15 research outputs found
The memory and learning enhancing effects of Atristamine
The object of the present study, 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one (Atristamine), has been deeply studied as a promising antidepressant with the unique spectrum of additional neuropharmacological properties. Previously, the memory-enhancing effects of Atristamine have already been studied in the passive-avoidance test after scopolamine-induced amnesia in mice. Thus, the study of the effects of Atristamine on the spatial learning and memory in the Morris water maze under physiological conditions was the next logical step of our research.
According to the results obtained, Atristamine (100 mg/kg) has almost the same effect on the main markers of the memory-enhancing activity (the escape latency and distance moved) as Piracetam (300 mg/kg) and Phenibut (20 mg/kg) chosen as the well-studied and widely-used memory enhancers. The escape latency decreased in the Atristamine group by 3.2 times compared to the vehicle control group, whereas Piracetam and Phenibut caused a significant reduction of this indicator by 4.3 and 3.7 times, respectively. Moreover, the rats from the Atristamine group swam 5.1 times shorter distance to the platform in the probe trial compared to animals from the vehicle control group. The distance moved was 3-fold shorter in the Piracetam group and decreased by 5.2 times in the Phenibut group.
All drugs used in this study caused considerable changes of inter-quadrant preferences of animals. Based on the analysis of the inter-quadrant behaviour of rats, it has been found that there are considerable differences in search strategies associated, probably, with distinct mechanisms of the memory and learning enhancing action of the drugs used
ΠΠΈΠ³ΠΎΠΊΡΠΈΠ½ Ρ Π½ΠΈΠ·ΡΠΊΡΠΉ Π΄ΠΎΠ·Ρ ΠΏΠΎΡΠΈΠ»ΡΡ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠΈΠ²Π½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½Ρ ΡΠ° Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Ρ Π½Π° ΠΌΠΎΠ΄Π΅Π»ΡΡ Ρ Π΅ΠΌΠΎΡΠ½Π΄ΡΠΊΠΎΠ²Π°Π½ΠΈΡ ΡΡΠ΄ΠΎΠΌ ΡΠ· ΡΡΠ·Π½ΠΈΠΌΠΈ Π½Π΅ΠΉΡΠΎΡ ΡΠΌΡΡΠ½ΠΈΠΌΠΈ ΠΌΠ΅Ρ Π°Π½ΡΠ·ΠΌΠ°ΠΌΠΈ
"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated.
The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms.
Material and methods: A total of 192 random-bred male albino mice weighting 22β25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (Β½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in Β½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents.
Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent β lamotrigine) regardless of the pathogenesis of experimental paroxysms.
Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigineΒ«ΠΠ΅ΠΏΡΠΎΡΠΈΠ²ΠΎΡΠΏΠΈΠ»Π΅ΠΏΡΠΈΡΠ΅ΡΠΊΠΈΠ΅Β» ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ ΠΈΠΌΠ΅ΡΡ Π²ΡΡΠ°ΠΆΠ΅Π½Π½ΡΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» ΠΊΠ°ΠΊ Π²ΡΠΏΠΎΠΌΠΎΠ³Π°ΡΠ΅Π»ΡΠ½ΡΠ΅ ΡΡΠ΅Π΄ΡΡΠ²Π° Π² Π»Π΅ΡΠ΅Π½ΠΈΠΈ ΠΏΠΎΠ»ΠΈΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΠΎΠΉ ΡΠΏΠΈΠ»Π΅ΠΏΡΠΈΠΈ. Π Π°Π½Π΅Π΅ Π±ΡΠ»ΠΎ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΎ Π²Π»ΠΈΡΠ½ΠΈΠ΅ Π½ΠΈΠ·ΠΊΠΈΡ
Π΄ΠΎΠ· Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½Π°, ΠΊΠΎΡΠΎΡΡΠ΅ Π½Π΅ ΠΎΠΊΠ°Π·ΡΠ²Π°ΡΡ Π²Π»ΠΈΡΠ½ΠΈΡ Π½Π° ΠΌΠΈΠΎΠΊΠ°ΡΠ΄, Π½Π° Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠΈΠ²Π½ΡΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» ΠΊΠ»Π°ΡΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΈΡΠΎΠΊΠΎ ΠΈΡΠΏΠΎΠ»ΡΠ·ΡΠ΅ΠΌΡΡ
ΠΏΡΠΎΡΠΈΠ²ΠΎΡΠΏΠΈΠ»Π΅ΠΏΡΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π² ΡΡΠ»ΠΎΠ²ΠΈΡΡ
ΡΡΠ΄ΠΎΡΠΎΠ³, ΠΈΠ½Π΄ΡΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠΌ ΠΈ ΠΌΠ°ΠΊΡΠΈΠΌΠ°Π»ΡΠ½ΡΠΌ ΡΠ»Π΅ΠΊΡΡΠΎΡΠΎΠΊΠΎΠΌ.
Π¦Π΅Π»ΡΡ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ Π±ΡΠ»ΠΎ ΠΈΠ·ΡΡΠΈΡΡ Π²Π»ΠΈΡΠ½ΠΈΠ΅ Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½Π° Π² ΡΡΠ±ΠΊΠ°ΡΠ΄ΠΈΠΎΡΠΎΠ½ΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄ΠΎΠ·Π΅ Π½Π° ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½Π° ΠΈ Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Π° Π½Π° ΠΌΠΎΠ΄Π΅Π»ΡΡ
ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ
ΡΡΠ΄ΠΎΡΠΎΠ³ Ρ ΡΠ°Π·Π½ΡΠΌΠΈ Π½Π΅ΠΉΡΠΎΡ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠ°ΠΌΠΈ.
ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ. ΠΡΠ΅Π³ΠΎ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ 192 Π±Π΅Π»ΡΡ
ΡΠ°Π½Π΄ΠΎΠΌΠ±ΡΠ΅Π΄Π½ΡΡ
ΠΌΡΡΠ΅ΠΉ-ΡΠ°ΠΌΡΠΎΠ² Π²Π΅ΡΠΎΠΌ 22β25 Π³. ΠΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½ ΠΈ Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ Π²Π½ΡΡΡΠΈΠΆΠ΅Π»ΡΠ΄ΠΎΡΠ½ΠΎ Π² ΡΡΠ»ΠΎΠ²Π½ΠΎ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠΉ (ED50) ΠΈ ΡΡΠ±ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠΉ (Β½ ED50) Π΄ΠΎΠ·Π°Ρ
: ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½ β Π² Π΄ΠΎΠ·Π°Ρ
100 ΠΈ 50 ΠΌΠ³/ΠΊΠ³; Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½ β Π² Π΄ΠΎΠ·Π°Ρ
25 ΠΈ 12,5 ΠΌΠ³/ΠΊΠ³. ΠΠΈΠ³ΠΎΠΊΡΠΈΠ½ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΏΠΎΠ΄ΠΊΠΎΠΆΠ½ΠΎ Π² ΡΡΠ±ΠΊΠ°ΡΠ΄ΠΈΠΎΡΠΎΠ½ΠΈΡΠ΅ΡΠΊΠΎΠΉ Π΄ΠΎΠ·Π΅ 0,8 ΠΌΠ³/ΠΊΠ³ Π² Π΄ΠΎΠΏΠΎΠ»Π½Π΅Π½ΠΈΠ΅ ΠΊ ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½Ρ ΠΈ Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Ρ Π² Β½ ED50. ΠΠΈΠΊΡΠΎΡΠΎΠΊΡΠΈΠ½ (2,5 ΠΌΠ³/ΠΊΠ³ ΠΏΠΎΠ΄ΠΊΠΎΠΆΠ½ΠΎ); ΡΠΈΠΎΡΠ΅ΠΌΠΈΠΊΠ°ΡΠ±Π°Π·ΠΈΠ΄ (25 ΠΌΠ³/ΠΊΠ³ Π²Π½ΡΡΡΠΈΠ±ΡΡΡΠΈΠ½Π½ΠΎ); ΡΡΡΠΈΡ
Π½ΠΈΠ½ (1,2 ΠΌΠ³/ΠΊΠ³ ΠΏΠΎΠ΄ΠΊΠΎΠΆΠ½ΠΎ); ΠΊΠ°ΠΌΡΠΎΡΡ (1000 ΠΌΠ³/ΠΊΠ³ Π²Π½ΡΡΡΠΈΠ±ΡΡΡΠΈΠ½Π½ΠΎ) ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ ΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΡ
Π°Π³Π΅Π½ΡΠΎΠ².
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ: ΠΡΡΠ²Π»Π΅Π½ΠΎ, ΡΡΠΎ Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ ΠΎΠΊΠ°Π·ΡΠ²Π°Π΅Ρ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΠΎΠ΅ ΡΡΠ°Π±ΠΈΠ»ΡΠ½ΠΎΠ΅ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΠΎΠ΅ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ Π½Π° ΠΌΠΎΠ΄Π΅Π»ΡΡ
ΠΏΠ°ΡΠΎΠΊΡΠΈΠ·ΠΌΠΎΠ² Ρ ΡΠ°Π·Π½ΡΠΌΠΈ Π½Π΅ΠΉΡΠΎΡ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΠ°ΠΌΠΈ, Π½ΠΎ ΡΠ°ΠΊΠΆΠ΅ Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΠΎ ΡΡΠΈΠ»ΠΈΠ²Π°Π΅Ρ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½Π° (Π² ΠΌΠ΅Π½ΡΡΠ΅ΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ β Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Π°) Π½Π΅Π·Π°Π²ΠΈΡΠΈΠΌΠΎ ΠΎΡ ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π° ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΡΡ
ΡΡΠ΄ΠΎΡΠΎΠ³.
ΠΡΠ²ΠΎΠ΄Ρ. ΠΠ° ΠΎΡΠ½ΠΎΠ²Π°Π½ΠΈΠΈ ΠΏΠΎΠ»ΡΡΠ΅Π½Π½ΡΡ
ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠΎΠ² ΠΌΠΎΠΆΠ½ΠΎ ΡΠ΄Π΅Π»Π°ΡΡ Π²ΡΠ²ΠΎΠ΄, ΡΡΠΎ Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½ ΠΈΠΌΠ΅Π΅Ρ Π²ΡΡΠΎΠΊΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π» Π² ΠΊΠ°ΡΠ΅ΡΡΠ²Π΅ Π°Π΄ΡΡΠ²Π°Π½ΡΠ½ΠΎΠ³ΠΎ Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΠΎΠ³ΠΎ ΡΡΠ΅Π΄ΡΡΠ²Π° Π² ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ½ΠΎΠΌ Π»Π΅ΡΠ΅Π½ΠΈΠΈ ΡΠΏΠΈΠ»Π΅ΠΏΡΠΈΠΈ, ΠΏΠΎΡΠΊΠΎΠ»ΡΠΊΡ ΠΎΠ½ ΠΏΠΎΠ²ΡΡΠ°Π΅Ρ ΡΡΡΠ΅ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π½ΠΈΠ·ΠΊΠΈΡ
Π΄ΠΎΠ· ΡΡΠ°Π΄ΠΈΡΠΈΠΎΠ½Π½ΡΡ
ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΡ
ΡΡΠ΅Π΄ΡΡΠ² ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΠΈΠ½Π° ΠΈ Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Π°Β«ΠΠ΅ΠΏΡΠΎΡΠΈΠ΅ΠΏΡΠ»Π΅ΠΏΡΠΈΡΠ½ΡΒ» ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΈ ΠΌΠ°ΡΡΡ Π²ΠΈΡΠ°Π·Π½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΡΠΊ Π΄ΠΎΠΏΠΎΠΌΡΠΆΠ½Ρ Π·Π°ΡΠΎΠ±ΠΈ Ρ Π»ΡΠΊΡΠ²Π°Π½Π½Ρ ΠΏΠΎΠ»ΡΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠ΅Π·ΠΈΡΡΠ΅Π½ΡΠ½ΠΎΡ Π΅ΠΏΡΠ»Π΅ΠΏΡΡΡ. Π Π°Π½ΡΡΠ΅ Π±ΡΠ»ΠΎ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½ΠΎ Π²ΠΏΠ»ΠΈΠ² Π½ΠΈΠ·ΡΠΊΠΈΡ
Π΄ΠΎΠ· Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½Ρ, ΡΠΊΡ Π½Π΅ ΡΠΈΠ½ΡΡΡ Π΅ΡΠ΅ΠΊΡΡ Π½Π° ΠΌΡΠΎΠΊΠ°ΡΠ΄, Π½Π° Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠΈΠ²Π½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΠΊΠ»Π°ΡΠΈΡΠ½ΠΈΡ
ΡΠΈΡΠΎΠΊΠΎΠ²ΠΆΠΈΠ²Π°Π½ΠΈΡ
ΠΏΡΠΎΡΠΈΠ΅ΠΏΡΠ»Π΅ΠΏΡΠΈΡΠ½ΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² Π·Π° ΡΠΌΠΎΠ² ΡΡΠ΄ΠΎΠΌ, ΡΠ½Π΄ΡΠΊΠΎΠ²Π°Π½ΠΈΡ
ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠΌ ΡΠ° ΠΌΠ°ΠΊΡΠΈΠΌΠ°Π»ΡΠ½ΠΈΠΌ Π΅Π»Π΅ΠΊΡΡΠΎΡΠΎΠΊΠΎΠΌ.
