ACETYLCHOLINESTERASE INHIBITORS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF EGA-[N-METHYL-N-(3-ALKYLCARBAMOYLOXYPHENYL)METHYL] AMINOALKOXYHETEROARYL DERIVATIVES

Acetylcholinesterase (AChE) inhibitors are one of the most actively in vestigated classes of compounds in the search for an effective treatme nt of Alzheimer's disease. This work describes the synthesis, AChE inh ibitory activity, and structure-activity relationships of some compoun ds related to a recently discovered series of AChE inhibitors: the rba moyloxyphenyl)methyl]aminoalkoxyxanthen-9-ones. The influence of struc tural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibit ory activity and were more active than physostigmine. In particular, c ompound 13, an azaxanthone derivative, displayed the best rat cortex A ChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE th an for BuChE). When tested in the isolated enzyme, compound 13 was les s active, suggesting some differences either in drug availability/biot ransformation or in the inhibitor-sensitive residues of the enzyme whe n biologically positioned in rat brain membranes.