Pharmacological activity of amantadine: effect of N-alkyl substitution

Abstract

Abstract Alkyl substitution on the nitrogen atom of the anti-parkinsonian drug amantadine resulted in changes in its pharmacological potency. Greater behavioural stimulation (i.e. increased motor activity) was observed following s.c. injection of several of the analogues, with optimal activity produced by N-n-propyl substitution. These molecular changes did not alter the activity of amantadine on inhibition of dopamine uptake or its weak affinity for dopamine receptors in-vitro. Several of the analogues were more effective than the parent compound in increasing the concentration of dopamine metabolites (suggesting an increase in dopamine utilization) following systemic injection, and these effects generally followed the same pattern as observed in the test of behavioural activity. These results provide further support for the concept that the activity of amantadine may be improved by molecular alterations, although the pharmacological basis for this activity remains obscure.