ΠΠ΅ΡΠΎΡ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ Π±ΡΠ»ΠΎ Π²ΠΈΠ²ΡΠΈΡΠΈ Π²ΠΏΠ»ΠΈΠ² Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½Ρ Π² ΡΡΠ±ΠΊΠ°ΡΠ΄ΡΠΎΡΠΎΠ½ΡΡΠ½ΡΠΉ Π΄ΠΎΠ·Ρ Π½Π° ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½Ρ ΡΠ° Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Ρ Π½Π° ΠΌΠΎΠ΄Π΅Π»ΡΡ
Π΅ΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΠΈΡ
ΡΡΠ΄ΠΎΠΌ ΡΠ· ΡΡΠ·Π½ΠΈΠΌΠΈ Π½Π΅ΠΉΡΠΎΡ
ΡΠΌΡΡΠ½ΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΡΠ·ΠΌΠ°ΠΌΠΈ.
ΠΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΡΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈ. Π£ΡΡΠΎΠ³ΠΎ Π±ΡΠ»ΠΎ Π²ΠΈΠΊΠΎΡΠΈΡΡΠ°Π½ΠΎ 192 Π±ΡΠ»ΠΈΡ
ΡΠ°Π½Π΄ΠΎΠΌΠ±ΡΠ΅Π΄Π½ΠΈΡ
ΠΌΠΈΡΠ΅ΠΉ-ΡΠ°ΠΌΡΡΠ² Π²Π°Π³ΠΎΡ 22β25 Π³. ΠΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½ ΡΠ° Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ Π²Π½ΡΡΡΡΡΠ½ΡΠΎΡΠ»ΡΠ½ΠΊΠΎΠ²ΠΎ Π² ΡΠΌΠΎΠ²Π½ΠΎ Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ (ED50) ΡΠ° ΡΡΠ±Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ (Β½ ED50) Π΄ΠΎΠ·Π°Ρ
: ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½ β Ρ Π΄ΠΎΠ·Π°Ρ
100 ΡΠ° 50 ΠΌΠ³/ΠΊΠ³; Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½ β Ρ Π΄ΠΎΠ·Π°Ρ
25 ΡΠ° 12,5 ΠΌΠ³/ΠΊΠ³. ΠΠΈΠ³ΠΎΠΊΡΠΈΠ½ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΏΡΠ΄ΡΠΊΡΡΠ½ΠΎ Π² ΡΡΠ±ΠΊΠ°ΡΠ΄ΡΠΎΡΠΎΠ½ΡΡΠ½ΡΠΉ Π΄ΠΎΠ·Ρ 0,8 ΠΌΠ³/ΠΊΠ³ Π½Π° Π΄ΠΎΠ΄Π°ΡΡ Π΄ΠΎ ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½Ρ ΡΠ° Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Ρ Π² Β½ ED50. ΠΡΠΊΡΠΎΡΠΎΠΊΡΠΈΠ½ (2,5 ΠΌΠ³/ΠΊΠ³ ΠΏΡΠ΄ΡΠΊΡΡΠ½ΠΎ); ΡΡΠΎΡΠ΅ΠΌΡΠΊΠ°ΡΠ±Π°Π·ΠΈΠ΄ (25 ΠΌΠ³/ΠΊΠ³ Π²Π½ΡΡΡΡΡΠ½ΡΠΎΠΎΡΠ΅ΡΠ΅Π²ΠΈΠ½Π½ΠΎ); ΡΡΡΠΈΡ
Π½ΡΠ½ (1,2 ΠΌΠ³/ΠΊΠ³ ΠΏΡΠ΄ΡΠΊΡΡΠ½ΠΎ); ΠΊΠ°ΠΌΡΠΎΡΡ (1000 ΠΌΠ³/ΠΊΠ³ Π²Π½ΡΡΡΡΡΠ½ΡΠΎΠΎΡΠ΅ΡΠ΅Π²ΠΈΠ½Π½ΠΎ) Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΠ²Π°Π»ΠΈ ΡΠΊ ΡΡΠ΄ΠΎΠΌΠ½Ρ Π°Π³Π΅Π½ΡΠΈ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ: ΠΠΈΡΠ²Π»Π΅Π½ΠΎ, ΡΠΎ Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½ Π½Π΅ ΡΡΠ»ΡΠΊΠΈ ΡΠΈΠ½ΠΈΡΡ Π²Π»Π°ΡΠ½Ρ ΡΡΠ°Π±ΡΠ»ΡΠ½Ρ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½Ρ Π΄ΡΡ Π½Π° ΠΌΠΎΠ΄Π΅Π»ΡΡ
ΠΏΠ°ΡΠΎΠΊΡΠΈΠ·ΠΌΡΠ² ΡΠ· ΡΡΠ·Π½ΠΈΠΌΠΈ Π½Π΅ΠΉΡΠΎΡ
ΡΠΌΡΡΠ½ΠΈΠΌΠΈ ΠΌΠ΅Ρ
Π°Π½ΡΠ·ΠΌΠ°ΠΌΠΈ, Π°Π»Π΅ ΡΠ°ΠΊΠΎΠΆ Π·Π½Π°ΡΠ½ΠΎ ΠΏΠΎΡΠΈΠ»ΡΡ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠΈΠ²Π½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½Ρ (ΠΌΠ΅Π½ΡΠΎΡ ΠΌΡΡΠΎΡ β Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½Ρ) Π½Π΅Π·Π°Π»Π΅ΠΆΠ½ΠΎ Π²ΡΠ΄ ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Ρ Π΅ΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ°Π»ΡΠ½ΠΈΡ
ΡΡΠ΄ΠΎΠΌ.
ΠΠΈΡΠ½ΠΎΠ²ΠΊΠΈ. ΠΠ° ΠΏΡΠ΄ΡΡΠ°Π²Ρ ΠΎΡΡΠΈΠΌΠ°Π½ΠΈΡ
ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡΠ² ΠΌΠΎΠΆΠ½Π° Π·ΡΠΎΠ±ΠΈΡΠΈ Π²ΠΈΡΠ½ΠΎΠ²ΠΎΠΊ, ΡΠΎ Π΄ΠΈΠ³ΠΎΠΊΡΠΈΠ½ ΠΌΠ°Ρ Π²ΠΈΡΠΎΠΊΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΡΠΊ Π°Π΄βΡΠ²Π°Π½ΡΠ½ΠΈΠΉ Π»ΡΠΊΠ°ΡΡΡΠΊΠΈΠΉ Π·Π°ΡΡΠ± Ρ ΠΊΠΎΠΌΠΏΠ»Π΅ΠΊΡΠ½ΠΎΠΌΡ Π»ΡΠΊΡΠ²Π°Π½Π½Ρ Π΅ΠΏΡΠ»Π΅ΠΏΡΡΡ, ΠΎΡΠΊΡΠ»ΡΠΊΠΈ Π²ΡΠ½ ΠΏΡΠ΄Π²ΠΈΡΡΡ Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡΡΡ Π½ΠΈΠ·ΡΠΊΠΈΡ
Π΄ΠΎΠ· ΡΡΠ°Π΄ΠΈΡΡΠΉΠ½ΠΈΡ
ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΈΡ
Π·Π°ΡΠΎΠ±ΡΠ² ΠΊΠ°ΡΠ±Π°ΠΌΠ°Π·Π΅ΠΏΡΠ½Ρ ΡΠ° Π»Π°ΠΌΠΎΡΡΠΈΠ΄ΠΆΠΈΠ½
ΠΠ½Π³ΡΠ±ΡΡΠΎΡΠΈ SGLT-2 ΡΠΊ ΠΏΠΎΡΠ΅Π½ΡΡΠΉΠ½Ρ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½ΡΠΈ: Π΅ΠΌΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½, Π°Π»Π΅ Π½Π΅ Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½, ΡΠΈΠ½ΠΈΡΡ Π²ΠΈΡΠ°Π·Π½ΠΈΠΉ Π΅ΡΠ΅ΠΊΡ Ρ ΠΏΠΎΡΠ΅Π½ΡΡΡΡ Π΄ΡΡ Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΡ Π½Π°ΡΡΡΡ Π·Π° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΈΡ ΡΡΠ΄ΠΎΠΌ
On the way to the search for effective adjuvant medicines for epilepsy treatment, antidiabetic medicines such as sodium-glucose cotransporter-2 inhibitors, which are expressed not only in the kidneys but also in the brain, attract attention. From previous studies, it is known that dapagliflozin improves electroencephalographic parameters in rats on the model of pentylenetetrazole-induced seizures. However, the anticonvulsant potential of other medicines from this group needs to be clarified.
The aim of the study is to estimate the effect of empagliflozin, dapagliflozin per se and their combinations with sodium valproate on pentylenetetrazole-induced seizures, as well as on muscle tone and motor coordination in mice.
Material and methods. 42 random-bred male albino mice weighing 24-28 g were used in the experiments. Empagliflozin (20 mg/kg) and dapagliflozin (50 mg/kg) were administered intragastrically for 3 days. The classic anticonvulsant sodium valproate (150 mg/kg) per se, in combination with the medicines mentioned above, was administered in a similar regimen. On the second day, 30 minutes after administering all medicines, their effect on muscle tone and coordination of movements was determined in the rotarod test. On the third day, 30 minutes after the last administration of the medicines, their effect on pentylenetetrazole-induced (80 mg/kg subcutaneously) seizures was studied.
Results. For the first time, a pronounced anticonvulsant effect of empagliflozin was established both when used alone (a significant increase in latency of the convulsions and a decrease in lethality by 43 %) and especially in combination with sodium valproate (a significant increase in latency of the convulsions, a decrease in the number and severity of seizures and a decrease in lethality by 83 %), as well as the absence of a muscle relaxant effect in both cases. Dapagliflozin has neither its anticonvulsant properties nor its effect on the action of sodium valproate. However, this medicine caused muscle relaxation, especially when combined with sodium valproate.
Conclusions. The results suggest that empagliflozin, unlike dapagliflozin, has a high potential as an adjuvant medicine in treating epilepsy, as it enhances the efficacy of the classic anticonvulsant sodium valproate without muscle relaxant side effectsΠΠ° ΡΠ»ΡΡ
Ρ ΠΏΠΎΡΡΠΊΡ Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΠΈΡ
Π°Π΄βΡΠ²Π°Π½ΡΠ½ΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² Π΄Π»Ρ Π»ΡΠΊΡΠ²Π°Π½Π½Ρ Π΅ΠΏΡΠ»Π΅ΠΏΡΡΡ ΠΏΡΠΈΠ²Π΅ΡΡΠ°ΡΡΡ ΡΠ²Π°Π³Ρ ΠΏΡΠΎΡΠΈΠ΄ΡΠ°Π±Π΅ΡΠΈΡΠ½Ρ Π·Π°ΡΠΎΠ±ΠΈ β ΡΠ½Π³ΡΠ±ΡΡΠΎΡΠΈ Π½Π°ΡΡΡΠΉ-Π³Π»ΡΠΊΠΎΠ·Π½ΠΎΠ³ΠΎ ΠΊΠΎΠ½ΡΡΠ°Π½ΡΠΏΠΎΡΡΠ΅ΡΠ°-2, ΡΠΊΠΈΠΉ Π΅ΠΊΡΠΏΡΠ΅ΡΡΡΡΡΡΡ Π½Π΅ Π»ΠΈΡΠ΅ Π² Π½ΠΈΡΠΊΠ°Ρ
, Π° ΠΉ Ρ Π³ΠΎΠ»ΠΎΠ²Π½ΠΎΠΌΡ ΠΌΠΎΠ·ΠΊΡ. Π ΠΏΠΎΠΏΠ΅ΡΠ΅Π΄Π½ΡΡ
Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Ρ Π²ΡΠ΄ΠΎΠΌΠΎ, ΡΠΎ Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½ ΠΏΠΎΠΊΡΠ°ΡΡΡ Π΅Π»Π΅ΠΊΡΡΠΎΠ΅Π½ΡΠ΅ΡΠ°Π»ΠΎΠ³ΡΠ°ΡΡΡΠ½Ρ ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊΠΈ ΡΡΡΡΠ² ΡΠ· ΠΌΠΎΠ΄Π΅Π»Π»Ρ ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΈΡ
ΡΡΠ΄ΠΎΠΌ. ΠΠΎΡΡΠ΅Π±ΡΡ Π·βΡΡΡΠ²Π°Π½Π½Ρ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½ΡΠ½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΡΠ½ΡΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² ΡΡΡΡ Π³ΡΡΠΏΠΈ.
