Prog. Neuro-Psychopharmoco1. & Biol. Psych&. 1988, Vol. 12, pp. 967-987 Printed in Great Britain. All rights reserved 027&5846/88$0.00 + .50 Copyright 0 1988 Pergamon Press plc zyxwvu DESIGN AND EARLY CLINICAL EVALUATION OF SELECTIVE INHIBITORS OF MONOAMINE OXIDASE MICHAEL G. PALFREYMAN, IAN A. MCDONALD, PHILIPPE BEY, PAUL J. SCHECHTER AND ALBERT SJOERDSMA Merrell Dow Research Institute Cincinnati, Ohio, USA (Final form, February, 1988) Abstract Palfreyman, Michael G., Ian A. McDonald, Philippe Bey, Paul J. Schechter, and Albert Sjoerdsma: Design and early clinical evaluation of selective inhibitors of monoamine oxidase Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12:967-987 - 1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC=C(R)CH,NH have been designed as enzyme-activated, irreversible inhibitors o< these enzymes. Two compounds, MDL 72145 (R=3,4 dimethoxyphenyl) and MDL zyxwvutsrqponm 72974 (R=4-fluorophenethyl), are selective and irreversible inhibi- tors of MAO type B which in vivo show high inhibitory potency against -- the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and m&keys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without the cardiovascular effects of oral tyramine. potentiating should prove useful in Parkinson’s disease. Compounds of this type 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-S-fluoromethylene-m-tyrosine). This amino acid is decarboxylate?d by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R=3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, plasma substantially decreased urinary MHPG and DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders. 967