A NEW STRATEGY FOR THE DESIGN OF MONOAMINE-OXIDASE INACTIVATORS - EXPLORATORY STUDIES WITH TERTIARY ALLYLIC AND PROPARGYLIC AMINO-ALCOHOLS

A new strategy for the design of monoamine oxidase (MAO) inhibitors is proposed. The strategy is based on the premise that tertiary-amine co ntaining MAO-inactivators which operate by alkylation of active site n ucleophiles are activated in sial by single electron transfer (SET) to the MAO-flavin cofactor to form aminium cation radicals which undergo secondary fragmentation reactions to produce reactive electrophiles, The purpose of the current work was to assess the feasibility and appl icability of this proposal for the design of new families of MAO-inact ivacors. Based on the documented retro-aldol type fragmentation reacti vity of beta-amino-alcohol cation radicals, tertiary beta-allylic and -propargylic beta-amino-alcohols were expected to serve as precursors of conjugated ketones in SET-promoted processes. Evidence supporting t his hypothesis was gained from studies of model SET-photoreactions of members of this amino-alcohol family with 3-methyl-lumiflavin (3MLF). The efficient production of 4a- and 4a,5-flavin adducts in these excit ed-state reactions demonstrates that aminium radicals. arising by SET- oxidation of tertiary beta-allylic and -propargylic beta-amino-alcohol s, fragment to generate alpha,beta-unsaturated ketones which react rap idly with the simultaneously formed 3MLF-hydroflavin anion. The second feature of the MAO-inactivator design strategy pathway was tested by examining reactions of the MAOs with substances which contain electrop hilic, conjungated enone and ynone moieties tethered to amine function s to ensure delivery to the enzyme active sites. The covalent modifica tion of active site cysteine thiol residues by the unsaturated ketone groups in these substances was confirmed by demonstrating that they se rve as active site-directed, time-dependent, nonredox based, inactivat ors of MAO-A and MAO-B. In the key test of the feasibility of the new MAO-inactivator design strategy, it was shown that selected tertiary b eta-allylic and -propargylic beta-amino-alcohols undergo redox reactio ns in the MAO-A active site which result in inactivation of the enzyme via covalent modification of a single cysteine residue. The experimen tal results which support the conclusions stated above are presented a nd discussed in this paper.