ΠΠ΅ΡΠΎΡ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ Π±ΡΠ»Π° ΠΏΠΎΡΡΠ²Π½ΡΠ»ΡΠ½Π° ΠΎΡΡΠ½ΠΊΠ° Π²ΠΏΠ»ΠΈΠ²Ρ Π΅ΠΌΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½Ρ ΡΠ° Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½Ρ per se Ρ Π² ΠΊΠΎΠΌΠ±ΡΠ½Π°ΡΡΡ Π· Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ Π½Π° ΠΏΠ΅ΡΠ΅Π±ΡΠ³ ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΈΡ
ΡΡΠ΄ΠΎΠΌ, Π° ΡΠ°ΠΊΠΎΠΆ Π½Π° ΠΌβΡΠ·ΠΎΠ²ΠΈΠΉ ΡΠΎΠ½ΡΡ Ρ ΠΊΠΎΠΎΡΠ΄ΠΈΠ½Π°ΡΡΡ ΡΡΡ
ΡΠ² Ρ ΠΌΠΈΡΠ΅ΠΉ.
ΠΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΡΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈ. ΠΠΎΡΠ»ΡΠ΄ΠΈ Π²ΠΈΠΊΠΎΠ½Π°Π½ΠΎ Π½Π° 42 Π±ΡΠ»ΠΈΡ
ΡΠ°Π½Π΄ΠΎΠΌΠ±ΡΠ΅Π΄Π½ΠΈΡ
ΠΌΠΈΡΠ°Ρ
ΠΌΠ°ΡΠΎΡ 24-28 Π³. ΠΠΌΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½ (20 ΠΌΠ³/ΠΊΠ³) Ρ Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½ (50 ΠΌΠ³/ΠΊΠ³) Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ Π²Π½ΡΡΡΡΡΠ½ΡΠΎΡΠ»ΡΠ½ΠΊΠΎΠ²ΠΎ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 3 Π΄Π½ΡΠ². Π Π°Π½Π°Π»ΠΎΠ³ΡΡΠ½ΠΎΠΌΡ ΡΠ΅ΠΆΠΈΠΌΡ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ ΠΊΠ»Π°ΡΠΈΡΠ½ΠΈΠΉ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½Ρ Π²Π°Π»ΡΠΏΡΠΎΠ°Ρ Π½Π°ΡΡΡΡ (150 ΠΌΠ³/ΠΊΠ³) per se Ρ Π² ΠΊΠΎΠΌΠ±ΡΠ½Π°ΡΡΡ ΡΠ· Π·Π°Π·Π½Π°ΡΠ΅Π½ΠΈΠΌΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°ΠΌΠΈ. ΠΠ° Π΄ΡΡΠ³ΠΈΠΉ Π΄Π΅Π½Ρ ΡΠ΅ΡΠ΅Π· 30 Ρ
Π² ΠΏΡΡΠ»Ρ Π²Π²Π΅Π΄Π΅Π½Π½Ρ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½ΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² Π²ΠΈΠ·Π½Π°ΡΠ°Π»ΠΈ ΡΡ
Π½ΡΠΉ Π²ΠΏΠ»ΠΈΠ² Π½Π° ΠΌβΡΠ·ΠΎΠ²ΠΈΠΉ ΡΠΎΠ½ΡΡ Ρ ΠΊΠΎΠΎΡΠ΄ΠΈΠ½Π°ΡΡΡ ΡΡΡ
ΡΠ² Ρ ΡΠ΅ΡΡΡ ΡΡΡΠΈΠΆΠ½Ρ, ΡΠΎ ΠΎΠ±Π΅ΡΡΠ°ΡΡΡΡΡ. ΠΠ° ΡΡΠ΅ΡΡΠΉ Π΄Π΅Π½Ρ ΡΠ΅ΡΠ΅Π· 30 Ρ
Π² ΠΏΡΡΠ»Ρ ΠΎΡΡΠ°Π½Π½ΡΠΎΠ³ΠΎ Π²Π²Π΅Π΄Π΅Π½Π½Ρ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² Π΄ΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π»ΠΈ ΡΡ
Π½ΡΠΉ Π²ΠΏΠ»ΠΈΠ² Π½Π° ΠΏΠ΅ΡΠ΅Π±ΡΠ³ ΡΡΠ΄ΠΎΠΌ, ΡΠΊΡ ΠΌΠΎΠ΄Π΅Π»ΡΠ²Π°Π»ΠΈ ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠΌ (80 ΠΌΠ³/ΠΊΠ³ ΠΏΡΠ΄ΡΠΊΡΡΠ½ΠΎ).
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ. ΠΠΏΠ΅ΡΡΠ΅ Π²ΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΎ Π²ΠΈΡΠ°Π·Π½ΠΈΠΉ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΈΠΉ Π΅ΡΠ΅ΠΊΡ Π΅ΠΌΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½Ρ ΡΠΊ Π·Π° ΡΠ·ΠΎΠ»ΡΠΎΠ²Π°Π½ΠΎΠ³ΠΎ Π²ΠΈΠΊΠΎΡΠΈΡΡΠ°Π½Π½Ρ (Π΄ΠΎΡΡΠΎΠ²ΡΡΠ½Π΅ Π·Π±ΡΠ»ΡΡΠ΅Π½Π½Ρ Π»Π°ΡΠ΅Π½ΡΠ½ΠΎΠ³ΠΎ ΠΏΠ΅ΡΡΠΎΠ΄Ρ ΡΡΠ΄ΠΎΠΌ Ρ Π·ΠΌΠ΅Π½ΡΠ΅Π½Π½Ρ Π»Π΅ΡΠ°Π»ΡΠ½ΠΎΡΡΡ Π½Π° 43 %), ΡΠ°ΠΊ Ρ ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ Π² ΠΊΠΎΠΌΠ±ΡΠ½Π°ΡΡΡ Π· Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡΡ (Π΄ΠΎΡΡΠΎΠ²ΡΡΠ½Π΅ Π·Π±ΡΠ»ΡΡΠ΅Π½Π½Ρ Π»Π°ΡΠ΅Π½ΡΠ½ΠΎΠ³ΠΎ ΠΏΠ΅ΡΡΠΎΠ΄Ρ, Π·ΠΌΠ΅Π½ΡΠ΅Π½Π½Ρ ΠΊΡΠ»ΡΠΊΠΎΡΡΡ ΡΠ° ΡΡΠΆΠΊΠΎΡΡΡ ΡΡΠ΄ΠΎΠΌ Ρ Π·Π½ΠΈΠΆΠ΅Π½Π½Ρ Π»Π΅ΡΠ°Π»ΡΠ½ΠΎΡΡΡ Π½Π° 83 %), Π° ΡΠ°ΠΊΠΎΠΆ Π²ΡΠ΄ΡΡΡΠ½ΡΡΡΡ ΠΌΡΠΎΡΠ΅Π»Π°ΠΊΡΠ°Π½ΡΠ½ΠΎΠ³ΠΎ Π΅ΡΠ΅ΠΊΡΡ Π² ΠΎΠ±ΠΎΡ
Π²ΠΈΠΏΠ°Π΄ΠΊΠ°Ρ
. Π£ Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½Ρ Π½Π΅ Π²ΠΈΡΠ²Π»Π΅Π½ΠΎ Π°Π½Ρ Π²Π»Π°ΡΠ½ΠΈΡ
Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠΈΠ²Π½ΠΈΡ
Π²Π»Π°ΡΡΠΈΠ²ΠΎΡΡΠ΅ΠΉ, Π°Π½Ρ Π²ΠΏΠ»ΠΈΠ²Ρ Π½Π° Π΄ΡΡ Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΡ Π½Π°ΡΡΡΡ, ΠΏΡΠΎΡΠ΅ ΡΠ΅ΠΉ ΠΏΡΠ΅ΠΏΠ°ΡΠ°Ρ Π²ΠΈΠΊΠ»ΠΈΠΊΠ°Π² ΠΌΡΠΎΡΠ΅Π»Π°ΠΊΡΠ°ΡΡΡ, ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ Π·Π° ΠΊΠΎΠΌΠ±ΡΠ½Π°ΡΡΡ Π· Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΠΎΠΌ Π½Π°ΡΡΡΡ.
ΠΠΈΡΠ½ΠΎΠ²ΠΊΠΈ. Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ Π΄Π°ΡΡΡ ΠΏΡΠ΄ΡΡΠ°Π²Ρ Π΄Π»Ρ Π²ΠΈΡΠ½ΠΎΠ²ΠΊΡ, ΡΠΎ Π΅ΠΌΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½, Π½Π° Π²ΡΠ΄ΠΌΡΠ½Ρ Π²ΡΠ΄ Π΄Π°ΠΏΠ°Π³Π»ΡΡΠ»ΠΎΠ·ΠΈΠ½Ρ, ΠΌΠ°Ρ Π²ΠΈΡΠΎΠΊΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΡΠΊ Π°Π΄βΡΠ²Π°Π½ΡΠ½ΠΈΠΉ Π»ΡΠΊΠ°ΡΡΡΠΊΠΈΠΉ Π·Π°ΡΡΠ± Ρ Π»ΡΠΊΡΠ²Π°Π½Π½Ρ Π΅ΠΏΡΠ»Π΅ΠΏΡΡΡ, ΠΎΡΠΊΡΠ»ΡΠΊΠΈ Π²ΡΠ½ ΠΏΡΠ΄Π²ΠΈΡΡΡ Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡΡΡ ΠΊΠ»Π°ΡΠΈΡΠ½ΠΎΠ³ΠΎ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΎΠ³ΠΎ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ Π²Π°Π»ΡΠΏΡΠΎΠ°ΡΡ Π½Π°ΡΡΡΡ Π±Π΅Π· ΠΏΠΎΠ±ΡΡΠ½ΠΎΡ ΠΌΡΠΎΡΠ΅Π»Π°ΠΊΡΠ°Π½ΡΠ½ΠΎΡ Π΄Ρ
Low-dose Digoxin Enhances the Anticonvulsive Potential of Carbamazepine and Lamotrigine in Chemo-induced Seizures with Different Neurochemical Mechanisms
"Non-antiepileptic" drugs have a strong potential as adjuvants in multidrug-resistant epilepsy treatment. In previous study the influence of low doses of digoxin, which do not affect the myocardium, on the anticonvulsant potential of classical commonly used anti-epileptic drugs under conditions of seizures, induced by pentylenetetrazole and maximal electroshock, has been investigated.
The aim of the study was to investigate the influence of digoxin at a sub-cardiotonic dose on the anticonvulsant potential of carbamazepine and lamotrigine in experimental seizures with different neurochemical mechanisms.
Material and methods: A total of 192 random-bred male albino mice weighting 22β25 g were used. Carbamazepine and lamotrigine were administered intragastrically in conditionally effective (ED50) and sub-effective (Β½ ED50) doses: carbamazepine at doses of 100 and 50 mg/kg; lamotrigine at doses of 25 and 12.5 mg/kg. Digoxin was administered subcutaneously at a sub-cardiotonic dose of 0.8 mg/kg as an adjuvant to carbamazepine and lamotrigine in Β½ ED50. Picrotoxin (2.5 mg/kg subcutaneously); thiosemicarbazide (25 mg/kg intraperitoneally); strychnine (1.2 mg/kg subcutaneously); camphor (1000 mg/kg intraperitoneally) were used as convulsant agents.
Results: It was found that digoxin not only has its own permanent anticonvulsant effect on different models of paroxysms with different neurochemical mechanisms of development, but also significantly enhances the anticonvulsant potential of carbamazepine (to a lesser extent β lamotrigine) regardless of the pathogenesis of experimental paroxysms.
Conclusion: Based on the results, it can be concluded that digoxin has a high potential as an adjuvant medicine in complex epilepsy treatment because it enhances the efficiency of low-dose traditional anticonvulsants carbamazepine and lamotrigin
ΠΠ³Π»ΡΠ΄ ΠΏΠΎΡ ΡΠ΄Π½ΠΈΡ 1,2,4-ΡΡΠΈΠ°Π·ΠΎΠ»Ρ ΡΠ° 1,3,4-ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»Ρ ΡΠΊ ΠΏΠΎΡΠ΅Π½ΡΡΠΉΠ½ΠΈΡ Π·Π½Π΅Π±ΠΎΠ»ΡΠ²Π°Π»ΡΠ½ΠΈΡ ΡΠ° ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ Π·Π°ΡΠΎΠ±ΡΠ²
The aim. The purpose of this review is to summarize data on the synthesis and structural modification of heterocyclic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry.
Materials and methods. The research based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds.
Results. Modern medicinal chemistry faces many challenges, one of which is the determination of the activity and specificity of therapeutic agents. Recent scientific data showed that triazoles and/or thiadiazoles have broad spectrum of biological activities, in particular antimicrobial, antifungal, antiviral, anticancer and anticonvulsant. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their structure-activity relationship. For optimization and rational design of highly active molecules with optimal Β«drug-likeΒ» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized.
