Comparison of the Pharmacological Activity and Safety of 1-Adamantylguanidine and 3,5-Dimethyl-1-Adamantylguanidine to those of Memantine

Article abstract of DOI:10.1007/s11094-021-02343-x

Guanidine-containing analogs of amantadine and memantine, including 1-adamantylguanidine hydrochloride (IEM-2151) and 3,5-dimethyl-1-adamantylguanidine hydrochloride (IEM-2163), were synthesized and studied. IEM-2151 and IEM-2163 had greater antihypoxic, anticonvulsant, and neuroprotective activity than memantine; exhibited equally potent antiparkinsonian, antidepressant, and analgesic activity with memantine; and had higher therapeutic indices than memantine.

Full text of DOI:10.1007/s11094-021-02343-x

DOI 10.1007/s11094-021-02343-x
Pharmaceutical Chemistry Journal, Vol. 54, No. 12, March, 2021 (Russian Original Vol. 54, No. 12, December, 2020)
SEARCH FOR NEW DRUGS
COMPARISON OF THE PHARMACOLOGICAL ACTIVITY
AND SAFETY OF 1-ADAMANTYLGUANIDINE
AND 3,5-DIMETHYL-1-ADAMANTYLGUANIDINE
TO THOSE OF MEMANTINE
1,*
V. E. Gmiro and S. E. Serdyuk
1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 54, No. 12, pp. 8 – 14, December, 2020.
Original article submitted December 26, 2019.
Guanidine-containing analogs of amantadine and memantine, including 1-adamantylguanidine hydrochloride
(IEM-2151) and 3,5-dimethyl-1-adamantylguanidine hydrochloride (IEM-2163), were synthesized and stud-
ied. IEM-2151 and IEM-2163 had greater antihypoxic, anticonvulsant, and neuroprotective activity than
memantine; exhibited equally potent antiparkinsonian, antidepressant, and analgesic activity with memantine;
and had higher therapeutic indices than memantine.
Keywords: memantine, IEM-2151, IEM-2163, parkinsonism, analgesia.
Adamantane-containing compounds such as 1-amino-
administration to rats and was four times less toxic than
memantine [13].
adamantane (amantadine) and 3,5-dimethyl-1-aminoada-
mantane (memantine) are now widely used to treat brain
ischemia, acute and chronic neurodegenerative central-ner-
vous-system diseases, and Alzheimer’s and Parkinson’s dis-
eases [1 – 7]. Recently, memantine was proposed for treating
neuropathic pain and melancholic depression [3, 8, 9] and
Alzheimer’s disease and schizophrenia [10, 11].
The goal of the present article was a pharmacological
study of guanidine-containing analogs of amantadine and
memantine, i.e., compounds IEM-2151 and IEM-2163.
Serious drawbacks of amantadine and memantine are
weak therapeutic activity that requires them to be used at the
highest doses and significant neurotoxicity at doses only
IEM-2151
Amantadine
Memantine
3
– 5 times greater than the therapeutic ones. These com-
pounds have narrow therapeutic indices and are categorized
as drugs with a small range of therapeutic activity [12 – 14].
Replacement of an amine by a guanidine group is known
in several cases to enhance pharmacological activity. For ex-
ample, replacement of the amines in 1,4-diaminobutane by
guanidines produced highly active arcaine (1,4-diguanidino-
butane), which possessed 3 – 5 times greater HMDA block-
ing, antihypoxic, and anticonvulsant activity upon systemic
IEM-2163
1
-Adamantylguanidine (IEM-2151) was synthesized
[
15] and studied for anti-influenza activity. Other informa-
1
tion on the pharmacological properties of IEM-2151 were
not found by us. Compound IEM-2163 was synthesized and
studied by us for the first time.
Institute of Experimental Medicine, 12 Akad. Pavlova St., St. Petersburg,
1
97376 Russia.
*
e-mail: gmiro2119@gmail.com
1198
0
091-150X/21/5412-1198 © 2021 Springer Science+Business Media, LLC

Comparison of the Pharmacological Activity
1199
The present work studied the synthesis; antihypoxic,
anticonvulsant, antiparkinsonian, analgesic, antidepressant,
and neuroprotective activity; and acute toxicity and safety of
IEM-2151 and IEM-2163 as compared to the standard ada-
mantane-containing glutamate HMDA blocker memantine.
