Nootropic and Antihypoxic Properties of Novel Derivatives of 1,2-Dihydro-3H-1,4-Benzodiazepin-2-one
Among eight recently synthesized 3-phthalimidoacyloxy- and phthalimidoacyloxyethoxy-1,2-dihydro-3H-1,4-benzodiazepin-2-ones, three compounds that enhanced the indices of cognitive functions in albino rats by 24-43%, as compared with those in control animals, were found. In the Morris water maze test, these agents used in doses of 10 mg/kg positively influenced the index of long-term memory in contrast to the hormone leptin (10 nM) that enhanced the index of short-term memory but did not influence long-term memory. Pyracetam enhanced the indices of both short-term memory and long-term memory, but only in a much greater dose (400 mg/kg). Injections of the above-mentioned three tested compounds into rats resulted in a decrease in the power of the delta EEG rhythm and also in rises in the powers of theta and (especially) beta oscillations. All eight tested compounds (in doses 10 mg/kg) demonstrated clearly pronounced antihypoxic effects under conditions of acute hypoxia in a closed space test in experiments on mice. Two compounds showed the maximum efficiency; those increased the survival time of mice by 76% and 50%, respectively, as compared with the control. Therefore, the eight tested compounds demonstrate, along with high antihypoxic efficiency, a specific aspect of pharmacological activity somewhat unusual for benzodiazepins; these compounds improve the long-term memory and learning capability and exert specific effects on the EEG characteristics. These compounds are characterized by low toxicity; their LD50 exceeds 550 mg/kg.
Keywordsbenzodiazepins memory learning antihypoxic activity power of the EEG rhythms
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