesis and Pharmacological Properties
31
N-(6-Bromohexyl)phthalimide (7). A mixture of 37 g
boiling and cooled, and water containing the oily residue was
decanted; this was supplemented with 20 ml of heptane,
brought to boiling, and the mix was again extracted with
20 ml of heptane; after drying at 100°C in vacuo, a white
crystalline residue was obtained which was boiled in 20 ml
of isopropanol; the hot solution was filtered and a white crys-
talline precipitate formed from the filtrate; this was collected
by filtration and dried. This produced 4 g (32%) of
1-phenylcyclohexyl-(6-phthalimidohexyl)amine hydrochlo-
ride, T 185 – 187°C. The PMR spectrum (DMSO-d ), d,
of potassium phthalimide, 61 ml of 1,6-dibromohexane, and
2
00 ml of dimethylformamide was mixed at 90 – 100°C for
h, after which the reaction mix was poured into 2 liters of
4
water; the lower organic layer was separated, dimethyl-
formamide was evaporated, and the dibromohexane residue
and container residue were boiled in 1 liter of heptane; the
solution was decanted from the undissolved residue; the
white crystalline precipitate forming from the heptane solu-
tion was collected by filtration, washed with hexane, and
dried to yield 23 g of substance, which was crystallized from
m
6
ppm, was: 9.20 (bs, 2H, NH HCl); 7.83 – 7.36 (m, 5H, Ar);
7
0 ml of isopropanol. This produced 23 g of N-(6-bromo-
3.49 (m, 2H, CH ); 2.65 (m, 2H, CH ); 2.34 – 1.02 (m, 18H,
2 2
hexyl)phthalimide (37% in relation to the starting potassium
phthalimide), Tm 56 – 58°C. The atomic formula was
C H BrNO (published value T 59 – 61°C [18]).
9CH2).
1-(6-Aminohexylamino-1-phenylcyclohexyl dihydro-
chloride (IEM-2062). A mixture of 3.7 g of 1-phenylcyclo-
hexyl-(6-phthalimidohexyl)amine hydrochloride, 0.5 ml of
hydrazine hydrate, and 15 ml of isopropanol was boiled for
1.5 h, the mixture was evaporated and the residue was sup-
plemented with 25 ml of water and 3 ml of concentrated
HCl, heated to 80 – 90°C, cooled, and filtered. The aqueous
filtrate was evaporated and the residue was boiled in 10 ml of
isopropanol, filtered, and dried. This produced 1.45 g (58%)
of 1-(6-aminohexylamino)-1-phenylcyclohexyl dihydrochlo-
ride, T 208 – 210°C. The atomic formula was C H Cl N .
1
4
16
2
m
1
-Phenylcyclohexyl-(6-phthalimidohexyl)amine hy-
drochloride (8). A mixture of 5 g of 1-phenylcyclo-
hexylamine, 8.85 g of N-(6-bromohexyl)phthalimide, 4 g of
K CO , and 30 ml of n-propanol was boiled for 7 h; the solu-
2
3
tion was filtered, the filtrate was evaporated and mixed with
5 ml of ether; the mixture was filtered, the ether filtrate was
2
evaporated and the residue (7.9 g) was dissolved with heat-
ing in 15 ml of isopropanol; 2 ml of concentrated HCl was
added, the mixture was evaporated and the residue was sup-
plemented with 15 ml of water; the mixture was brought to
m
18 32
2
2
The PMR spectrum (DMSO-d ), d, ppm, was: 9.34 (bs, 2H,
6
TABLE 1. Antihypoxic, Anticonvulsant, Antiparkinsonism, and Antidepressant Effects of IEM-2062 and Memantine.
Antiparkinsonism activity in
Antihypoxic activity in
hemic hypoxia test*
Anticonvulsant activity in
corasol convulsions test**
Antidepressant activity in
Porsolt test****
haloperidol catalepsy
test***
Compound
Dose, i.m.
severity of corasol convul- duration of immobility in duration of immobility in re-
survival time of rats, min
sions, points
net, sec
113 ± 8
111 ± 7
78 ± 4
peat swimming, sec
Distilled water
Memantine
-
56 ± 5
4.8 ± 0.4
181 ± 14.3
1 mg/kg
149 ± 15.0
3
5
mg/kg
mg/kg
63 ± 5
77 ± 4
4.2 ± 0.7
3.4 ± 0.5
92 ± 11.2
2
1
0 mg/kg
0 mg/kg
18 ± 4
68 ± 7
1
1
1
2
86 ± 7
1.9 ± 0.4
46 ± 4.1
IEM-2062
0.03 mg/kg
2
0
.1 mg/kg
.3 mg/kg
4.0 ± 0.3
3.2 ± 0.7
20 ± 7
101 ± 11.3
2
1
0
74 ± 8
22 ± 4
66 ± 10.2
1
1
2
2.3
1
mg/kg
mg/kg
94 ± 12
2.0 ± 0.6
22 ± 2
29 ± 5.1
2
.3
2.3
3
111 ± 11
1.4 ± 0.3
*
Sodium nitrite 80 mg/kg, i.m.
