Various 4- and 8-aminoquinolines, which are effective
antimalarial agents, were examined as potential pretreatment compounds for prolongation of the time to 50% block of nerve-elicited muscle twitches in isolated mouse diaphragms exposed to botulinum type A
neurotoxin. The 4-aminoquinolines (
chloroquine,
amodiaquine) and
quinacrine, an
acridine derivative similar to
chloroquine, prolonged the time required for botulinum type A
neurotoxin to block neuromuscular transmission by more than 3-fold; 8-aminoquinolines (
primaquine and
WR242511) had no antibotulinum type A
neurotoxin activity.
Pyrimethamine, an
antimalarial drug lacking the
quinoline ring structure, was also ineffective. Rank order potencies based on equimolar effective concentrations for the test compounds were
quinacrine >
amodiaquine >
chloroquine >
quinine or
quinidine. Maximum protection from botulinum type A
neurotoxin-induced neuromuscular block was achieved when muscles were exposed to
drug prior to or simultaneously with the toxin. A delay of more than 20 min abolished the protective ability of the
antimalarial agents, presumably owing to the release of the toxin from endosomes in quantities sufficient to initiate neuromuscular block. All of the test compounds except
quinine and
quinidine depressed muscle contractions when concentrations exceeded 20 microM. In addition,
amodiaquine at 50 microM induced muscle
contracture. A combination of agents at low concentrations that act at different steps of botulinum type A
neurotoxin poisoning potentiated the prolongation of time to 50% block in an approximately additive fashion. Thus
N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (2 microM) and
quinacrine (5 microM), when administered in combination, produced up to a 4-fold increase in time to 50% block. A similar level of protection with
quinacrine alone required a 4-fold increase in the aminoquinoline concentration. Although the mechanism of protection by these
antimalarial agents is probably through the raising of endosomal pH, the possibility that some of these drugs could also act by inhibiting toxin-induced channel formation cannot be ruled out.