Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties

Abstract

This chapter discusses the synthesis of a series of aliphatic N-methylpropargylamine monoamine oxidase (MAO)-B inhibitors and examines their structural and functional relationships. The R(–)-enantiomers are much more active than the S(+)-enantiomers at inhibiting MAO-B activity. Some of these compounds protect mouse nigrostriatal dopamine neurons against the neurotoxin MPTP and the mouse hippocampal noradrenergic system against the neurotoxin N-(2-chloroethyl)-N-ethyl- 2-bromobenzylamine (DSP-4). They rescue hippocampal neurons after damage induced by ischemia and kainic acid treatment, as well as motoneurons in young mice following facial nerve axotomy. Such rescue effects are unrelated to the inhibition of MAO-B activity. Some of the aliphatic propargylamines enhance the survival of neuroblastoma cells co-cultured with astrocytes, following serum depletion. They stimulate the expression of AADC (aromatic L-amino acid Decarboxylase) mRNA and inhibit GFAP mRNA expression. They do not possess amphetamine-like properties and exhibit no effect on noradrenaline or dopamine uptake and do not increase hypertensive effects in the tyramine pressor test. Unlike R(–)-deprenyl, 2-HxMP does not potentiate dopamine toxicity in vitro. © 1995, Academic Press Inc.