ABSTRACT
A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke.
Subject(s)
Pyrrolidines/chemistry , Sodium Channel Blockers/chemical synthesis , Stroke/drug therapy , Animals , Disease Models, Animal , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Infarction, Middle Cerebral Artery/drug therapy , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Pyrrolidines/pharmacology , Pyrrolidines/therapeutic use , Rats , Sodium Channel Blockers/pharmacology , Sodium Channel Blockers/therapeutic use , Structure-Activity RelationshipABSTRACT
In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.