Conclusions. It has been shown that heterocyclic systems containing fragments of triazole and / or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drugsΠΠ΅ΡΠ°. ΠΠ΅ΡΠΎΡ Π΄Π°Π½ΠΎΠ³ΠΎ ΠΎΠ³Π»ΡΠ΄Ρ Ρ ΡΠ·Π°Π³Π°Π»ΡΠ½Π΅Π½Π½Ρ Π΄Π°Π½ΠΈΡ
ΠΏΡΠΎ ΡΠΈΠ½ΡΠ΅Π· ΡΠ° ΡΡΡΡΠΊΡΡΡΠ½Ρ ΠΌΠΎΠ΄ΠΈΡΡΠΊΠ°ΡΡΡ Π³Π΅ΡΠ΅ΡΠΎΡΠΈΠΊΠ»ΡΡΠ½ΠΈΡ
ΡΠΈΡΡΠ΅ΠΌ Π· ΡΡΡΠ°Π·ΠΎΠ»ΡΠ½ΠΈΠΌ ΡΠ° ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»ΡΠ½ΠΈΠΌ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΠ°ΠΌΠΈ Π² ΠΌΠΎΠ»Π΅ΠΊΡΠ»Π°Ρ
ΡΠΊ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΠΈΡ
ΠΎΠ±βΡΠΊΡΡΠ² Ρ Π±ΡΠΎΠΎΡΠ³Π°Π½ΡΡΠ½ΡΠΉ ΡΠ° ΠΌΠ΅Π΄ΠΈΡΠ½ΡΠΉ Ρ
ΡΠΌΡΡ.
ΠΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΡΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈ. Π£ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ Π·Π°ΡΡΠΎΡΠΎΠ²Π°Π½ΠΎ Π±ΡΠ±Π»ΡΠΎΡΠ΅ΠΌΠ°Π½ΡΠΈΡΠ½ΠΈΠΉ ΡΠ° Π°Π½Π°Π»ΡΡΠΈΡΠ½ΠΈΠΉ ΠΌΠ΅ΡΠΎΠ΄ΠΈ Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΡΡΠΈ Π±ΡΠ±Π»ΡΠΎΠ³ΡΠ°ΡΡΡΠ½Ρ Ρ ΡΠ΅ΡΠ΅ΡΠ°ΡΠΈΠ²Π½Ρ Π±Π°Π·ΠΈ Π΄Π°Π½ΠΈΡ
, Π° ΡΠ°ΠΊΠΎΠΆ Π±Π°Π·ΠΈ Π΄Π°Π½ΠΈΡ
Ρ
ΡΠΌΡΡΠ½ΠΈΡ
ΡΠΏΠΎΠ»ΡΠΊ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ. Π‘ΡΡΠ°ΡΠ½Π° ΠΌΠ΅Π΄ΠΈΡΠ½Π° Ρ
ΡΠΌΡΡ ΡΡΠΈΠΊΠ°ΡΡΡΡΡ Π· Π±Π°Π³Π°ΡΡΠΌΠ° ΠΏΡΠΎΠ±Π»Π΅ΠΌΠ°ΠΌΠΈ, ΠΎΠ΄Π½Π° Π· ΡΠΊΠΈΡ
β Π½Π΅ΠΎΠ±Ρ
ΡΠ΄Π½ΡΡΡΡ Π²ΠΈΠ·Π½Π°ΡΠ΅Π½Π½Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΡΠ° ΡΠΏΠ΅ΡΠΈΡΡΡΠ½ΠΎΡΡΡ ΠΏΠΎΡΠ΅Π½ΡΡΠΉΠ½ΠΎΠ³ΠΎ ΡΠ΅ΡΠ°ΠΏΠ΅Π²ΡΠΈΡΠ½ΠΎΠ³ΠΎ Π°Π³Π΅Π½ΡΠ°. ΠΡΡΠ°Π½Π½Ρ Π½Π°ΡΠΊΠΎΠ²Ρ Π΄Π°Π½Ρ Π²ΠΊΠ°Π·ΡΡΡΡ Π½Π° ΡΠ΅, ΡΠΎ ΠΏΠΎΡ
ΡΠ΄Π½ΠΈΠΌ ΡΡΡΠ°Π·ΠΎΠ»Ρ ΡΠ°/ΡΠΈ ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»Ρ ΠΏΡΠΈΡΠ°ΠΌΠ°Π½Π½ΠΈΠΉ ΡΠΈΡΠΎΠΊΠΈΠΉ ΡΠΏΠ΅ΠΊΡΡ Π±ΡΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΎΡ Π΄ΡΡ, Π·ΠΎΠΊΡΠ΅ΠΌΠ° ΠΏΡΠΎΡΠΈΠΌΡΠΊΡΠΎΠ±Π½Π°, ΠΏΡΠΎΡΠΈΠ³ΡΠΈΠ±ΠΊΠΎΠ²Π°, ΠΏΡΠΎΡΠΈΠ²ΡΡΡΡΠ½Π°, ΠΏΡΠΎΡΠΈΡΠ°ΠΊΠΎΠ²Π° ΡΠ° Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½ΡΠ½Π°. Π‘ΠΈΠ½ΡΠ΅ΡΠΈΡΠ½Ρ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ, Π΄ΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΈ Π·Π°ΠΏΡΠΎΠΏΠΎΠ½ΡΠ²Π°ΡΠΈ Π½ΠΈΠ·ΠΊΡ Π½ΠΎΠ²ΠΈΡ
ΡΠΏΡΡΠΌΡΠ²Π°Π½Ρ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΠΎΠ³ΠΎ Π΄ΠΈΠ·Π°ΠΉΠ½Ρ Π±ΡΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΈΡ
ΠΏΠΎΡ
ΡΠ΄Π½ΠΈΡ
ΡΡΡΠ°Π·ΠΎΠ»Ρ ΡΠ°/ΡΠΈ ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»Ρ, Π° ΡΠ°ΠΊΠΎΠΆ ΠΎΠ΄Π΅ΡΠΆΠ°ΡΠΈ ΡΡΠΎΠΊΡΡΠΎΠ²Π°Π½Ρ Π±ΡΠ±Π»ΡΠΎΡΠ΅ΠΊΠΈ, ΡΠΎ Π½Π°ΡΠ°Ρ
ΠΎΠ²ΡΡΡΡ ΡΠΎΡΠ½Ρ Π½ΠΎΠ²ΠΈΡ
ΡΠΏΠΎΠ»ΡΠΊ. Π¦Ρ ΠΎΠ³Π»ΡΠ΄ΠΎΠ²Π° ΡΡΠ°ΡΡΡ Ρ ΡΠΏΡΠΎΠ±ΠΎΡ ΡΠ·Π°Π³Π°Π»ΡΠ½ΠΈΡΠΈ Π΄Π°Π½Ρ ΡΠΎΠ΄ΠΎ ΡΡ
Π°Π½Π°Π»ΡΠ³Π΅Π·ΡΡΡΠΎΡ ΡΠ° ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π·Π° ΠΎΡΡΠ°Π½Π½Ρ Π΄Π΅ΡΡΡΠΈΠ»ΡΡΡΡ. Π£ ΡΠΎΠ±ΠΎΡΡ ΠΏΡΠΎΠ°Π½Π°Π»ΡΠ·ΠΎΠ²Π°Π½ΠΎ ΡΡΠ΄ΠΈ ΠΏΠΎΡ
ΡΠ΄Π½ΠΈΡ
ΡΡΡΠ°Π·ΠΎΠ»Ρ ΡΠ°/ΡΠΈ ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»Ρ, ΡΠ° Π½Π°Π²Π΅Π΄Π΅Π½ΠΎ Π·Π°Π»Π΅ΠΆΠ½ΠΎΡΡΡ Β«ΡΡΡΡΠΊΡΡΡΠ°-Π°ΠΊΡΠΈΠ²Π½ΡΡΡΡΒ». ΠΠ»Ρ ΠΎΠΏΡΠΈΠΌΡΠ·Π°ΡΡΡ Ρ ΡΠ°ΡΡΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ Π΄ΠΈΠ·Π°ΠΉΠ½Ρ Π²ΠΈΡΠΎΠΊΠΎΠ°ΠΊΡΠΈΠ²Π½ΠΈΡ
ΠΌΠΎΠ»Π΅ΠΊΡΠ» Π· ΠΎΠΏΡΠΈΠΌΠ°Π»ΡΠ½ΠΈΠΌΠΈ Β«Π»ΡΠΊΠΎΠΏΠΎΠ΄ΡΠ±Π½ΠΈΠΌΠΈΒ» Ρ
Π°ΡΠ°ΠΊΡΠ΅ΡΠΈΡΡΠΈΠΊΠ°ΠΌΠΈ ΡΠ° Π²ΠΈΠ·Π½Π°ΡΠ΅Π½Π½Ρ ΠΌΠΎΠΆΠ»ΠΈΠ²ΠΎΠ³ΠΎ ΠΌΠ΅Ρ
Π°Π½ΡΠ·ΠΌΡ Π±ΡΠΎΠ»ΠΎΠ³ΡΡΠ½ΠΎΡ Π΄ΡΡ ΠΏΡΠΎΠ²Π΅Π΄Π΅Π½ΠΎ ΡΠ·Π°Π³Π°Π»ΡΠ½Π΅Π½Π½Ρ Π΄Π°Π½ΠΈΡ
ΡΠΎΠ΄ΠΎ SAR- Ρ QSAR-Π°Π½Π°Π»ΡΠ·Ρ Ρ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΠΎΠ³ΠΎ Π΄ΠΎΠΊΡΠ½Π³Ρ ΡΠ΅ΡΠ΅Π΄ Π΄Π°Π½ΠΎΠ³ΠΎ ΠΊΠ»Π°ΡΡ Π³Π΅ΡΠ΅ΡΠΎΡΠΈΠΊΠ»ΡΡΠ½ΠΈΡ
ΡΠΏΠΎΠ»ΡΠΊ.
ΠΠΈΡΠ½ΠΎΠ²ΠΊΠΈ. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΠΎ Π³Π΅ΡΠ΅ΡΠΎΡΠΈΠΊΠ»ΡΡΠ½Ρ ΡΠΈΡΡΠ΅ΠΌΠΈ, ΡΠΎ ΠΌΡΡΡΡΡΡ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΠΈ ΡΡΡΠ°Π·ΠΎΠ»Ρ ΡΠ°/ΡΠΈ ΡΡΠ°Π΄ΡΠ°Π·ΠΎΠ»Ρ, Ρ ΡΡΡΡΡΠ²ΠΈΠΌ Π΄ΠΆΠ΅ΡΠ΅Π»ΠΎΠΌ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΠΈΡ
Π°Π½Π°Π»ΡΠ³Π΅ΡΠΈΡΠ½ΠΈΡ
ΡΠ°/ΡΠΈ ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
Π·Π°ΡΠΎΠ±ΡΠ². ΠΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΎ, ΡΠΎ Π·Π³Π°Π΄Π°Π½Ρ Π³Π΅ΡΠ΅ΡΠΎΡΠΈΠΊΠ»ΡΡΠ½Ρ ΠΏΠΎΡ
ΡΠ΄Π½Ρ Π²ΠΎΠ»ΠΎΠ΄ΡΡΡΡ Π²ΠΈΡΠΎΠΊΠΎΡ ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΡΡΡΡ Π΄ΡΡ, ΠΌΠ°Π»ΠΎΡ ΡΠΎΠΊΡΠΈΡΠ½ΡΡΡΡ ΡΠ° Π΅ΡΠ΅ΠΊΡΠΎΠΌ, ΡΠΎ ΡΠΏΡΠ²ΠΌΡΡΠ½ΠΈΠΉ Π· ΡΡΠ½ΡΡΡΠΈΠΌΠΈ Π»ΡΠΊΠ°ΡΡΡΠΊΠΈΠΌΠΈ Π·Π°ΡΠΎΠ±Π°ΠΌ
The psycho- and neurotropic profiling of novel 3-(N-R,Rβ²-aminomethyl)-2-methyl-1H-quinolin-4-ones in vivo
The article presents the study of psycho- and neurotropic properties of novel 3-(N-R,Rβ²-aminomethyl)-2-methyl-1H-quinolin-4-ones in vivo. The research was carried out using the open field test, elevated plus maze, rotarod test, tail suspension test, passive avoidance test after scopolamine-induced amnesia and acute normobaric hypoxia with hypercapnia. As a result, two promising substances have been found. According to our results 3-[[(4-methoxyphenyl)amino]methyl]-2-methyl-1H-quinolin-4-one in the dose of 10β―mg/kg shows a specific sedative effect and a considerable anti-amnesic activity. The most interesting N-[(2-methyl-4-oxo-1H-quinolin-3-yl)methyl]-N-phenylbenzamide (100β―mg/kg) combines a potent anti-anxiety action, the anti-amnesic activity and a considerable antihypoxic effect. They are of interest for further profound studies as promising psychoactive compounds. Keywords: 1H-quinolin-4-ones, Open field test, Elevated plus maze, Tail suspension test, Passive avoidance test, Acute hypoxi
Π‘ΠΈΠ½ΡΠ΅Π· ΡΠ° ΠΎΡΡΠ½ΠΊΠ° ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π½ΠΎΠ²ΠΈΡ 1-Π±Π΅Π½Π·ΠΈΠ»Π·Π°ΠΌΡΡΠ΅Π½Π½ΠΈΡ ΠΏΠΎΡ ΡΠ΄Π½ΠΈΡ n-[(2,4-Π΄ΠΈΡ Π»ΠΎΡΠΎΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΡΠΎΠΊΡΠΎ-1Π½-Ρ ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄Ρ
The aim. Synthesis of 1-benzylsubstituted derivatives of N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1h-quinazolin-3-yl)acetamide, and determination of affinity to GABAergic biotargets with the following anticonvulsant activity estimation using PTZ-induced seizures model in mice.