IEM-2151 was prepared via the literature method [15] by
reacting 1-aminoadamantane (1) with cyanogen bromide to
form 1-adamantylcyanamide (2), which was heated with am-
monium chloride to afford 1-adamantylguanidine hydrochlo-
ride (IEM-2151). The target compound was prepared before
as the nitrate [15] although we prepared it as the hydrochlo-
ride, which was more amenable to clinical trials.
perature for 2 h. The resulting precipitate of 1-aminoada-
mantane hydrobromide was filtered off. The Et O filtrate
2
was evaporated. The solid was crystallized from a mixture of
H O (30 mL) and EtOH (50 mL) to afford 1-adamantylcy-
2
anamide (23 g, 66%), mp 147 – 149°C (147 – 149°C [15]).
2) 1-Adamatylguanidine hydrochloride. A mixture of
1-adamantylcyanamide (7.04 g, 0.04 mol) and NH Cl (6.6 g,
4
0.12 mol) was heated at 175°C for 2 h and then refluxed in
i-PrOH (40 mL) and filtered. The filtrate was evaporated.
The solid was extracted with hot H O. The cooled aqueous
2
solution was washed with Et O and made basic with aqueous
2
KOH. The resulting white crystalline precipitate of the base
was rinsed with H O and dried to afford 1-adamantylguani-
2
dine (2.4 g, 31%), mp 194 – 195°C (195°C [15]). The base
was converted as usual to the HCl salt, mp 207 – 208°C.
C H ClN . PMR spectrum (DMSO-d ), d, ppm: 7.73 (s,
1
2
11
20
3
6
1
H, -NH-), 7.14 (m, 4H, -NH-C(=NH)-NH HCl), 2.04 (s, 3
2
CH, Ad), 1.88 (s, 6 CH, Ad), 1.71 – 1.57 (m, 6 CH, Ad). The
purity of IEM-2151 that was calculated from the elemental
analysis was 99.2 – 99.4% [16].
IEM-2151
IEM-2163 was unreported in the literature and was pre-
pared analogously.
3,5-Dimethyl-1-adamantylguanidine hydrochloride
(IEM-2163)
1
) 3,5-Dimethyl-1-adamantylcyanamide. A 1-L three-
necked flask equipped with a stirrer and dropping funnel was
loaded with a solution of 3,5-dimethyl-1-adamantylamine
41 g, 0.228 mol) in Et O (400 mL), cooled to 5°C, stirred,
(
2
and treated with a solution of BrCN (12.1 g, 0.106 mol) in
3
4
Et O (100 mL) at a rate such that the temperature of the reac-
2
tion mixture stayed at 5 – 6°C. The cooling was removed.
The mixture was stirred another 30 min at room temperature.
The resulting precipitate of 3,5-dimethyl-1-aminoadaman-
tane hydrobromide was filtered off. The filtrate was evapo-
rated to ~100 mL and treated with H O (50 mL) and conc.
2
HCl (5 mL). The Et O layer was separated and evaporated.
2
The solid was crystallized from hexane (50 mL) to afford the
product (22 g, 93%), mp 52 – 54°C. PMR spectrum
IEM-2163
(
DMSO-d ), d, ppm: 6.8 (br.s, 1H); 2.12 (m, 1H); 1.5 (d,
6
EXPERIMENTAL CHEMICAL PART
2
H); 1.33 (d, 2H), 1.27 (m, 6H), 1.1 (m, 2H); 0.84 (s, 6H).
) 3,5-Dimethyl-1-adamantylguanidine hydrochlo-
ride. A mixture of 3,5-dimethyl-1-adamantylcyanamide
12.9 g, 0.062 mol) and NH Cl (10 g, 0.18 mol) was heated
2
PMR spectra were taken in DMSO-d6 on a Bruker
Avance 400 spectrometer. Chemical shifts were given on the
d-scale (ppm). Elemental analyses were performed using a
PerkinElmer CHN PE 2400 automated analyzer and agreed
with those calculated. Starting 1-aminoadamantane and
(
4
at 220 – 225°C for 1 h and then treated with a solution of
K CO (10 g) and heptane (70 mL). The mixture was
2
3
refluxed and cooled to room temperature. The precipitate
was separated by decantation and treated with KOH (30 g) in
H O (30 mL). The mixture was extracted with Et O
3
,5dimethyl-1-aminoadamantane were purchased (Aldrich).
