SYNTHESIS AND SELECTIVE MONOAMINE-OXIDASE B-INHIBITING PROPERTIES OF 1-METHYL-1,2,3,6-TETRAHYDROPYRID-4-YL CARBAMATE DERIVATIVES - POTENTIAL PRODRUGS OF (R)-NORDEPRENYL AND (S)-NORDEPRENYL

The results of previous studies have established that the monoamine ox idase-catalyzed oxidation of 1-methyl-1,2,3,6-tetrahydropyridyl deriva tives bearing heteroatom substituents at C-4 generates 2,3-dihydropyri dinium intermediates that undergo spontaneous hydrolysis to release th e C-4 substituent and form the amino enone 1-methyl-2,3-dihydro-4-pyri done. We have attempted to adapt this metabolic pathway to the prepara tion of amine-containing prodrugs that may target the central nervous system which is rich in monoamine oxidase A and B. In this paper we re port the synthesis and the in vitro and in vivo metabolic fate of the tetrahydropyridyl carbamate derivatives which are designed to release (S)- and (R)-nordeprenyl. These carbamates are selective monoamine oxi dase A substrates. An ex vivo assay has shown that the R-enantiomer is an effective and selective inhibitor of brain mitochondrial monoamine oxidase B.