Materials and methods. Standard organic synthesis methods were used; the structure of the synthesized compounds was proved by elemental analysis, 1H and 13C NMR spectroscopy, and LC/MS method; composition of the synthesized compounds β by elemental analysis, their individuality β by TLC and LC/MS methods. AutoDockTools-1.5.6, as well as AutoDock Vina software, was used to perform molecular docking. Anticonvulsant activity was studied using pentylenetetrazole-induced seizures in mice.
Results. A targeted N-[(2,4-dichlorophenyl)methyl]-2-(1-(R-benzyl)-2,4-dioxo-quinazolin-3-yl)acetamides were obtained by alkylation of N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide by corresponding 1-chloromethylbenzene in dimethylformamide environment with excess of potassium carbonate at a temperature 70-80 ΛΠ‘. Prediction of activity of 1-benzyl derivatives in the pentylenetetrazole-induced seizures in an in vivo experiment was carried out according to the obtained results of docking studies β affinity calculation for GABA receptor and GABA enzyme active sites, as well as analysis of conformational placement in them. In relation to the binding energy, the studied ligands were inferior to the reference drugs: GABA receptor positive allosteric modulators β benzamidine and diazepam, and GABA inhibitor β vigabatrin. The synthesized substances did not show anticonvulsant activity: only 2 compounds have shown a tendency to their activity manifestation according to the criterion of integral protective indicator β reduction of mortality by 17 % compared to control, as well as prolonging the time death of the animals. Comparison with the preliminary obtained results of the activity of the promising anticonvulsant N-[(2,4-dichlorophenyl)methyl] -2-(2,4-dioxo-1H-quinazolin-3-yl) acetamide N-[(2,4-dichlorophenyl)methyl]-2-(2,4-dioxo-1H-quinazolin-3-yl)acetamide made possible to prove the pharmacophore role of the cyclic amide fragment in anticonvulsant activity manifestation.
Conclusion. The synthesis of N-[(2,4-dichlorophenyl)methyl]-2-(1-(R-benzyl)-2,4-dioxo-quinazolin-3-yl)acetamides, which have not still described in the literature, was carried out, as well as the structure of the mentioned compounds was proved. Unfortunately, the substances did not show anticonvulsant activity on the model of pentylenetetrazole-induced seizures. However, the obtained results allowed establishing the key role of the NHCO cyclic fragment on anticonvulsant activity. A positive correlation between the results of in vivo studies and in silico calculations was found β the model of pentylenetetrazole-induced seizures and docking into the active sites of PAMs GABAΠ receptor and enzyme inhibitor GABAΠΠ’, which allows to recommend the given docking methodology as a tool to streamline and optimize the screening on the mentioned modelΠ¦Π΅Π»Ρ. Π‘ΠΈΠ½ΡΠ΅Π· 1-Π±Π΅Π½Π·ΠΈΠ»Π·Π°ΠΌΠ΅ΡΠ΅Π½Π½ΡΡ
ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΡ
N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΠΈΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΠΈΠΎΠΊΡΠΎ-1Π)-Ρ
ΠΈΠ½Π°Π·ΠΎΠ»ΠΈΠ½-3-ΠΈΠ»)Π°ΡΠ΅ΡΠ°ΠΌΠΈΠ΄Π°, ΠΎΠΏΡΠ΅Π΄Π΅Π»Π΅Π½ΠΈΠ΅ Π°ΡΡΠΈΠ½ΠΈΡΠ΅ΡΠ° ΠΊ ΠΠΠΠΠ΅ΡΠ³ΠΈΡΠ΅ΡΠΊΠΈΡ
Π±ΠΈΠΎΠΌΠΈΡΠ΅Π½Π΅ΠΉ Ρ ΠΏΠΎΡΠ»Π΅Π΄ΡΡΡΠΈΠΌ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ Π½Π° PTZ -ΠΌΠΎΠ΄Π΅Π»ΠΈ ΡΡΠ΄ΠΎΡΠΎΠ³ Ρ ΠΌΡΡΠ΅ΠΉ.
ΠΠ°ΡΠ΅ΡΠΈΠ°Π»Ρ ΠΈ ΠΌΠ΅ΡΠΎΠ΄Ρ. Π ΡΠ°Π±ΠΎΡΠ΅ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π»ΠΈ ΡΡΠ°Π½Π΄Π°ΡΡΠ½ΡΠ΅ ΠΌΠ΅ΡΠΎΠ΄Ρ ΠΎΡΠ³Π°Π½ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΠΈΠ½ΡΠ΅Π·Π°, ΡΡΡΡΠΊΡΡΡΠ° ΡΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π΅Π½Π° ΡΠ»Π΅ΠΌΠ΅Π½ΡΠ½ΡΠΌ Π°Π½Π°Π»ΠΈΠ·ΠΎΠΌ, 1H ΠΈ 13Π‘ Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΡΠΊΠΎΠΏΠΈΠ΅ΠΉ, LC/MS, ΡΠΎΡΡΠ°Π² β ΡΠ»Π΅ΠΌΠ΅Π½ΡΠ½ΡΠΌ Π°Π½Π°Π»ΠΈΠ·ΠΎΠΌ, ΠΈΠ½Π΄ΠΈΠ²ΠΈΠ΄ΡΠ°Π»ΡΠ½ΠΎΡΡΡ β Π’Π‘Π₯ ΠΈ Ρ
ΡΠΎΠΌΠ°ΡΠΎ-ΠΌΠ°ΡΡ-ΡΠΏΠ΅ΠΊΡΡΠΎΠΌΠ΅ΡΡΠΈΠ΅ΠΉ. ΠΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΠΉ Π΄ΠΎΠΊΠΈΠ½Π³ ΠΎΡΡΡΠ΅ΡΡΠ²Π»Π΅Π½ AutoDockTools-1.5.6 ΠΈ AutoDock Vina. ΠΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½Π°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΈΠ·ΡΡΠ΅Π½Π° Π½Π° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΎΠΉ ΠΌΠΎΠ΄Π΅Π»ΠΈ ΡΡΠ΄ΠΎΡΠΎΠ³ Ρ ΠΌΡΡΠ΅ΠΉ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΡ. Π¦Π΅Π»Π΅Π²ΡΠ΅ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΠΈΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(1-(R-Π±Π΅Π½Π·ΠΈΠ»)-2,4-Π΄ΠΈΠΎΠΊΡΠΎ-Ρ
ΠΈΠ½Π°Π·ΠΎΠ»ΠΈΠ½-3-ΠΈΠ»)Π°ΡΠ΅ΡΠ°ΠΌΠΈΠ΄Ρ ΠΏΠΎΠ»ΡΡΠ΅Π½Ρ Π°Π»ΠΊΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΡΠ΅Π½ΠΈΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΠΈΠΎΠΊΡΠΎ-1H-Ρ
ΠΈΠ½Π°Π·ΠΎΠ»ΠΈΠ½-3-ΠΈΠ»)Π°ΡΠ΅ΡΠ°ΠΌΠΈΠ΄Π° ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²ΡΡΡΠΈΠΌΠΈ 1-Ρ
Π»ΠΎΡΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·Π΅Π½Π°ΠΌΠΈ Π² ΡΡΠ΅Π΄Π΅ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΠΎΡΠΌΠ°ΠΌΠΈΠ΄Π° Π² ΠΏΡΠΈΡΡΡΡΡΠ²ΠΈΠΈ ΠΈΠ·Π±ΡΡΠΊΠ° ΠΊΠ°Π»ΠΈΡ ΠΊΠ°ΡΠ±ΠΎΠ½Π°ΡΠ° ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΠ΅ 70-80 ΛΠ‘. ΠΡΠΎΠ³Π½ΠΎΠ·ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ 1-Π±Π΅Π½Π·ΠΈΠ»ΠΏΡΠΎΠΈΠ·Π²ΠΎΠ΄Π½ΡΡ
Π½Π° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΎΠΉ ΠΌΠΎΠ΄Π΅Π»ΠΈ ΡΡΠ΄ΠΎΡΠΎΠ³ Π² in vivo ΡΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΠ΅ ΠΎΡΡΡΠ΅ΡΡΠ²Π»Π΅Π½ΠΎ ΠΏΠΎ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌ Π΄ΠΎΠΊΠΈΠ½Π³ΠΎΠ²ΡΡ
ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΉ β ΡΠ°ΡΡΠ΅ΡΠ° Π°ΡΡΠΈΠ½Π½ΠΎΡΡΠΈ ΠΊ Π°ΠΊΡΠΈΠ²Π½ΡΠΌ ΡΠ°ΠΉΡΠ°ΠΌ ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΠ° ΠΈ ΡΠ½Π·ΠΈΠΌΠ° ΠΠΠΠΠΠ’, Π° ΡΠ°ΠΊΠΆΠ΅ Π°Π½Π°Π»ΠΈΠ·Π° ΠΊΠΎΠ½ΡΠΎΡΠΌΠ°ΡΠΈΠΎΠ½Π½ΠΎΠ³ΠΎ ΡΠ°Π·ΠΌΠ΅ΡΠ΅Π½ΠΈΡ Π² Π½ΠΈΡ
. ΠΡΡΠ»Π΅Π΄ΡΠ΅ΠΌΡΠ΅ Π»ΠΈΠ³Π°Π½Π΄Ρ ΡΡΡΡΠΏΠ°Π»ΠΈ ΠΏΠΎ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ ΡΠ½Π΅ΡΠ³ΠΈΠΈ ΡΠ²ΡΠ·ΡΠ²Π°Π½ΠΈΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°ΠΌ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ: ΠΏΠΎΠ»ΠΎΠΆΠΈΡΠ΅Π»ΡΠ½ΡΠΌ Π°Π»Π»ΠΎΡΡΠ΅ΡΠΈΡΠ΅ΡΠΊΠΈΠΌ ΠΌΠΎΠ΄ΡΠ»ΡΡΠΎΡΠ°ΠΌ ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΠ° β Π±Π΅Π½Π·Π°ΠΌΠΈΠ΄ΠΈΠ½Ρ ΠΈ Π΄ΠΈΠ°Π·Π΅ΠΏΠ°ΠΌΡ, ΠΈ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ ΠΠΠΠΠΠ’ β Π²ΠΈΠ³Π°Π±Π°ΡΡΠΈΠ½Ρ. Π‘ΠΈΠ½ΡΠ΅Π·ΠΈΡΠΎΠ²Π°Π½Π½ΡΠ΅ Π²Π΅ΡΠ΅ΡΡΠ²Π° Π½Π΅ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΠΈΡΠΎΠ²Π°Π»ΠΈ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ: ΡΠΎΠ»ΡΠΊΠΎ 2 ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ Π²ΡΡΠ²ΠΈΠ»ΠΈ ΡΠ΅Π½Π΄Π΅Π½ΡΠΈΡ ΠΊ ΠΏΡΠΎΡΠ²Π»Π΅Π½ΠΈΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΏΠΎ ΠΊΡΠΈΡΠ΅ΡΠΈΡ ΠΈΠ½ΡΠ΅Π³ΡΠ°Π»ΡΠ½ΠΎΠ³ΠΎ Π·Π°ΡΠΈΡΠ½ΠΎΠ³ΠΎ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ β ΡΠΌΠ΅Π½ΡΡΠ΅Π½ΠΈΠ΅ Π»Π΅ΡΠ°Π»ΡΠ½ΠΎΡΡΠΈ Π½Π° 17 % ΠΏΠΎ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ Ρ ΠΊΠΎΠ½ΡΡΠΎΠ»Π΅ΠΌ ΠΈ ΠΏΡΠΎΠ΄Π»Π΅Π²Π°Ρ Π²ΡΠ΅ΠΌΡ Π΄ΠΎ Π³ΠΈΠ±Π΅Π»ΠΈ ΠΆΠΈΠ²ΠΎΡΠ½ΡΡ
. Π‘ΠΎΠΏΠΎΡΡΠ°Π²Π»Π΅Π½ΠΈΠ΅ Ρ ΠΏΡΠ΅Π΄Π²Π°ΡΠΈΡΠ΅Π»ΡΠ½ΡΠΌΠΈ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠ³ΠΎ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½ΡΠ° N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΡΠ΅Π½ΠΈΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΠΈΠΎΠΊΡΠΎ-1H-Ρ
ΠΈΠ½Π°Π·ΠΎΠ»ΠΈΠ½-3-ΠΈΠ»)Π°ΡΠ΅ΡΠ°ΠΌΠΈΠ΄Π° ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΎ Π΄ΠΎΠΊΠ°Π·Π°ΡΡ ΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠΎΡΠ½ΡΡ ΡΠΎΠ»Ρ ΡΠΈΠΊΠ»ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ Π°ΠΌΠΈΠ΄Π½ΠΎΠ³ΠΎ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΠ° Π² ΠΏΡΠΎΡΠ²Π»Π΅Π½ΠΈΠΈ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ.
