Development of N,N-Dimethylglycine-Amantadine for Adjunctive Dopaminergic Application: Synthesis, Structure and Biological Activity

Abstract

N-methyl-D-aspartate (NMDA) receptor blockade can improve L-DOPA (l-3,4-dihydroxyphenylalanine)-induced dyskinesias in Parkinson’s disease (PD) patients. Amantadine is a well-tolerated and effective antiparkinsonian agent, recently found to possess NMDA antagonistic properties. Oxidative damage may contribute to dopaminergic (DAergic) neurodegeneration in the substantia nigra of patients with PD. N,N-dimethylglycine (DMG) (also known as vitamin B15 or pangamic acid) acts as an antioxidant, extending the lifespan of animal cells through protection from oxidation. In this study, we synthesized and tested in vivo the newly obtained compound N,N-dimethylglycine-amantadine (DMG-Am) for antiparkinsonian activity. MPTP (1-methyl-4–phenyl-1, 2, 3, 6-tetrahydropyridine) is a widely used neurotoxin to induce an experimental model which mimics Parkinson disease-like symptoms. The neuroprotective capacity of the new amantadine derivative DMG-Am was evaluated by its potential to ameliorate the neuromuscular coordination and behavioral changes worsened by the toxin. Our experimental results showed that DMG-Am applied for 12 consecutive days, 5 days simultaneously and 7 days after MPTP, restored motor and memory performance of the animals to the control level, indication of beneficial protective effect of this compound. In summary, our results reveal the potential of newly synthesized DMG-Am as promising antiparkinsonian agent.