* Corasol 80 mg/kg i.m. convulsion severity on a scale of 0 – 6 points
** Duration of immobility in net (sec) 60 min after haloperidol 1 mg/kg
*
*
*
1
*** Duration of immobility (sec) during 5-min repeat swimming in the Porsolt test.
p < 0.05 compared with control
2
3
p < 0.01 compared with control
p < 0.05 compared with memantine

3
2
V. E. Gmiro et al.
NH HCl); 8.11 (bs, 3H, NH HCl); 7.68 – 7.39 (m, 5H, Ph);
i.m. doses of test compound solution in distilled water were
given 30 min before haloperidol. The antiparkinsonism
(anticataleptic) activities of IEM-2062 and reference agent
memantine were assessed quantitatively in terms of reduc-
tions in the duration of immobility (sec) as compared with
controls (distilled water).
2
6
.18; 2.65 (m, 4H, 2CH N); 2.36 – 1.46 (m, 12H, CH ); 1.12
2 2
(
m, 8H, 4CH ). The purity of IEM-2062 calculated from ele-
2
mental analysis data [19] was 99.7 – 99.8%.
EXPERIMENTAL BIOLOGICAL SECTION
Analgesic effects were evaluated in terms of increases in
the latent period of the tail withdrawal reflex in rats [25, 26].
Stimulation was modeled in the tailflick test by immersing
the rat’s tail into hot water at a temperature of 52 ± 0.1°C.
Tail withdrawal latent periods (time from stimulation to
withdrawal) were determined every 3 min. Pain sensitivity
was evaluated using rats with short latent periods (4 – 5 sec)
in the last 15 min before substance administration. Solutions
of IEM-2062 and reference agent memantine were given i.m.
in increasing doses until maximal analgesia (tail withdrawal
reflex latent period 30 sec) was obtained in the last three pain
sensitivity measurements. The analgesic activities of
IEM-2062 and memantine were assessed quantitatively by
determining the mean minimum effective dose eliciting max-
imal analgesia in rats (latent period of tail withdrawal reflex
Studies were performed on male Wistar rats weighing
1
60 – 170 g and mongrel white mice weighing 20 – 22 g.
Each control and experimental group consisted of 5 – 8 ani-
mals.
Antihypoxic effects were studied in a hemic hypoxia
model induced by administration of sodium nitrite (80 mg,
i.m.) to rats [20, 21]. Study substances dissolved in distilled
water were given to rats by single i.m. doses 30 min before
administration of sodium nitrite. The antihypoxic activities
of IEM-2062 and reference compound memantine were eval-
uated by determining increases in the mean survival times of
the rats (min) from those obtained with controls (i.m. dis-
tilled water) after each dose of IEM-20562 and memantine.
Anticonvulsant effects of substances were evaluated us-
ing a corasol convulsing model (corasol 80 mg/kg, i.m.) in
rats. The severity of corasol convulsions was assessed using
a standard five-point scale 30 min after corasol administra-
tion [22]. Study substances dissolved in distilled water were
given as single i.m. doses 30 min before corasol. Convulsion
severity was assessed in points for each dose of IEM-2062
and reference agent memantine. Anticonvulsant actions of
substances were evaluated in terms of reductions in convul-
sion severity in points as compared with controls.
30 sec).
The antidepressant effects of substances were studied
using a two-day Porsolt swimming test in rats [27]. Rats
were studied in the swimming test by placing them in a glass
cylinder containing water (22°C). On day 1, the duration of
immobility in the 15-min swimming test was not determined.
On day 2 of the swimming test, the total duration of immo-
bility (sec) was determined in a 5-min repeat swimming test.
Solutions of IEM-2062 in distilled water, control solution
(water), and reference agent memantine were given as single
Antiparkinsonism effects of substances were evaluated
using a model of catalepsy induced by i.m. administration of
haloperidol (Gedeon Richter, Hungary, solution for i.v. and
i.m. administration, 5 mg/ml; 1-ml ampule) at a dose of
i.m. doses 30 min before repeat swimming in rats. The anti-
depressant activities of IEM-2062 and memantine were as-
sessed in terms of reductions in the total duration of immo-
bility as compared with controls (distilled water) during the
5-min repeat swimming period.