ΠΡΠ²ΠΎΠ΄Ρ. ΠΡΡΡΠ΅ΡΡΠ²Π»Π΅Π½ ΡΠΈΠ½ΡΠ΅Π· ΠΈ Π΄ΠΎΠΊΠ°Π·Π°Π½ΠΎ ΡΡΡΠΎΠ΅Π½ΠΈΠ΅ Π½Π΅ ΠΎΠΏΠΈΡΠ°Π½Π½ΡΡ
Π² Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΠ΅ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΠΈΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(1-(R-Π±Π΅Π½Π·ΠΈΠ»)-2,4-Π΄ΠΈΠΎΠΊΡΠΎ-Ρ
ΠΈΠ½Π°Π·ΠΎΠ»ΠΈΠ½-3-ΠΈΠ»)Π°ΡΠ΅ΡΠ°ΠΌΠΈΠ΄ΠΎΠ². ΠΠ° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΎΠΉ ΠΌΠΎΠ΄Π΅Π»ΠΈ ΡΡΠ΄ΠΎΡΠΎΠ³ Ρ ΠΌΡΡΠ΅ΠΉ ΠΈΡΡΠ»Π΅Π΄ΡΠ΅ΠΌΡΠ΅ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ, ΠΊ ΡΠΎΠΆΠ°Π»Π΅Π½ΠΈΡ, Π½Π΅ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΠΈΡΠΎΠ²Π°Π»ΠΈ ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ. ΠΠ΄Π½Π°ΠΊΠΎ ΠΏΠΎΠ»ΡΡΠ΅Π½Π½ΡΠ΅ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΈ ΡΡΡΠ°Π½ΠΎΠ²ΠΈΡΡ ΠΊΠ»ΡΡΠ΅Π²ΡΡ ΡΠΎΠ»Ρ ΡΠΈΠΊΠ»ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΠ° NHCO Π½Π° ΠΏΡΠΎΡΠΈΠ²ΠΎΡΡΠ΄ΠΎΡΠΎΠΆΠ½ΡΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ. ΠΠΏΡΠ΅Π΄Π΅Π»Π΅Π½Π° ΠΏΠΎΠ»ΠΎΠΆΠΈΡΠ΅Π»ΡΠ½Π°Ρ ΠΊΠΎΡΡΠ΅Π»ΡΡΠΈΡ ΠΌΠ΅ΠΆΠ΄Ρ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌΠΈ in vivo ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠΉ ΠΈ in silico ΡΠ°ΡΡΠ΅ΡΠΎΠ² β ΠΌΠΎΠ΄Π΅Π»Ρ ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΡΡ
ΡΡΠ΄ΠΎΡΠΎΠ³ ΠΈ Π΄ΠΎΠΊΠΈΠ½Π³ Π² Π°ΠΊΡΠΈΠ²Π½ΡΠ΅ ΡΠ°ΠΉΡΡ PAMs ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΠ° ΠΈ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠ° ΡΠ½Π·ΠΈΠΌΠ° ΠΠΠΠΠΠ’, ΡΡΠΎ ΠΏΠΎΠ·Π²ΠΎΠ»ΡΠ΅Ρ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΠΎΠ²Π°ΡΡ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Π½ΡΡ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ»ΠΎΠ³ΠΈΡ Π΄ΠΎΠΊΠΈΠ½Π³Π° ΠΊΠ°ΠΊ ΠΈΠ½ΡΡΡΡΠΌΠ΅Π½Ρ ΠΊΠ°ΠΊ ΡΠ°ΡΠΈΠΎΠ½Π°Π»ΠΈΠ·Π°ΡΠΈΠΈ ΠΈ ΠΎΠΏΡΠΈΠΌΠΈΠ·Π°ΡΠΈΠΈ ΡΠΊΡΠΈΠ½ΠΈΠ½Π³Π°ΠΠ΅ΡΠ°. Π‘ΠΈΠ½ΡΠ΅Π· 1-Π±Π΅Π½Π·ΠΈΠ»Π·Π°ΠΌΡΡΠ΅Π½ΠΈΡ
ΠΏΠΎΡ
ΡΠ΄Π½ΠΈΡ
N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΡΠΎΠΊΡΠΎ-1Π)-Ρ
ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄Ρ, Π²ΠΈΠ·Π½Π°ΡΠ΅Π½Π½Ρ Π°ΡΡΠ½ΡΡΠ΅ΡΡ Π΄ΠΎ ΠΠΠΠΠ΅ΡΠ³ΡΡΠ½ΠΈΡ
Π±ΡΠΎΠΌΡΡΠ΅Π½Π΅ΠΉ Π· Π½Π°ΡΡΡΠΏΠ½ΠΈΠΌ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½ΡΠΌ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π½Π° PTZ-ΠΌΠΎΠ΄Π΅Π»Ρ ΡΡΠ΄ΠΎΠΌ Ρ ΠΌΠΈΡΠ΅ΠΉ.
ΠΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΡΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈ. Π£ ΡΠΎΠ±ΠΎΡΡ Π²ΠΈΠΊΠΎΡΠΈΡΡΠΎΠ²ΡΠ²Π°Π»ΠΈ ΡΡΠ°Π½Π΄Π°ΡΡΠ½Ρ ΠΌΠ΅ΡΠΎΠ΄ΠΈ ΠΎΡΠ³Π°Π½ΡΡΠ½ΠΎΠ³ΠΎ ΡΠΈΠ½ΡΠ΅Π·Ρ, ΡΡΡΡΠΊΡΡΡΠ° ΡΠΈΠ½ΡΠ΅Π·ΠΎΠ²Π°Π½ΠΈΡ
ΡΠΏΠΎΠ»ΡΠΊ Π΄ΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π΅Π»Π΅ΠΌΠ΅Π½ΡΠ½ΠΈΠΌ Π°Π½Π°Π»ΡΠ·ΠΎΠΌ, 1H ΡΠ° 13Π‘ Π―ΠΠ -ΡΠΏΠ΅ΠΊΡΡΠΎΡΠΊΠΎΠΏΡΡΡ, LC/MS, ΡΠΊΠ»Π°Π΄ Π΅Π»Π΅ΠΌΠ΅Π½ΡΠ½ΠΈΠΌ Π°Π½Π°Π»ΡΠ·ΠΎΠΌ, ΡΠ½Π΄ΠΈΠ²ΡΠ΄ΡΠ°Π»ΡΠ½ΡΡΡΡ β Π’Π¨Π₯ ΡΠ° Ρ
ΡΠΎΠΌΠ°ΡΠΎ-ΠΌΠ°Ρ-ΡΠΏΠ΅ΠΊΡΡΠΎΠΌΠ΅ΡΡΡΡΡ. ΠΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΠΈΠΉ Π΄ΠΎΠΊΡΠ½Π³ Π·Π΄ΡΠΉΡΠ½Π΅Π½ΠΎ AutoDockTools-1.5.6 ΡΠ° AutoDock Vina. ΠΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½Ρ Π°ΠΊΡΠΈΠ²Π½ΡΡΡΡ Π²ΠΈΠ²ΡΠ΅Π½ΠΎ Π½Π° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΡΠΉ ΠΌΠΎΠ΄Π΅Π»Ρ ΡΡΠ΄ΠΎΠΌ Ρ ΠΌΠΈΡΠ΅ΠΉ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ. Π¦ΡΠ»ΡΠΎΠ²Ρ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(1-(R-Π±Π΅Π½Π·ΠΈΠ»)-2,4-Π΄ΠΈΠΎΠΊΡΠΎ-Ρ
ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄ΠΈ ΠΎΠ΄Π΅ΡΠΆΠ°Π½ΠΎ Π°Π»ΠΊΡΠ»ΡΠ²Π°Π½Π½ΡΠΌ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΠΈΠΎΠΊΡΠΎ-1H-Ρ
ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄Ρ Π²ΡΠ΄ΠΏΠΎΠ²ΡΠ΄Π½ΠΈΠΌΠΈ 1-Ρ
Π»ΠΎΡΠΎΠΌΠ΅ΡΠΈΠ»Π±Π΅Π½Π·Π΅Π½Π°ΠΌΠΈ Ρ ΡΠ΅ΡΠ΅Π΄ΠΎΠ²ΠΈΡΡ Π΄ΠΈΠΌΠ΅ΡΠΈΠ»ΡΠΎΡΠΌΠ°ΠΌΡΠ΄Ρ Π² ΠΏΡΠΈΡΡΡΠ½ΠΎΡΡΡ Π½Π°Π΄Π»ΠΈΡΠΊΡ ΠΊΠ°Π»ΡΠΉ ΠΊΠ°ΡΠ±ΠΎΠ½Π°ΡΡ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ 70β80 ΛΠ‘. ΠΡΠΎΠ³Π½ΠΎΠ·ΡΠ²Π°Π½Π½Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ 1-Π±Π΅Π½Π·ΠΈΠ»ΠΏΠΎΡ
ΡΠ΄Π½ΠΈΡ
Π½Π° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΡΠΉ ΠΌΠΎΠ΄Π΅Π»Ρ ΡΡΠ΄ΠΎΠΌ Π² in vivo Π΅ΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½ΡΡ Π·Π΄ΡΠΉΡΠ½Π΅Π½ΠΎ Π·Π° ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌΠΈ Π΄ΠΎΠΊΡΠ½Π³ΠΎΠ²ΠΈΡ
Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Ρ β ΡΠΎΠ·ΡΠ°Ρ
ΡΠ½ΠΊΡ Π°ΡΡΠ½Π½ΠΎΡΡΡ Π΄ΠΎ Π°ΠΊΡΠΈΠ²Π½ΠΈΡ
ΡΠ°ΠΉΡΡΠ² ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΠ° ΡΠ° Π΅Π½Π·ΠΈΠΌΡ ΠΠΠΠΠΠ’, Π° ΡΠ°ΠΊΠΎΠΆ Π°Π½Π°Π»ΡΠ·Ρ ΠΊΠΎΠ½ΡΠΎΡΠΌΠ°ΡΡΠΉΠ½ΠΎΠ³ΠΎ ΡΠΎΠ·ΠΌΡΡΠ΅Π½Π½Ρ Π² Π½ΠΈΡ
. ΠΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½Ρ Π»ΡΠ³Π°Π½Π΄ΠΈ ΠΏΠΎΡΡΡΠΏΠ°Π»ΠΈΡΡ Π·Π° ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊΠΎΠΌ Π΅Π½Π΅ΡΠ³ΡΡ Π·Π²βΡΠ·ΡΠ²Π°Π½Π½Ρ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°ΠΌ ΠΏΠΎΡΡΠ²Π½ΡΠ½Π½Ρ: ΠΏΠΎΠ·ΠΈΡΠΈΠ²Π½ΠΈΠΌ Π°Π»ΠΎΡΡΠ΅ΡΠΈΡΠ½ΠΈΠΌ ΠΌΠΎΠ΄ΡΠ»ΡΡΠΎΡΠ°ΠΌ ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΠ° β Π±Π΅Π½Π·Π°ΠΌΡΠ΄ΠΈΠ½Ρ ΡΠ° Π΄ΡΠ°Π·Π΅ΠΏΠ°ΠΌΡ, ΡΠ° ΡΠ½Π³ΡΠ±ΡΡΠΎΡΡ ΠΠΠΠΠΠ’ β Π²ΡΠ³Π°Π±Π°ΡΡΠΈΠ½Ρ. Π‘ΠΈΠ½ΡΠ΅Π·ΠΎΠ²Π°Π½Ρ ΡΠ΅ΡΠΎΠ²ΠΈΠ½ΠΈ Π½Π΅ ΠΏΡΠΎΠ΄Π΅ΠΌΠΎΠ½ΡΡΡΡΠ²Π°Π»ΠΈ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ: Π»ΠΈΡΠ΅ 2 ΡΠΏΠΎΠ»ΡΠΊΠΈ Π²ΠΈΡΠ²ΠΈΠ»ΠΈ ΡΠ΅Π½Π΄Π΅Π½ΡΡΡ Π΄ΠΎ ΠΏΡΠΎΡΠ²Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π·Π° ΠΊΡΠΈΡΠ΅ΡΡΡΠΌ ΡΠ½ΡΠ΅Π³ΡΠ°Π»ΡΠ½ΠΎΠ³ΠΎ Π·Π°Ρ
ΠΈΡΠ½ΠΎΠ³ΠΎ ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊΠ° β Π·ΠΌΠ΅Π½ΡΠ΅Π½Π½Ρ Π»Π΅ΡΠ°Π»ΡΠ½ΠΎΡΡΡ Π½Π° 17 % ΠΏΠΎΡΡΠ²Π½ΡΠ½ΠΎ Π· ΠΊΠΎΠ½ΡΡΠΎΠ»Π΅ΠΌ ΡΠ° ΠΏΠΎΠ΄ΠΎΠ²ΠΆΡΡΡΠΈ ΡΠ°Ρ Π΄ΠΎ Π·Π°Π³ΠΈΠ±Π΅Π»Ρ ΡΠ²Π°ΡΠΈΠ½. Π‘ΠΏΡΠ²ΡΡΠ°Π²Π»Π΅Π½Π½Ρ Π· ΠΏΠΎΠΏΠ΅ΡΠ΅Π΄Π½ΡΠΌΠΈ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌΠΈ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΠΎΠ³ΠΎ Π°Π½ΡΠΈΠΊΠΎΠ½Π²ΡΠ»ΡΡΠ°Π½ΡΠ° N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(2,4-Π΄ΠΈΠΎΠΊΡΠΎ-1H-Ρ
ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄Ρ Π΄ΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΎ Π΄ΠΎΠ²Π΅ΡΡΠΈ ΡΠ°ΡΠΌΠ°ΠΊΠΎΡΠΎΡΠ½Ρ ΡΠΎΠ»Ρ ΡΠΈΠΊΠ»ΡΡΠ½ΠΎΠ³ΠΎ Π°ΠΌΡΠ΄Π½ΠΎΠ³ΠΎ ΡΡΠ°Π³ΠΌΠ΅Π½ΡΡ Π² ΠΏΡΠΎΡΠ²Ρ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½ΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ.