2
2
1
-Adamantylguanidine hydrochloride (IEM-2151)
(100 mL). The Et O solution was treated with conc. HCl
2
1
) 1-Adamantylcyanamide. A 1-L three-necked flask
(5 mL, 35%). The resulting precipitate was separated, shaken
equipped with a stirrer, thermometer, and dropping funnel
was loaded with a solution of 1-aminoadamantane (45 g) in
with Me CO, and filtered. Yield 5 g, mp 222 – 223°C. Crys-
2
tallization from H O (70 mL) afforded 3,5-dimethyl-1-ada-
2
Et O (600 mL), stirred, and treated with cooling in a water
mantylguanidine hydrochloride (2.6 g, 16%), mp
2
bath (6 – 8°C) with a solution of cyanogen bromide (23 g) in
234 – 235°C. C H ClN . PMR spectrum (DMSO-d ), d,
1
3
24
3
6
Et O (100 mL), keeping the temperature of the reaction mix-
ppm: 7.76 (s, 1H, -NH-); 7.12 (m, 4H, -NH-C(=NH)-NH2
HCl), 2.1 (s, 1H, Ad); 1.72 (s, 2H, Ad); 1.58 – 1.40 (m, 6CH,
2
ture at 6 – 8°C. Then, the mixture was stirred at room tem-

1
200
V. E. Gmiro and S. E. Serdyuk
Ad); 1.22 (d, 3CH, Ad); 1.08 (d, 1H, Ad); 0.83 (s, 6H,
CH ). The purity of IEM-2163 that was calculated from the
ence was injected once i.m. 30 min before the repeated
swimming. Antidepressant activity of IEM-2151, IEM-2163,
and memantine was assessed from the decrease of total im-
2
3
elemental analysis was 99.4 – 99.5% [17].
mobilization time as compared to a control (H O) for 5 min
2
of repeated swimming. Test data were statistically processed
using the Student criterion.
EXPERIMENTAL PHARMACOLOGICAL PART
Analgesic activity of the compounds was evaluated in
rats from the length of the latent period for a tail flick
The studies used male Wistar rats (160 – 170 g) and in-
bred white mice (20 – 22 g). Control and test groups in-
cluded 5 – 8 animals.
[22, 23]. The painful stimulus in the tail-flick test was im-
Antihypoxic activity was studied using a hemic hypoxia
model induced by injection of sodium nitrite (80 mg/kg,
i.m.) to rats [13, 17]. The tested compounds dissolved in
mersion of the rat tail in hot (52 ± 0.1°C) water. The latent
period for a tail flick (time of avoidance of the painful stimu-
lus) was determined every 3 min. Rats with short latent peri-
ods for the reflex (4 – 5 sec) in the last 15 min before injec-
tion of the compounds were used to evaluate the pain sensi-
tivity. A solution of IEM-2151, IEM-2163, or memantine (in
H O were injected to rats once intramuscularly (i.m.) 30 min
2
before sodium nitrite administration. Antihypoxic activity of
IEM-2151 and IEM-2163 and memantine as a reference was
evaluated by determining the increase of mean lifespan (min)
H O) as a reference was injected i.m. in increasing doses un-
2
of the rats as compared to a control (i.m. injection of H O)
til the maximum analgesia (latent period for a tail flick of
>30 sec) was reached for the last three measurements of pain
sensitivity. Analgesic activity of IEM-2151, IEM-2163, and
memantine was quantitatively determined as the mean mini-
mum effective dose that induced the maximum analgesia in
the rats (latent period for a tail flick of >30 sec).
2
after injection of each dose of IEM-2151, IEM-2163, and
memantine. Test data were statistically processed using the
Student criterion.
Anticonvulsant activity of the compounds was studied
in rats using a pentylenetetrazole-induced (corazole) convul-
sion model (corazole, 80 mg/kg i.m.). The severity of the
corazole convulsions was evaluated using the commonly ac-
cepted 5-ball scale for 30 min after corazole injection [18].
