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).
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ALviva Biopharmaceuticals Inc., 218-111 Research Drive, Saskatoon, SK, Canada S7N 3R2.
Boulton
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011437:Propylamines / Q000494:pharmacology* / Q000627:therapeutic use
D018696:Neuroprotective Agents; D011437:Propylamines; C009054:propargylamine; D010293:Pargyline