ΠΠΈΡΠ½ΠΎΠ²ΠΊΠΈ. ΠΠ΄ΡΠΉΡΠ½Π΅Π½ΠΎ ΡΠΈΠ½ΡΠ΅Π· ΡΠ° Π΄ΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π±ΡΠ΄ΠΎΠ²Ρ Π½Π΅ ΠΎΠΏΠΈΡΠ°Π½ΠΈΡ
Π² Π»ΡΡΠ΅ΡΠ°ΡΡΡΡ N-[(2,4-Π΄ΠΈΡ
Π»ΠΎΡΠΎΡΠ΅Π½ΡΠ»)ΠΌΠ΅ΡΠΈΠ»]-2-(1-(R-Π±Π΅Π½Π·ΠΈΠ»)-2,4-Π΄ΠΈΠΎΠΊΡΠΎ-Ρ
ΡΠ½Π°Π·ΠΎΠ»ΡΠ½-3-ΡΠ»)Π°ΡΠ΅ΡΠ°ΠΌΡΠ΄ΡΠ². ΠΠ° ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΡΠΉ ΠΌΠΎΠ΄Π΅Π»Ρ ΡΡΠ΄ΠΎΠΌ Ρ ΠΌΠΈΡΠ΅ΠΉ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½Ρ ΡΠΏΠΎΠ»ΡΠΊΠΈ Π½Π° ΠΆΠ°Π»Ρ Π½Π΅ Π²ΠΈΡΠ²ΠΈΠ»ΠΈ ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠΎΡ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ. ΠΠ΄Π½Π°ΠΊ, ΠΎΠ΄Π΅ΡΠΆΠ°Π½Ρ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠΈ Π΄ΠΎΠ·Π²ΠΎΠ»ΠΈΠ»ΠΈ Π²ΡΡΠ°Π½ΠΎΠ²ΠΈΡΠΈ ΠΊΠ»ΡΡΠΎΠ²Ρ ΡΠΎΠ»Ρ ΡΠΈΠΊΠ»ΡΡΠ½ΠΎΠ³ΠΎ NHCO ΡΡΠ°Π³ΠΌΠ΅Π½ΡΡ Π½Π° ΠΏΡΠΎΡΠΈΡΡΠ΄ΠΎΠΌΠ½Ρ Π°ΠΊΡΠΈΠ²Π½ΡΡΡΡ. ΠΠΈΠ·Π½Π°ΡΠ΅Π½ΠΎ ΠΏΠΎΠ·ΠΈΡΠΈΠ²Π½Ρ ΠΊΠΎΡΠ΅Π»ΡΡΡΡ ΠΌΡΠΆ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ°ΠΌΠΈ in vivo Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Ρ ΡΠ° in silico ΡΠΎΠ·ΡΠ°Ρ
ΡΠ½ΠΊΡΠ² β ΠΌΠΎΠ΄Π΅Π»Ρ ΠΏΠ΅Π½ΡΠΈΠ»Π΅Π½ΡΠ΅ΡΡΠ°Π·ΠΎΠ»ΠΎΠ²ΠΈΡ
ΡΡΠ΄ΠΎΠΌ ΡΠ° Π΄ΠΎΠΊΡΠ½Π³ Π² Π°ΠΊΡΠΈΠ²Π½Ρ ΡΠ°ΠΉΡΠΈ PAMs ΠΠΠΠΠ ΡΠ΅ΡΠ΅ΠΏΡΠΎΡΡ ΡΠ° ΡΠ½Π³ΡΠ±ΡΡΠΎΡΠ° Π΅Π½Π·ΠΈΠΌΡ ΠΠΠΠΠΠ’, ΡΠΎ Π΄ΠΎΠ·Π²ΠΎΠ»ΡΡ ΡΠ΅ΠΊΠΎΠΌΠ΅Π½Π΄ΡΠ²Π°ΡΠΈ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Ρ ΠΌΠ΅ΡΠΎΠ΄ΠΎΠ»ΠΎΠ³ΡΡ Π΄ΠΎΠΊΡΠ½Π³Ρ ΡΠ½ΡΡΡΡΠΌΠ΅Π½Ρ ΡΠΊ Π΄Π»Ρ ΡΠ°ΡΡΠΎΠ½Π°Π»ΡΠ·Π°ΡΡΡ ΡΠ° ΠΎΠΏΡΠΈΠΌΡΠ·Π°ΡΡΡ ΡΠΊΡΠΈΠ½ΡΠ½Π³Ρ Π½Π° Π²ΠΊΠ°Π·Π°Π½ΡΠΉ ΠΌΠΎΠ΄Π΅Π»
An Overview on 1,2,4-triazole and 1,3,4-thiadiazole Derivatives as Potential Anesthesic and Anti-inflammatory Agents
The aim. The purpose of this review is to summarize data on the synthesis and structural modification of heterocyclic systems with triazole and thiadiazole fragments in molecules as promising objects in bioorganic and medicinal chemistry.
Materials and methods. The research based on bibliosemantic and analytical methods using bibliographic and abstract databases, as well as databases of chemical compounds.
Results. Modern medicinal chemistry faces many challenges, one of which is the determination of the activity and specificity of therapeutic agents. Recent scientific data showed that triazoles and/or thiadiazoles have broad spectrum of biological activities, in particular antimicrobial, antifungal, antiviral, anticancer and anticonvulsant. Synthetic research allows to propose a whole number of new molecular design directions of biological active triazole and/or thiadiazole derivatives, as well as to obtain directed library that include hundreds of new compounds. This review is an effort to summarize data of its analgesic and anti-inflammatory activity over the last decade. We summarized and analyzed the series of triazole and/or thiadiazole derivatives and provided data of their structure-activity relationship. For optimization and rational design of highly active molecules with optimal Β«drug-likeΒ» characteristics and discovering of possible mechanism of action SAR, QSAR analysis and molecular docking were summarized.
Conclusions. It has been shown that heterocyclic systems containing fragments of triazole and / or thiadiazole are a significant source of promising analgesic and/or anti-inflammatory agents. It has been established that the mentioned heterocyclic derivatives have a high selectivity of action, low toxicity and an effect commensurate with standard drug
ΠΠΏΠ»ΠΈΠ² Π½Π΅ΡΡΠ΅ΡΠΎΡΠ΄Π½ΠΈΡ ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ² ΡΡΠ·Π½ΠΎΠ³ΠΎ ΠΌΠ΅Ρ Π°Π½ΡΠ·ΠΌΡ Π΄ΡΡ Π½Π° ΠΏΠ΅ΡΠ΅Π±ΡΠ³ ΡΡΡΠ΅Ρ-ΡΠ΅Π°ΠΊΡΡΡ, ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΈΠΉ ΡΡΠ°Π½ Π½ΠΈΡΠΎΠΊ, ΠΏΠ΅ΡΡΠ½ΠΊΠΈ ΡΠ° ΡΠ΅ΡΡΡ Π½Π° ΠΌΠΎΠ΄Π΅Π»Ρ Π³ΠΎΡΡΡΠΎΠ³ΠΎ Π·Π°Π³Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΡ ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ
Inhibitors of the arachidonic acid cascade have significant potential as the agents for the prevention of severe cold injuries. The results of the previous studies have demonstrated the pronounced frigoprotective properties of certain non-steroidal anti-inflammatory drugs, primarily diclofenac sodium, etoricoxib, darbufelone mesylate, under the conditions of acute general cooling.
The aim of the study: to investigate the effect of non-steroidal anti-inflammatory drugs with various mechanisms of action on the course of the stress reaction, the functional state of the kidneys, liver, and heart using the model of acute general cooling.
Materials and Methods: The experiment was carried out using 35 outbreed male rats weighing 256Β±5 g. The studied drugs were administered intragastrically 30 minutes before cold injury modelling: diclofenac sodium at a dose of 7 mg/kg, etoricoxib at a dose of 5 mg/kg, darbufelone mesylate at a dose of 20 mg/kg. Acute general cooling was induced by exposure at β18 Β°C for 2 hours. The efficacy of the studied drugs was evaluated by the values as follows: the body temperature (measured rectally), the course of a stress reaction according to the criteria of βthe stress triadβ, the functional state of the kidney and liver according to the changes in the blood serum biochemical parameters, the functional state of the heart according to the electrocardiogram.
Results: It was found that etoricoxib and darbufelone mesylate, and especially diclofenac sodium, demonstrate frigoprotective properties, reducing the severity of hypothermia, have stress-protective activity and a beneficial effect on the functional state of the kidneys. All investigated non-steroidal anti-inflammatory drugs prevent a decrease in myocardial contractility (by the effect on the systolic index) and lengthening of the QT interval caused by acute cold injury. Diclofenac sodium, unlike etoricoxib and darbufelone mesylate, does not enhance the effect of acute general cooling on intraventricular conduction. Under acute exposure to cold, no significant changes in the functional state of the liver were observed, including the groups receiving the nonsteroidal anti-inflammatory medicines.
Conclusions: The prophylactic administration of the arachidonic acid cascade inhibitors, especially the non-selective COX-2 inhibitor diclofenac sodium, reduces the severity of the stress response, contributes to the maintenance of the renal and cardiac function. There are no significant changes in the functional state of the liver under conditions of the experimentΠΠ½Π³ΡΠ±ΡΡΠΎΡΠΈ ΠΊΠ°ΡΠΊΠ°Π΄Ρ Π°ΡΠ°Ρ
ΡΠ΄ΠΎΠ½ΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ ΠΌΠ°ΡΡΡ Π·Π½Π°ΡΠ½ΠΈΠΉ ΠΏΠΎΡΠ΅Π½ΡΡΠ°Π» ΡΠΊ Π·Π°ΡΠΎΠ±ΠΈ Π΄Π»Ρ ΠΏΡΠΎΡΡΠ»Π°ΠΊΡΠΈΠΊΠΈ ΡΡΠΆΠΊΠΈΡ
Ρ
ΠΎΠ»ΠΎΠ΄ΠΎΠ²ΠΈΡ
ΡΡΠ°Π²ΠΌ. Π£ ΠΏΠΎΠΏΠ΅ΡΠ΅Π΄Π½ΡΡ
Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½ΡΡ
Π΄ΠΎΠ²Π΅Π΄Π΅Π½ΠΎ Π²ΠΈΡΠ°Π·Π½Ρ ΡΡΠΈΠ³ΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½Ρ Π²Π»Π°ΡΡΠΈΠ²ΠΎΡΡΡ Π΄Π΅ΡΠΊΠΈΡ
Π½Π΅ΡΡΠ΅ΡΠΎΡΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡΠ², Π½Π°ΡΠ°ΠΌΠΏΠ΅ΡΠ΅Π΄ Π΄ΠΈΠΊΠ»ΠΎΡΠ΅Π½Π°ΠΊΡ Π½Π°ΡΡΡΡ, Π΅ΡΠΎΡΠΈΠΊΠΎΠΊΡΠΈΠ±Ρ, Π΄Π°ΡΠ±ΡΡΠ΅Π»ΠΎΠ½Ρ ΠΌΠ΅Π·ΠΈΠ»Π°ΡΡ, Π² ΡΠΌΠΎΠ²Π°Ρ
Π³ΠΎΡΡΡΠΎΠ³ΠΎ Π·Π°Π³Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΡ
ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ.
ΠΠ΅ΡΠ° Π΄ΠΎΡΠ»ΡΠ΄ΠΆΠ΅Π½Π½Ρ: Π΄ΠΎΡΠ»ΡΠ΄ΠΈΡΠΈ Π²ΠΏΠ»ΠΈΠ² Π½Π΅ΡΡΠ΅ΡΠΎΡΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
Π·Π°ΡΠΎΠ±ΡΠ² ΡΡΠ·Π½ΠΎΠ³ΠΎ ΠΌΠ΅Ρ
Π°Π½ΡΠ·ΠΌΡ Π΄ΡΡ Π½Π° ΠΏΠ΅ΡΠ΅Π±ΡΠ³ ΡΡΡΠ΅Ρ-ΡΠ΅Π°ΠΊΡΡΡ, ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΈΠΉ ΡΡΠ°Π½ Π½ΠΈΡΠΎΠΊ, ΠΏΠ΅ΡΡΠ½ΠΊΠΈ ΡΠ° ΡΠ΅ΡΡΡ Π½Π° ΠΌΠΎΠ΄Π΅Π»Ρ Π³ΠΎΡΡΡΠΎΠ³ΠΎ Π·Π°Π³Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΡ
ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ.