Neuroprotective activity of the compounds was studied
using an ataxia model (behavioral toxicity) induced by
MK-801 [20, 24] in male Wistar rats (12 – 14 weeks old,
160 – 180 g). IEM-2151 was selected for this test as the most
promising for clinical trials because the acute toxicity of
IEM-2151 was six times less than that of IEM-2163 (LD50
300 and 50 mg/kg, respectively, i.m. in mice). MK-801 at an
i.m. dose of 0.4 mg/kg had potent neurotoxic activity (behav-
ioral toxicity) that developed after 15 – 20 min (latent pe-
riod) and manifested as a triad of hyperlocomotion, stere-
otypy, and ataxia (uncoordinated movements, falling on the
side, disturbance of antigravitational reflexes) in 100% of the
rats within 60 min after injection of MK-801. The severity of
ataxia was evaluated in balls on the following scale: 0, no
ataxia; 1, uncoordinated movements, hyperlocomotion; 2,
hyperlocomotion, stereotypy, falling on side; 3, complete
disturbance of antigravitational reflexes. Neuroprotective ac-
tivity was assessed from the ability of the compounds to
eliminate severe ataxia (2 – 3 balls) induced by the neuroto-
xic activity of MK-801. The latent period of ataxia (in groups
of five rats; without ataxia, the latent period was 60 min), the
maximum severity of ataxia in balls, and the percent of rats
with light (1 ball) and severe (2 – 3 balls) ataxia of the total
number of rats in the group were determined for each dose of
the test compound for 60 min after MK-801 injection. Aque-
ous solutions of the test compound and memantine and halo-
peridol as references were injected once i.m. in 0.1 – 0.3 mL
30 min before MK-801 injection (0.4 mg/kg, i.m.). The test
compounds and memantine and haloperidol as references
were injected intragastrically in 0.8 – 1.0 mL 30 min before
MK-801 injection (0.4 mg/kg, i.m.) for oral administration.
Neuroprotective activity was quantitatively evaluated by cal-
culating the range of effective doses for which the maximum
The tested compounds dissolved in H O were injected once
2
i.m. 30 min before corazole administration. The severity of
convulsions in balls was determined for each dose of
IEM-2151, IEM-2163, and memantine as a reference.
Anticonvulsant activity of the compounds was evaluated
from the decrease of convulsion severity in balls as com-
pared to a control. Test data were statistically processed us-
ing the Mann—Whitney test.
Antiparkinsonian activity of the compounds was stud-
ied in rats using a catalepsy model induced by i.m. injection
of haloperidol at a dose of 1 mg/kg. The magnitude of the
catalepsy was evaluated from the immobilization time (s) of
rats placed onto a large grid at a 45° angle 60 min after
haloperidol injection. The maximum catalepsy of rats con-
sidered their complete immobilization on the grid for 120 sec
of observation [19, 20]. A solution of the test compound in
distilled H O was injected once i.m. 30 min before haloperi-
2
dol injection. Antiparkinsonian (anticataleptic) activity of
IEM-2151, IEM-2163, and memantine as a reference was
quantitatively determined from the decrease of immobiliza-
tion time (s) as compared to a control (H O). Test data were
2
statistically processed using the Student criterion.
Antidepressant activity of the compounds was studied
in rats in a 2-day Porsolt swim test [21]. The swim test was
conducted by placing a rat in a glass cylinder with H O
2
(
22°C). The immobilization time of the rats was not recorded
for 15 min on the first day of the swim test. The total immo-
bilization time (s) was determined for 5 min of repeated
swimming on the second day of the test. A solution of
IEM-2151 in H O, a control (H O), or memantine as a refer-
2
2

Comparison of the Pharmacological Activity
1201
neuroprotective effect was reached (ED – ED100) and (ED50
fect because the survival of the rats increased by 1.5 times
(from 56 to 86 min as compared to the control, p < 0.05, Ta-
ble 1).
80
–
ED ).
80
Acute toxicity of IEM-2151, IEM-2163, and memantine
was determined after i.p. administration of them to intact
mice at toxic doses until 100% lethality was obtained. The
dose of the compound causing the death of 50% of the mice
1-Adamantylguanidine (IEM-2151) after i.m. injection at
a dose of 1 mg/kg, which was 20 times less than for
memantine, caused a stronger antihypoxic effect because the
survival of the rats increased by 1.9 times (from 56 to
104 min as compared to the control, p < 0.05, Table 1). It is
noteworthy at IEM-2151 caused a statistically significant
antihypoxic effect (rat lifespan 90 – 104 min) over the whole
range of studied doses (1 – 6 mg/kg).
(
LD ) was calculated.
