STRUCTURAL FEATURES OF AMINOQUINOLINES NECESSARY FOR ANTAGONIST ACTIVITY AGAINST BOTULINUM NEUROTOXIN

Certain aminoquinoline antimalarial compounds, such as chloroquine, an tagonize the paralytic actions of botulinum neurotoxins (BoNT). These studies have been extended to determine the critical structural groups necessary for synthetic aminoquinolines to have antagonist activity a gainst BoNT. Isolated mouse hemidiaphragms were maintained at 36 degre es C and indirectly stimulated; the resulting isometric twitch tension s were recorded as a measure of synaptic function. The muscles were ex posed to the test compounds before being treated with a challenge conc entration of BoNT (typically 0.2 nM of serotype A). The time to onset of 50% muscle paralysis due to BoNT was used to assess quantitatively the efficacy of the test compounds, which were then ranked on the basi s of the concentrations necessary to delay paralysis by a specified ti me increment. Of the compounds tested, those having a 7-chloro-4-amino quinoline configuration, similar to chloroquine (or the structurally s imilar 6-chloro-9-amino acridine group in quinacrine), were most effec tive. Truncation of the alkyl-amino-alkyl group from chloroquine and c onversion of the 4-amino nitrogen to a primary amine did not significa ntly alter its effectiveness as a BoNT antagonist, However, the 6-chlo ro- or 8-chloro-isomers of chloroquine were essentially ineffective. T hese results suggest that aminoquinolines antagonize the paralytic act ions of BoNT through interaction with a selective, stereospecific site that is not well correlated with antimalarial activity. (C) 1997 Else vier Science Ltd.