LONG-CHAIN ANALOGS OF PHYSOSTIGMINE AS POTENTIAL-DRUGS FOR ALZHEIMERS-DISEASE - NEW INSIGHTS INTO THE MECHANISM OF ACTION IN THE INHIBITIONOF ACETYLCHOLINESTERASE

Heptylphysostigmine is in advanced clinical trial as a drug for Alzhei mer's disease. 8-Morpholinooctylphysostigmine and 8-(cis-2,6-dimethylm orpholino)octylphysostigmine are currently undergoing pre-clinical eva luation. The mechanism of action of these compounds in the inhibition of acetylcholinesterase has been investigated. All the examined compou nds display non competitive-like kinetics of inhibition. There are no reversible components in the observed inhibition: the whole inhibitory effect is due to the time-dependent pseudo-irreversible carbamylation of the active site. Yet the observed time course of the inhibition do es not match a simple second order kinetics. An influence of the quate rnary structure of the enzyme on the more complex kinetics of carbamyl ation is hypothesized. Reactivation experiments on the inhibited enzym e show long lasting inhibitory effects for these compounds. The higher duration of the anticholinesterase effect of the morpholino derivativ es compared to heptylphysostigmine should provide the basis for their higher therapeutic potential. (C) 1997 Elsevier Science B.V.