Aliphatic propargylamines as symptomatic and neuroprotective treatments for neurodegenerative diseases

Over the past several years, we have developed a number of novel aliphatic propargylamine-related compounds. These can be divided into 14 main chemical families. These families have been shown to possess members that selectively and stereochemically (i.e. R-enantiomer) rescue neurons from p53-dependent apoptosis in vitro. In contrast, no rescue has been observed by the enantiomers of the opposite configuration or in p53-independent apoptosis. In vivo, several compounds have been shown to possess neural rescue properties in models of unilateral hypoxia/ischaemia, focal ischaemia, facial nerve axotomy, pmn mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse and MPTP non-human primate. Our prototype compound, R-2HMP, has been shown to be metabolised in a manner analogous to that of R-deprenyl but devoid of amphetaminergic metabolites. These compounds have been shown to be active through an interaction with the same binding site as R-deprenyl and CGP 3466. This site is suggested to be the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). (C) 2002 Elsevier Science Inc. All rights reserved.