Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor

The anti Parkinson drug, rasagiline [R-(+)-N-propargyl-1-aminoindan], an inhibitor of type B monoamine oxidase, has been shown to suppress apoptosis induced by neurotoxins and oxidative stress. A series of novel propargylaminoindans with a carbamate moiety to inhibit cholinesterase were developed from phamacophore of rasagiline to protect or rescue deteriorated neurons in Alzheimer's and Lewy Body disease and provide a beneficial effect on the cognitive deficits. Rasagiline analogues were found to protect dopaminergic SH-SY5Y cells against apoptosis induced by peroxynitrite donor. SIN-1. TV3326, [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, was as effective as rasagiline in preventing apoptosis, followed by its S-enantiomer, TV3279. The anti-apoptotic-neuroprotective activity was shown to reside in the propargylamine and not the carbamate moiety. This resulted in stabilization of the mitochondrial membrane potential, the collapse of which initiates the apoptotic cascade. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.