50
Safety of the compounds was assessed by calculating the
therapeutic index (TI), i.e., the ratio LD /ED of the toxic
50
50
dose causing the death of 50% of the mice (LD ) to the dose
50
preventing clonic-tonic corazole convulsions in 50% of the
rats (ED ). The TI was calculated using experimental results
3,5-Dimethyl-1-adamantylguanidine (IEM-2163) after
i.m. injection at a dose of 1 mg/kg, which was 20 times less
than for memantine, caused a stronger antihypoxic effect
than memantine because the survival of the rats increased by
1.8 times (from 56 to 101 min as compared to the control,
p < 0.05, Table 1). IEM-2163 at a dose of 6 mg/kg caused the
maximum antihypoxic effect because the survival of rats
with hemic hypoxia increased by 2.2 times (from 56 to
122 min, p < 0.05, Table 1). The antihypoxic activity of
IEM-2163 at this dose was 1.5 times greater than that of me-
mantine and 1.25 times greater than that of IEM-2151. It is
noteworthy that IEM-2163 caused a statistically significant
5
0
for the acute toxicity test in mice and the corazole convulsion
test in rats.
RESULTS AND DISCUSSION
Antihypoxic activity. Table 1 shows that the reference
drug memantine after i.m. injection at doses of 5 and
1
0 mg/kg caused statistically insignificant increases of the
lifespans of rats with hemic hypoxia from 56 min to 66 and
7 min, respectively. Memantine only at the maximum dose
of 20 mg/kg caused a statistically significant antihypoxic ef-
7
TABLE 1. Antihypoxic, Anticonvulsant, Antiparkinsonian, and Antidepressant Activity of IEM-2151 and Memantine
Antihypoxic activity
Anticonvulsant activity
2
in corazole convulsion test in haloperidol catalepsy test
Antiparkinsonian activity
Antidepressant activity
4
in Porsolt test
1
3
in thermal hypoxia test
Dose, i.m.,
mg/kg
Compound
rat lifespan,
min
corazole convulsion
severity, balls
immobilization time
on grid, s
immobilization time during
repeated swimming, s
Water (control)
Memantine
-
56 ± 5
4.8 ± 0.4
113 ± 8
111 ± 7
78 ± 4
181 ± 14.3
149 ± 15.0
1
3
5
63 ± 5
77 ± 4
4.2 ± 0.7
3.4 ± 0.5
92 ± 11.2
6
1
0
0
18 ± 4
5
5
5
2
86 ± 7
1.9 ± 0.4
46 ± 4.1
IEM-2151
0.3
1
63 ± 9
3.8 ± 0.4
5
5
5
104 ± 19
2.4 ± 0.7
70 ± 6
69 ± 6.8
5
5
5
5
3
90 ± 17
1.7 ± 0.4
56 ± 7
46 ± 7.8
5
5
6
5
6
94 ± 21
1.4 ± 0.3
25 ± 4
41 ± 7.3
IEM-2163
0.3
1
65 ± 8
3.3 ± 0.5
5
5
5
5
101 ± 18
2.0 ± 0.6
60 ± 8
49 ± 6.4
5
5
6
3
105 ± 21
1.4 ± 0.3
40 ± 75
34 ± 7.3
5
6
6
6
6
122 ± 27
1.0 ± 0.2
19 ± 4
30 ± 6.1
1
Sodium nitrate, 80 mg/kg, i.m.
2
3
4
5
6
Corazole, 80 mg/kg, i.m., convulsion severity on 0 – 6 ball scale.
Immobilization time (s) on grid 60 min after haloperidol administration at a dose of 1 mg/kg.
Immobilization time (s) during 5 min of repeated swimming in Porsolt test.
p < 0.05 vs. control.
p < 0.01 vs. control.

1
202
V. E. Gmiro and S. E. Serdyuk
antihypoxic effect (rat lifespan 101 – 122 min) over the
whole range of studied doses (1 – 6 mg/kg).
113 to 78 sec (Table 1). Memantine at a high dose of
10 mg/kg i.m. had the maximum effect and decreased the
time of haloperidol catalepsy by 6.3 times (from 113 to
18 sec, p < 0.01, Table 1).
