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NEWLY SYNTHESIZED AMANTАDINE DERIVATIVE: SAFETY AND NEUROPHARMACOLOGICAL ACTIVITY

IVANKA STANKOVA ^1*, MARIA LAZAROVA ², RADOSLAV CHAYROV ¹, ANDREI POPATANASOV ², LYUBKA TANCHEVA ², RENI KALFIN ²

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The clinical use of amantadine (AMT, Am) is limited because of safety, tolerability issues, and duration of its anti-dyskinetic efficacy. Hence, the aim of this study was to synthesize new amantadine analogues as potential antiparkinsonian agents: phenylalanyl-amantadine (1), (4-F)-phenylalanyl-amantadine (2) and tyrosinyl-amantadine (Tyr-Am) (3). Tyr-Am showed the best toxicological characteristics in male ICR mice: the lowest acute toxicity (LD50 320 mg/kg bw intraperitoneally, i.p.); ЕD50 = 16 mg/kg bw, i.p.; therapeutic index = 20; NOEL 5 mg/kg bw and threshold of acute action under 8 mg/kg bw, i.p. In single effective dose (16 mg/kg bw, i.p.), Tyr-Am prolonged the hexobarbital narcosis probably due to its interaction with hexobarbital on the metabolic level. It improved significantly the neuromuscular performance in mice. Moreover Tyr-Am improved spatial memory as well as the learning and memory processes in compare to controls both after single or multiple (6 days) treatment of rodents. The effect of Tyr-Am was better than those of the referent amantadine. In conclusion the newly synthesized amantadine derivative Tyr-Am has a good neurobiological activity comparable with those of amantadine and deserves further investigations as potential antiparkinsonian agent.