1
mg/kg in rats. The extent of catalepsy was assessed in
terms of the duration of immobility displayed by rats (sec) in
a large net at an angle of 45° 60 min after administration of
haloperidol. The greatest degree of catalepsy was seen in rats
as complete immobility in the net for 120 sec [23, 24]. Single
The acute toxicity of IEM-2062 and memantine was de-
termined by i.p. administration to intact mongrel mice (males
weighing 18 – 20 g, 8 – 1- individuals per group) at increas-
ing toxic doses until a 100% lethal effect was obtained. The
TABLE 2. Acute Toxicity, Therapeutic Index, and Analgesic Activity of IEM-2062 and Memantine.
Acute toxicity in mice
LD50, mg/kg, i.p.*
Therapeutic index (TI)
LD50/ED50**
Minimum effective dose (mg/kg), i.m.
producing maximum analgesia in the
tail withdrawal reflex in rats****
Compound
*
**
Memantine
IEM-2062
79 ± 15
7.9 (79/10)
21.1 ± 3.1
0.5 ± 0.1 1
1
***1
123 ± 20
164 (123/0.75)
*
Toxic doses killing 50% of mice (LD ).
50
* ED50 – minimum effective dose eliminating generalized convulsions in 50% of rats
*
*
** LD /ED values are given in parentheses. TI was calculated using experimental results in the corasol convulsions test in rats and the
5
0
50
acute toxicity test in mice.
*** Latent period of tail withdrawal reflex >30 secretary.
*
1
P < 0.05 compared with memantine

Synthesis and Pharmacological Properties
33
mean doses of compounds inducing the death of 50% of
mice (LD ) were assessed by graphic interpolation [20].
Antiparkinsonism effects. Rats given i.m. haloperidol
1 mg/kg showed immobility lasting 110 – 120 sec (maxi-
mum catalepsy) when placed on a large net at an angle of 45°
60 min after administration. Reference agent memantine
given i.m. at a dose of 3 mg/kg produce a minor - only
1.4-fold - decrease in haloperidol catalepsy as compared with
controls (distilled water), as it decreased the duration of im-
mobility on the net from 113 to 78 sec (Table 1). At the
larger dose of 10 mg/kg, i.m. memantine produced a 6.3-fold
reduction in the magnitude of haloperidol catalepsy, from
113 to 18 sec (Table 1).
5
0
The safety of IEM-2062 and memantine was evaluated
by calculating the therapeutic index – the ratio of the toxic
dose killing 50% of the mice (LD ) to the dose preventing
50
clonic-tonic corasol convulsions in 50% of the rats (ED ),
5
0
i.e., TI = LD /ED .
5
0
50
Test compound 1-(6-aminohexylamino)-1-phenylcyclo-
hexyl dihydrochloride (IEM-2062) was synthesized at the In-
stitute of Experimental Medicine, Russian Academy of Med-
ical Sciences, and the standard NMDA blocker memantine
(
purity ³ 98%) was obtained from Sigma. Experimental data
I. m. IEM-2062 0.03 mg/kg produced a significant
(1.7-fold) decrease in haloperidol catalepsy as compared
with controls, as it reduced the duration of immobility in the
net from 113 to 68 sec (Table 1). IEM-2062, like memantine,
was most effective over the dose range 0.1 – 1.0 mg, de-
creasing haloperidol catalepsy from 113 by factors of
were analyzed statistically using Student’s test.
RESULTS AND DISCUSSION
Analgesic effects. Table 1 shows that i.m. doses of refer-
ence agent memantine at 5 and 10 mg/kg produced minor in-
creases in the survival time of rats with hemic hypoxia as
compared with controls, from 56 min to 66 and 77 min re-
spectively. Only the maximum memantine dose of 20 mg/kg
produced a significant antihypoxic effect, with a 1.5-fold
5.4 – 5.6, from 113 to 20 – 22 sec (Table 1). Thus, injections
of IEM-2062 and the standard antiparkinsonism drug
memantine had maximal antiparkinsonism effects, as they
virtually eliminated haloperidol catalepsy in rats. In contrast
to memantine, which was effective only at the maximum
dose of 10 mg/kg, IEM-2062 produced a significant antipar-
kinsonism effect over the wide dose range of 0.03 – 1 mg/kg.
Antidepressant effects. In rats of the control group
(
from 56 min in controls to 86 min) increase in survival time.