Anticonvulsant activity. Injection of corazole
(
80 mg/kg, i.m.) induced generalized clonic-tonic convul-
sions of 4 – 5 balls severity in 100% of the rats. Ta-
ble 1 shows that the reference drug memantine after i.m. in-
jection caused a statistically significant anticonvulsant effect
only at the maximum dose of 20 mg/kg because the severity
of the corazole convulsions decreased by 2.5 times (from 4.8
to 1.9 balls, p < 0.05, Table 1). IEM-2151 after i.m. injection
at doses of 3 and 6 mg/kg decreased the severity of corazole
convulsions by 2.8 – 3.4 times (from 4.8 to 1.7 and 1.4 balls,
respectively; p < 0.05; Table 1). IEM-2163 after i.m. injec-
tion at doses of 1, 3, and 6 mg/kg decreased the severity of
corazole convulsions by 2.4 – 4.8 times (from 4.8 to 2.0, 1.4,
and 1.0 ball, respectively; p < 0.05; Table 1).
Table 1 shows that IEM-2151 after i.m. injection at a
dose of 3 mg/kg halved the time of haloperidol catalepsy be-
cause the immobilization time on the grid decreased from
113 to 56 sec (p < 0.05, Table 1). IEM-2151 at a dose of
6
mg/kg i.m. had the maximum effect, decreasing the time of
haloperidol catalepsy by 4.5 times (from 113 to 25 sec,
p < 0.01, Table 1).
IEM-2163 after i.m. injection at doses of 1 and 3 mg/kg
caused statistically significant decreases by 1.9 and 2.8 times
of the time of haloperidol catalepsy because the immobiliza-
tion time on the grid decreased from 113 to 60 and 40 sec, re-
spectively (p < 0.05, Table 1). IEM-2163 at a dose of
Thus, IEM-2151 after injection to rats at a dose of
6
mg/kg i.m. had the maximum effect, like memantine, and
decreased the haloperidol catalepsy time by 6.6 times (from
13 to 17 sec, p < 0.01, Table 1).
6
mg/kg (3.3 times less than for memantine) caused an
anticonvulsant effect 1.4 times more pronounced than that of
memantine in the corazole convulsion model. IEM-2163
possessed the greatest anticonvulsant activity because it at a
dose of 6 mg/kg decreased the severity of corazole convul-
sions 1.9 times more strongly than memantine and 1.4 times
more strongly than IEM-2151. IEM-2151 and IEM-2163
caused statistically significant anticonvulsant effects in the
dose range 1 – 6 mg/kg, in contrast to memantine, which was
effective only at the maximum dose of 20 mg/kg.
1
Thus, IEM-2151, IEM-2163, and the standard antipar-
kinsonian drug memantine after i.m. injection possessed the
maximum antiparkinsonian activity because they practically
completely eliminated haloperidol catalepsy in rats. The
antiparkinsonian activity of IEM-2163 was 1.5 times more
potent than that of IEM-2151. IEM-2151 caused a statisti-
cally significant antiparkinsonian effect in the dose range
3
– 6 mg/kg; IEM-2163, in the broadest dose range of
– 6 mg/kg; in contrast with memantine, which was effec-
Antiparkinsonian activity. Haloperidol at a dose of
1
1
mg/kg i.m. caused immobilization for 110 – 120 sec (maxi-
tive only at the maximum dose of 10 mg/kg.
mum catalepsy) after 60 min in rats placed on a large grid at
a 45º angle.
Antidepressant activity. The total immobilization time
was 181 ± 14.3 sec for control rats (that were injected i.m.
The reference drug memantine at a dose of 3 mg/kg i.m.
decreased the time of haloperidol catalepsy by only 1.4 times
because the immobilization time on the grid decreased from
with H O 30 min before the test) on the second day of a
2
5-min Porsolt swim test (Table 1). This indicated that the
maximum depression developed in the control rats.
The reference drug memantine upon i.m. injection at
doses of 1 and 5 mg/kg caused statistically insignificant de-
creases by 1.2 and 1.9 times of the immobilization time
TABLE 2. Acute Toxicity, Therapeutic Index, and Analgesic Ac-
tivity of IEM-2151 and Memantine
(from 181 to 149 and 92 sec, respectively; Table 1) as com-
Acute toxicity
in mice
Therapeutic
index (TI)
Minimal effective
dose of compound
inducing maxi-
pared to the control (H O). Memantine only at a high dose of
2
20 mg/kg caused a statistically significant decrease by 3.9
times of the immobilization time of rats in the Porsolt test
(from 181 to 46 sec, p < 0.05, Table 1).
Compound
mum analgesia in
tail-flick test in
1
2
LD50, mg/kg i.p.
LD50/ED50
4
rats, mg/kg, i.m.