ΠΠ°ΡΠ΅ΡΡΠ°Π»ΠΈ ΡΠ° ΠΌΠ΅ΡΠΎΠ΄ΠΈ: ΠΠΊΡΠΏΠ΅ΡΠΈΠΌΠ΅Π½Ρ Π²ΠΈΠΊΠΎΠ½Π°Π½ΠΎ Π½Π° 35 Π±ΡΠ»ΠΈΡ
Π±Π΅Π·ΠΏΠΎΡΠΎΠ΄Π½ΠΈΡ
ΡΡΡΠ°Ρ
-ΡΠ°ΠΌΡΡΡ
ΠΌΠ°ΡΠΎΡ 256Β±5 Π³. ΠΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½Ρ Π·Π°ΡΠΎΠ±ΠΈ Π²Π²ΠΎΠ΄ΠΈΠ»ΠΈ Π²Π½ΡΡΡΡΡΠ½ΡΠΎΡΠ»ΡΠ½ΠΊΠΎΠ²ΠΎ Π·Π° 30 Ρ
Π². Π΄ΠΎ ΠΌΠΎΠ΄Π΅Π»ΡΠ²Π°Π½Π½Ρ Ρ
ΠΎΠ»ΠΎΠ΄ΠΎΠ²ΠΎΡ ΡΡΠ°Π²ΠΌΠΈ: Π΄ΠΈΠΊΠ»ΠΎΡΠ΅Π½Π°ΠΊ Π½Π°ΡΡΡΡ Π² Π΄ΠΎΠ·Ρ 7 ΠΌΠ³/ΠΊΠ³, Π΅ΡΠΎΡΠΈΠΊΠΎΠΊΡΠΈΠ± Ρ Π΄ΠΎΠ·Ρ 5 ΠΌΠ³/ΠΊΠ³, Π΄Π°ΡΠ±ΡΡΠ΅Π»ΠΎΠ½Ρ ΠΌΠ΅Π·ΠΈΠ»Π°Ρ Ρ Π΄ΠΎΠ·Ρ 20 ΠΌΠ³/ΠΊΠ³. ΠΠΎΡΡΡΠ΅ Π·Π°Π³Π°Π»ΡΠ½Π΅ ΠΎΡ
ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π²ΠΈΠΊΠ»ΠΈΠΊΠ°Π»ΠΈ ΡΠ»ΡΡ
ΠΎΠΌ Π΅ΠΊΡΠΏΠΎΠ·ΠΈΡΡΡ ΠΏΡΠΈ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ β18Β°Π‘ ΠΏΡΠΎΡΡΠ³ΠΎΠΌ 2 Π³ΠΎΠ΄. ΠΡΡΠ½ΡΠ²Π°Π»ΠΈ Π²ΠΏΠ»ΠΈΠ² Π΄ΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½ΠΈΡ
Π·Π°ΡΠΎΠ±ΡΠ² Π½Π° ΡΠ΅ΠΊΡΠ°Π»ΡΠ½Ρ ΡΠ΅ΠΌΠΏΠ΅ΡΠ°ΡΡΡΡ, ΠΏΠ΅ΡΠ΅Π±ΡΠ³ ΡΡΡΠ΅Ρ-ΡΠ΅Π°ΠΊΡΡΡ Π·Π° ΠΊΡΠΈΡΠ΅ΡΡΡΠΌΠΈ ΡΡΠΈΠ°Π΄ΠΈ Π‘Π΅Π»ΡΡ, ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΈΠΉ ΡΡΠ°Π½ Π½ΠΈΡΠΎΠΊ Ρ ΠΏΠ΅ΡΡΠ½ΠΊΠΈ Π·Π° Π·ΠΌΡΠ½Π°ΠΌΠΈ Π±ΡΠΎΡ
ΡΠΌΡΡΠ½ΠΈΡ
ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊΡΠ² ΡΠΈΡΠΎΠ²Π°ΡΠΊΠΈ ΠΊΡΠΎΠ²Ρ, Π° ΡΠ°ΠΊΠΎΠΆ Π½Π° ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΈΠΉ ΡΡΠ°Π½ ΡΠ΅ΡΡΡ Π·Π° Π΄Π°Π½ΠΈΠΌΠΈ Π΅Π»Π΅ΠΊΡΡΠΎΠΊΠ°ΡΠ΄ΡΠΎΠ³ΡΠ°ΠΌΠΈ.
Π Π΅Π·ΡΠ»ΡΡΠ°ΡΠΈ: ΠΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΎ, ΡΠΎ Π΅ΡΠΎΡΠΈΠΊΠΎΠΊΡΠΈΠ± ΡΠ° Π΄Π°ΡΠ±ΡΡΠ΅Π»ΠΎΠ½Ρ ΠΌΠ΅Π·ΠΈΠ»Π°Ρ, Π° ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ Π΄ΠΈΠΊΠ»ΠΎΡΠ΅Π½Π°ΠΊ Π½Π°ΡΡΡΡ Π΄Π΅ΠΌΠΎΠ½ΡΡΡΡΡΡΡ ΡΡΠΈΠ³ΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½Ρ Π²Π»Π°ΡΡΠΈΠ²ΠΎΡΡΡ, Π·ΠΌΠ΅Π½ΡΡΡΡΠΈ ΡΡΠΆΠΊΡΡΡΡ Π³ΡΠΏΠΎΡΠ΅ΡΠΌΡΡ, Π²ΠΈΡΠ²Π»ΡΡΡΡ ΡΡΡΠ΅ΡΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½Ρ Π°ΠΊΡΠΈΠ²Π½ΡΡΡΡ ΡΠ° ΡΠΏΡΠΈΡΡΠ»ΠΈΠ²ΠΈΠΉ Π²ΠΏΠ»ΠΈΠ² Π½Π° ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΈΠΉ ΡΡΠ°Π½ Π½ΠΈΡΠΎΠΊ. ΠΡΡ Π΄ΠΎΡΠ»ΡΠ΄ΠΆΡΠ²Π°Π½Ρ Π½Π΅ΡΡΠ΅ΡΠΎΡΠ΄Π½Ρ ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½Ρ Π·Π°ΡΠΎΠ±ΠΈ Π·Π°ΠΏΠΎΠ±ΡΠ³Π°ΡΡΡ Π·Π½ΠΈΠΆΠ΅Π½Π½Ρ ΡΠΊΠΎΡΠΎΡΠ»ΠΈΠ²ΠΎΡ Π·Π΄Π°ΡΠ½ΠΎΡΡΡ ΠΌΡΠΎΠΊΠ°ΡΠ΄Π° (Π·Π° Π²ΠΏΠ»ΠΈΠ²ΠΎΠΌ Π½Π° ΡΠΈΡΡΠΎΠ»ΡΡΠ½ΠΈΠΉ ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊ) ΡΠ° ΠΏΠΎΠ΄ΠΎΠ²ΠΆΠ΅Π½Π½Ρ ΡΠ½ΡΠ΅ΡΠ²Π°Π»Ρ QT, ΡΠΏΡΠΈΡΠΈΠ½Π΅Π½ΠΈΠΌ Π³ΠΎΡΡΡΠΎΡ Ρ
ΠΎΠ»ΠΎΠ΄ΠΎΠ²ΠΎΡ ΡΡΠ°Π²ΠΌΠΎΡ. ΠΠΈΠΊΠ»ΠΎΡΠ΅Π½Π°ΠΊ Π½Π°ΡΡΡΡ, Π½Π° Π²ΡΠ΄ΠΌΡΠ½Ρ Π²ΡΠ΄ Π΅ΡΠΎΡΠΈΠΊΠΎΠΊΡΠΈΠ±Ρ ΡΠ° Π΄Π°ΡΠ±ΡΡΠ΅Π»ΠΎΠ½Ρ ΠΌΠ΅Π·ΠΈΠ»Π°ΡΡ, Π½Π΅ ΠΏΠΎΡΠΈΠ»ΡΡ Π²ΠΏΠ»ΠΈΠ² Π³ΠΎΡΡΡΠΎΠ³ΠΎ Π·Π°Π³Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΠΎΡ
ΠΎΠ»ΠΎΠ΄ΠΆΠ΅Π½Π½Ρ Π½Π° Π²Π½ΡΡΡΡΡΠ½ΡΠΎΡΠ»ΡΠ½ΠΎΡΠΊΠΎΠ²Ρ ΠΏΡΠΎΠ²ΡΠ΄Π½ΡΡΡΡ. ΠΠ° Π³ΠΎΡΡΡΠΎΠ³ΠΎ Π²ΠΏΠ»ΠΈΠ²Ρ Ρ
ΠΎΠ»ΠΎΠ΄Ρ ΡΡΡΡΡΠ²ΠΈΡ
Π·ΠΌΡΠ½ ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΡΠ°Π½Ρ ΠΏΠ΅ΡΡΠ½ΠΊΠΈ, Ρ ΡΠΎΠΌΡ ΡΠΈΡΠ»Ρ Π½Π° ΡΠ»Ρ Π·Π°ΡΡΠΎΡΡΠ²Π°Π½Π½Ρ Π½Π΅ΡΡΠ΅ΡΠΎΡΠ΄Π½ΠΈΡ
ΠΏΡΠΎΡΠΈΠ·Π°ΠΏΠ°Π»ΡΠ½ΠΈΡ
Π·Π°ΡΠΎΠ±ΡΠ², Π½Π΅ ΡΠΏΠΎΡΡΠ΅ΡΡΠ³Π°ΡΡΡΡΡ.
ΠΠΈΡΠ½ΠΎΠ²ΠΊΠΈ: ΠΡΠΎΡΡΠ»Π°ΠΊΡΠΈΡΠ½Π΅ Π·Π°ΡΡΠΎΡΡΠ²Π°Π½Π½Ρ ΡΠ½Π³ΡΠ±ΡΡΠΎΡΡΠ² ΠΊΠ°ΡΠΊΠ°Π΄Ρ Π°ΡΠ°Ρ
ΡΠ΄ΠΎΠ½ΠΎΠ²ΠΎΡ ΠΊΠΈΡΠ»ΠΎΡΠΈ, ΠΎΡΠΎΠ±Π»ΠΈΠ²ΠΎ Π½Π΅ΡΠ΅Π»Π΅ΠΊΡΠΈΠ²Π½ΠΎΠ³ΠΎ ΡΠ½Π³ΡΠ±ΡΡΠΎΡΠ° Π¦ΠΠ-2 Π΄ΠΈΠΊΠ»ΠΎΡΠ΅Π½Π°ΠΊΡ Π½Π°ΡΡΡΡ, Π·ΠΌΠ΅Π½ΡΡΡ Π²ΠΈΡΠ°Π·Π½ΡΡΡΡ ΡΡΡΠ΅Ρ-ΡΠ΅Π°ΠΊΡΡΡ, ΠΏΠΎΡΡΡΠ΅Π½Ρ ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΡΠ°Π½Ρ Π½ΠΈΡΠΎΠΊ ΡΠ° ΡΠ΅ΡΡΡ Π·Π° ΡΠΌΠΎΠ² Ρ
ΠΎΠ»ΠΎΠ΄ΠΎΠ²ΠΎΡ ΡΡΠ°Π²ΠΌΠΈ. ΠΠ½Π°ΡΡΡΠΈΡ
Π·ΠΌΡΠ½ ΡΡΠ½ΠΊΡΡΠΎΠ½Π°Π»ΡΠ½ΠΎΠ³ΠΎ ΡΡΠ°Π½Ρ ΠΏΠ΅ΡΡΠ½ΠΊΠΈ Π·Π° ΡΠΌΠΎΠ² Π΄ΠΎΡΠ»ΡΠ΄Ρ Π½Π΅ Π²ΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½
Evaluation of 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) as Potential Anticonvulsant Agent
It was determined that the studied 5-[(Z)-(4-nitrobenzylidene)]-2-(thiazol-2-ylimino)-4-thiazolidinone (Les-6222) affects the cyclooxygenase pathway of the arachidonic acid cascade, the markers of damage to neurons on models of PTZ kindling. In the model of chronic epileptogenesis in mice (pentylenetetrazole kindling), a 4-thiazolidinone derivative showed high anticonvulsant activity, which is weaker than the effect of sodium valproate and higher than Celecoxib. The mentioned compound has a pronounced anti-inflammatory effect in the brain on the background of the PTZ kindling, reliably inhibiting COX-1 and COX-2. The predominant inhibition of COX-2 by 44.5% indicates this enzyme’s high selectivity of Les-6222. According to the molecular docking study results, the studied compound revealed the properties of COX-1/COX-2 inhibitor and especially 5-LOX/FLAP. The decreasing content of 8-isoprostane in the brain of mice of the Les-6222 group indicates a beneficial effect on cell membranes in the background of oxidative stress during the long-term administration of PTZ. In addition, Les-6222 significantly decreased the content of neuron-specific enolase, indicating neuroprotective properties in the background of chronic epileptogenesis. The obtained results experimentally substantiate the feasibility of further developing Les-6222 as a promising anticonvulsant agent