-(6-Aminohexylamino)-1-phenylcyclohexyl
dihydrochloride (IEM-2062) given i.m. at a dose of
.3 mg/kg produced minor increases in the survival time
with hemic hypoxia as compared with controls, from 56 to
4 min (Table 1). At 1 mg/kg, IEM-2062 induced a signifi-
1
(given i.m. distilled water 30 min before testing), the total
0
duration of immobility in the 5-min Porsolt swimming test
on day 2 was 181 ± 14.3 sec (Table 1), which is evidence of
the development of maximal depression in control rats. Ref-
erence agent memantine given i.m. at doses of 1 and 3 mg/kg
produced minor reductions, by factors of 1.2 and 1.9, in the
duration of immobility as compared with controls (distilled
water), from 181 to 149 and 92 sec respectively (Table 1).
Only the high dose of memantine (15 mg/kg) produced a sig-
nificant decrease in the duration of immobility in the Porsolt
test from the level in control rats, by a factor of 3.9, reducing
the duration of immobility from 181 to 46 sec.
7
cant antihypoxic effect, with a 1.7-fold increase in survival
time in rats, from 56 to 94 min (Table 1). At 3 mg/kg (6.7
times smaller dose than memantine), IEM-2062 induced a
1
.8-fold stronger antihypoxic effect than that seen with
memantine, with an increase in the rats’ survival time from
6 min in controls to 111 min (Table 1). It is important to
5
note that in contrast to memantine, which was effective only
at the maximum dose of 20 mg/kg, IEM-2062 induced a sig-
nificant antihypoxic effect (lifetime 94 – 111 min) over the
dose range 1 – 3 mg/kg.
I.m. IEM-2062 1 mg/kg significantly (by a factor of 2.6
compared with controls) decreased the duration of immobil-
ity from 181 to 66 sec (Table 1). The results presented in Ta-
ble 1 show that i.m. IEM-2062 3 mg/kg produced the great-
est (6.2-fold compared with controls) reduction in immobil-
ity in rats in the Porsolt test (decreasing the duration of
immobility from 181 to 29 sec). Thus, injections of
IEM-2062 at a dose of 3 mg/kg (five times smaller than with
memantine) produced a 1.6-fold greater antidepressant effect
compared with memantine in the Porsolt test. In contrast to
memantine, which was effective only at the maximum dose
of 15 mg/kg, IEM-2062 produced significant antidepressant
effects over the dose range 1 – 3 mg/kg.
Anticonvulsant effects. i.m. corasol (80 mg/kg) induced
the development of generalized clonic-tonic convulsions of
severity 4 – 5 points in 100% of rats. Table 1 shows that as
compared with controls (distilled water), i.m. reference agent
memantine induced significant anticonvulsant effects only at
the maximum dose of 20 mg/kg, with a 2.5-fold reduction in
the severity of corasol convulsions (from 4.8 to 1.9 points).
I.m. IEM-2062 at doses of 1 and 3 mg/kg produced signifi-
cant decreases in the severity of corasol convulsions (from
4
.8 to 2.0 and 1.4 points respectively), i.e., by factors of
.4 – 3.4. Thus, IEM-2062 injections at a dose of 3 mg/kg
6.7 times lower than that of memantine) to rats induced
.4-fold stronger anticonvulsant effects than memantine in
2
(
1
Analgesic effects. I.m. IEM-2062 and memantine at the
minimum effective doses of 0.5 and 21.1 mg/kg respectively
produced maximum levels of analgesia (latent period of tail
withdrawal reflex >30 sec). Thus, injections of IEM-2062,
like reference agent memantine, induced maximum analgesic
the corasol convulsion model. In contrast to memantine,
which was effective only at the maximum dose of 20 mg/kg,
IEM-2062 induced a significant anticonvulsant effect in the
dose range 1 – 3 mg/kg.

3
4
V. E. Gmiro et al.
2
3
4
5
. O. S. Levin and L. A. Batukaeva, Zh. Nevrol. Psikhiat. im.
S. S. Korsakova, 108(12), 16 – 23 (2008).
effects, though the dose was 42.2 times smaller than that of
memantine (p < 0.05, Table 2).
. G. Rammes, W. Danysz, and C. G. Parsons, Curr.
Neuropharmacol., 6(1), 55 – 78 (2008).
Acute toxicity. I.p. administration of reference agent
memantine killed 50% of mice (LD ) at a dose of 79 mg/kg.
50
. W. Danysz, C. G. Parsons, J. Kornhuber, et al., Neurosci.
Biobehav. Rev., 21(4), 455 – 468 (1997).
IEM-2062 had an LD50 of 123 mg/kg (Table 2). Thus, acute
toxicity of IEM-2062 was 1.6 times lower than that of
memantine (p < 0.05, Table 2).