IEM-2151 after i.m. injection at a dose of 1 mg/kg de-
creased the immobilization time by 2.6 times from 181 to
3
Memantine
79 ± 15
300 ± 40
50 ± 10
7.9 (79/10)
21.1 ± 3.1
2.8 ± 0.32
2.0 ± 0.35
69 sec (p < 0.05, Table 1). IEM-2163 upon i.m. injection at a
3
IEM-2151
IEM-2163
500 (300/0.6)
dose of 1 mg/kg reduced the immobilization time by 3.7
times from 181 to 49 sec (p < 0.05, Table 1).
3
100 (50/0.5)
Table 1 shows that IEM-2151 at i.m. doses of
3 – 6 mg/kg had the maximum effect and decreased immobi-
lization of rats by 3.9 – 4.4 times in the Porsolt test (from
181 to 46 and 41 sec, p < 0.05, Table 1).
1
Toxic dose of compound causing death of 50% of mice (LD ).
5
ED50 = minimal effective dose of compound eliminating general-
0
2
ized corazole convulsions in 50% of rats.
3
LD /ED ratio in parentheses. TI calculated using experimental
5
0
50
IEM-2163 upon i.m. injection at doses of 3 and 6 mg/kg
exhibited the greatest antidepressant activity because it re-
duced immobilization of rats in the Porsolt test most effec-
results from corazole convulsion test in rats and acute toxicity test in
mice.
4
Latent period of tail-flick response >30 sec.

Comparison of the Pharmacological Activity
1203
tively by 5.3 and 6.0 times as compared to the control (from
maximum antipsychotic effect because it eliminated ataxia in
practically 100% of the rats. However, haloperidol at this
dose caused pronounced catalepsy in the rats and suppressed
locomotor activity while IEM-2151 did not cause side effects
even at the maximum dose, in contrast to haloperidol and
memantine.
1
81 to 34 and 30 sec, respectively; p < 0.01; Table 1).
Thus, IEM-2151 and the reference drug memantine pos-
sessed equally high antidepressant activity (75% decreases
of immobilization of rats in the Porsolt test). However,
IEM-2151 caused the maximum antidepressant effect at a
dose six times less than that of memantine.
Acute toxicity of IEM-2163, IEM-2151, and memantine
in mice was quantitatively determined by calculating their
toxic doses after i.p. administration causing the death of 50%
of the mice (LD ).
The antidepressant activity of IEM-2163 was 1.3 – 1.4
times greater than that of memantine. IEM-2151 and
IEM-2163 caused statistically significant antidepressant ef-
fects in the dose range 1 – 6 mg/kg, in contrast to meman-
tine, which was effective only at the maximum dose of
5
0
Table 2 shows that the reference drug memantine at an
i.p. dose of 79 mg/kg caused the death of 50% of the mice
LD ). IEM-2151 had LD of 300 mg/kg; IEM-2163,
2
0 mg/kg.
Analgesic activity. Table 2 shows that IEM-2163,
(
5
0
50
50 mg/kg (Table 2). Therefore, the acute toxicity of
IEM-2151, and memantine upon i.m. injection at the mini-
mal effective dose of 2.0, 2.8, and 21.1 mg/kg, respectively,
caused the maximum analgesia (latent period of tail flick was
IEM-2151 was 3.8 times less than that of memantine; of
IEM-2163, 1.6 time greater than that of memantine. The
acute toxicity of IEM-2151 was 6 times less than that of
IEM-2163.
3
0 sec). Therefore, IEM-2163 and IEM-2151 upon i.m. in-
jection, like the reference drug memantine, cause the maxi-
mum analgesic effect but at doses 9.5 and 7.5 times less, re-
spectively, than memantine.
Safety of IEM-2151, IEM-2163, and memantine was as-
sessed by calculating their TI values, i.e., LD /ED , the ra-
5
0
50
tio of the toxic dose causing the death of 50% of the mice
LD ) to the dose preventing clonic-tonic corazole convul-
Neuroprotective activity. IEM-2151 at a dose of
(
1
2 mg/kg upon both systemic and oral (intragastric) adminis-
50
tration eliminated severe ataxia induced by MK-801 in 100%
of the rats while memantine at a dose of 10 mg/kg upon ad-
ministration by both modes eliminated severe ataxia in only
sions in 50% of the rats (ED50).
