Flaherty P, Castagnoli K, Wang Y X, Castagnoli N
Department of Chemistry, Virginia Tech, Blacksburg 24061-0212, USA.
J Med Chem. 1996 Nov 22;39(24):4756-61. doi: 10.1021/jm960477e.
The results of previous studies have established that the monoamine oxidase-catalyzed oxidation of 1-methyl-1,2,3,6-tetrahydropyridyl derivatives bearing heteroatom substituents at C-4 generates 2,3-dihydropyridinium intermediates that undergo spontaneous hydrolysis to release the C-4 substituent and form the amino enone 1-methyl-2,3-dihydro-4-pyridone. We have attempted to adapt this metabolic pathway to the preparation of amine-containing prodrugs that may target the central nervous system which is rich in monoamine oxidase A and B. In this paper we report 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 oxidase A substrates. An ex vivo assay has shown that the R-enantiomer is an effective and selective inhibitor of brain mitochondrial monoamine oxidase B.
先前的研究结果已证实，单胺氧化酶催化氧化在C-4位带有杂原子取代基的1-甲基-1,2,3,6-四氢吡啶基衍生物会生成2,3-二氢吡啶鎓中间体，该中间体可自发水解以释放C-4位取代基并形成氨基烯酮1-甲基-2,3-二氢-4-吡啶酮。我们试图采用这种代谢途径来制备可能靶向富含单胺氧化酶A和B的中枢神经系统的含胺前药。本文报道了旨在释放(S)-和(R)-去甲丙炔苯丙胺的四氢吡啶基氨基甲酸酯衍生物的合成及其体外和体内代谢命运。这些氨基甲酸酯是选择性单胺氧化酶A底物。一项体外试验表明，R-对映体是脑线粒体单胺氧化酶B的有效且选择性抑制剂。
