Potent reversible anticholinesterase agents. Bis- and mono-N-substituted benzoquinolinium halides

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Abstract
Bis- and mono-N-substituted benzoquinolinium salts and their analogs, prepared and evaluated as inhibitors of acetylcholinesterase (AcChe) and butyrylcholinesterase (BuChE), were also used to help identify some of the morphologic characteristics of the surface at or near the active sites of the cholinesterases. The shape, size, configuration and conformation of the onium moieties of the quaternary ammonium compounds were important factors in their anticholinesterase activity. A high concentration of the positive charge of the quaternary ammonium compound is not a critical factor for the cholinesterase inhibitory activity. The order of decreasing potency of cholinesterase inhibition of the benzoquinolinium compounds was acridinium > phenanthridinium > 5,6-benzoquinolinium > 7,8-benzoquinolinium. The inhibitory activity of the monobenzoquinolinium halides against cholinesterases is influenced by the N-substituent. A bis-quaternary ammonium compound with a flexible bridge linking the 2 N atoms was more potent in inhibiting AcChE and less potent in inhibiting BuChE than a bis-quaternary ammonium compound with a ridge bridge. The acridinium and phenanthridinium derivatives of the benzoquinolinium compounds are very potent reversible inhibitors against both AcChE and BuChE.