Design and early clinical evaluation of selective inhibitors of monoamine oxidase.
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)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors 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 monkeys. 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 potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated 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, substantially decreased urinary MHPG and plasma 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.
Palfreyman
M G
MG
Merrell Dow Research Institute, Cincinnati, Ohio.
McDonald
I A
IA
Bey
P
P
Schechter
P J
PJ
Sjoerdsma
A
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000498:Allyl Compounds; D000499:Allylamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001792:Blood Platelets / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002082:Butylamines / Q000494:pharmacology*; D002230:Carbidopa / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D051379:Mice; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism; D014439:Tyramine / Q000494:pharmacology
D000498:Allyl Compounds; D000588:Amines; D002082:Butylamines; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; C058000:mofegiline; D012701:Serotonin; D000499:Allylamine; D008734:Methoxyhydroxyphenylglycol; C040051:2-(3,4-dimethoxyphenyl)-3-fluoroallylamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase; D002230:Carbidopa; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine; D014439:Tyramine