Table 2 shows that the reference drug memantine upon
i.p. injection caused the death of 50% of the mice at a dose of
79 mg/kg and eliminated corazole convulsions in 50% of the
6
0% of the rats (Table 3), i.e., memantine was less active as a
rats (ED ) after i.m. injection at a dose of 10 mg/kg. There-
neuroprotector. A disadvantage of memantine is the very nar-
row effective dose range ED50 – ED60 in which a statistically
significant neuroprotective effect is achieved (8.8 –
50
fore, memantine had a low TI of 7.9, indicative of inadequate
safety for using memantine.
IEM-2151 upon i.p. injection caused the death of 50% of
the mice at a dose of 300 mg/kg (LD ) and eliminated
1
0 mg/kg, intragastric, Table 3). IEM-2151 had a greater ef-
fective dose range ED50 – ED80 (5.2 – 9.0 mg/kg, intragas-
tric) than memantine and an effective dose range ED80
5
0
–
corazole convulsions in 50% of the rats (ED ) after i.m. in-
50
ED100 (9 – 12 mg/kg, intragastric), which was missing for
memantine. The neuroleptic haloperidol at a dose of 1 mg/kg
with injection and oral administration caused the standard
jection at a low dose of 0.6 mg/kg. Therefore, IEM-2151 had
a high TI of 500. IEM-2163 upon i.p. injection caused the
death of 50% of the mice at a dose of 50 mg/kg (LD ) and
50
TABLE 3. Comparison of Neuroprotective Activity of Compounds in Rats in Ataxia Model Induced by MK-801 (0.4 mg/kg, i.m.)
Minimal effective dose of compound (mg/kg)
2
eliminating severe ataxia
Range of effective doses, mg/kg
Compound, dose,
mg/kg, admin. pathway
1
in 50% of rats (LD50
2.5 ± 0.5
)
in 80% of rats (ED50
)
ED50 – ED80
2.5 – 6.0
ED80 – ED100
6 – 12
9 – 12
–
IEM-2151, 12.0, i.m.
6.0 ± 0.6
IEM-2151, 12.0, intragastric
Memantine, 10.0, i.m.
5.2 ± 1.0
9.0 ± 1.5
5.2 – 9.0
3
7.5 ± 1.5
–
–
7.5 – 10.0
3
Memantine, 10.0, intragastric
Haloperidol, 1.0, i.m.
8.8 ± 1.5
8.8 – 10.0
–
0.18 ± 0.03
0.40 ± 0.05
0.3 ± 0.05
0.7 ± 0.1
0.2 – 0.3
0.4 – 0.7
0.3 – 1.0
0.7 – 1.0
Haloperidol, 1.0, intragastric
1
Control; i.m. H O, 1 mL/kg; intragastric H O, 10 mL/kg.
2
2
2
3
Ataxis severity 2 – 3 balls (2 balls – hyperlocomotion, stereotypy, falling on side; 3 balls – full disruption of antigravitational reflexes).
ED50 – ED60.

1
204
V. E. Gmiro and S. E. Serdyuk
5
6
. C. G. Parsons, W. Danysz, and G. Quack, Neuropharmacology,
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5
0
3
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a dose of 0.5 mg/kg. Therefore, IEM-2163 had a TI of 100.
Thus, IEM-2151 upon injection had a TI that was 63
times greater than that of memantine, i.e., was marginally
toxic and safe for use. IEM-2163 had a TI that was 12 times
greater than that of memantine but 5 times less than that of
IEM-2151.
(
7
8
. G. C. Palmer, Curr. Drug Targets, 2(3), 241 – 271 (2001).
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important advantages over clinically used memantine be-
cause they had antiparkinsonian, antidepressant, and analge-
sic activities that were equally potent to those of memantine
and antihypoxic, anticonvulsant, and neuroprotective activi-
ties that were superior to those of memantine. They also had
lower toxicities than memantine.
1
1
12. C. Ikonomidou, V. Stefovska, and L. Turski, Proc. Natl. Acad.
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higher antiparkinsonian activity and the high safety of
IEM-2151 and IEM-2163 as compared to memantine may be
explained not only by their NMDA-blocking properties but
also the additional capability to block NO synthesis [27].
The guanidine analogs of amantadine and memantine,
IEM-2151 and IEM-2163, are believed to represent a new
compound class with combined antiparkinsonian and neuro-
protective activity that could turn out to be more effective
and safer than memantine for treating parkinsonism, depres-
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