Novel carbamate cholinesterase inhibitors that release biologically active amines following enzyme inhibition

Conjugation of the phenol derived from rivastigmine with amphetamines gave access to novel carbamate cholinesterase inhibitors. All compounds possessed increased affinity and selectivity for AChE compared to rivastigmine and were orally bioavailable. Compound 4a, incorporating d-amphetamine, caused significant inhibition of cholinesterase in vivo at doses that were well tolerated. Release of amphetamine from 4a was demonstrated following in vitro and in vivo inhibition of cholinesterase. Compound 4a was also effective in alleviating scopolamine induced amnesia in a rat passive avoidance model.

Graphical abstractUpon inhibition of cholinesterase by 4a–d, pharmacologically active amines are released.Figure optionsDownload full-size imageDownload as PowerPoint slide