. C. G. Parsons, W. Danysz, and G. Quack, Neuropharmacol.,
38(6), 735 – 767 (1999).
Safety. I.p. administration of reference agent memantine
killed 50% of mice at a dose of 79 mg/kg (LD50), while i.m.
administration at a dose of 10 mg/kg eliminated corasol con-
vulsions in 50% of rats (ED ) (Table 2). Memantine there-
6. K. K. Jain, Expert. Opin. Investig. Drugs, 9(6), 1397 – 1406
(2000).
7. G. C. Palmer, Curr. Drug Targets, 2(3), 241 – 271 (2001).
8
. M. Rogers, A. Rasheed, A. Moradimeh, and S. J. Baumrucker,
Am. J. Hosp. Palliat. Care, 26(1), 57 – 59. Review (2009).
. K. Zdanys and R. R. Tampi, Prog. Neuropsychopharmacol.
Biol. Psychiatry, 32(6), 1362 – 1374, Review (2008).
50
fore has a small therapeutic index, of 7.9, which is evidence
that memantine lacks safety.
9
I.p. IEM-2062 killed 50% of mice at a dose of 123 mg
1
0. G. Rammes, W. Danysz, and C. G. Parsons, Curr.
Neuropharmacol., 6(1), 55 – 78 (2008).
1. C. Ikonomidou and V. Stefovska, Proc. Natl. Acad. Sci. USA,
(
LD ), while i.m. administration of the small dose of
50
0
.75 mg/kg eliminated corasol convulsions in 50% of rats
1
(
ED ). IEM-2062 therefore had a high therapeutic index, of
97(23), 12885 – 12890 (2000).
5
0
1
2
64. Thus, injections of IEM-2062 had a therapeutic index
0.8 times greater than that of memantine (p < 0.05, Ta-
12. V. E. Gmiro and S. E. Serdyuk, Éksperim. Klin. Farmakol.,
63(6), 3 – 8 (2000).
1
1
1
3. C. G. Parsons, G. Quack, I. Bresink, et al., Neuropharmacology,
4(10), 1239 – 1258 (1995).
4. V. E. Gmiro, S. E. Serdyuk, O. S. Veselkina, Byul. Éksperim.
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5. I. M. Fedorova, V. E. Gmiro,
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2008).
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ble 2), so it has relatively low toxicity and high safety for
use.
3
In vitro experiments on rat hippocampal slices showed
that IEM-2062 was 3.5 times more active than memantine in
terms of its NMDA-blocking activity, and also provided ef-
fective blockade of AMPA receptors [15]. The higher phar-
macological activity and lower toxicity of IEM-2062 can ev-
idently be explained by the fact that in contrast to the selec-
tive NMDA blocker memantine, IEM-2062 produced
combined blockade of NMDA and AMPA receptors in the
brain.
L. G. Magazanik,
and
(
1
8
1
1
8. Lancaster, Chemist’s Catalogue (2000 – 2001, p. 276.
9. I. A. Revel’skii, E. N. Kapinus, M. V. Fedoseeva, et al., Zh.
Anal. Khimii, 64(9), 949 – 953 (2009).
Thus, the overall properties of 1-(6-aminohexylamino)-
1
-phenylcyclohexyl dihydrochloride (IEM-2062) have sig-
2
0. Guidelines for Preclinical Studies of Drugs [in Russian],
A. N. Mironov (ed.), Grif i K, Moscow (2012), part 1.
1. V. E. Gmiro and S. E. Serdyuk, Éksperim. Klin. Farmakol.,
nificant advantages over the clinically utilized memantine, as
it has significantly greater antihypoxic, anticonvulsant, anti-
depressant, and analgesic activities than memantine, similar
antiparkinsonism activity to memantine, along with much
lower toxicity and greater safety than memantine. In contrast
to memantine, which was effective only at the single maxi-
mum dose of 15 – 20 mg/kg, IEM-2062 produced significant
pharmacological effects over the wider dose range of
2
63(6), 3 – 8 (2000).
22. S. E. Krahl, S. S. Senanayake, and A. Handforth, Epilepsy Res.,
38(2 – 3), 171 – 175 (2000).
23. A. Campbell, R. J. Baldessarini, and M. C. Cremens,
Neuropharmacology, 27(11), 1197 – 1199 (1988).
2
4. V. E. Gmiro and S. E. Serdyuk, Byul. Éksperim. Biol. Med.,
43(5), 554 – 556 (2007).
5. S. E. Serdyuk and V. E. Gmiro, Byul. Éksperim. Biol. Med.,
44(11), 535 – 537 (2007).
1
0
.3 – 3 mg/kg.
2
1
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