R-2HMP: an Orally Active Agent Combining Independent Antiapoptotic and MAO-B-Inhibitory Activities

During the past decade, much interest has been focused on the potential utility of monoamine oxidase (MAO) type B inhibitors in neurodegenerative diseases, in particular Parkinson’s disease. In this respect, R-deprenyl is the gold standard to which novel therapeutics are compared, providing symptomatic relief when administered either alone or in combination with L-dopa (9,96). While there is little doubt as to the symptomatic benefit provided by R-deprenyl, reports that R-deprenyl may slow the progression of Parkinson’s disease (50,61,64,95,96), suggestive of a neuroprotective effect, have been more controversial. This possibility has stimulated much research into the potential neural rescue, neuroprotective, and antiapoptotic effects of R-deprenyl, in particular, and other MAO inhibitors in general. While R-deprenyl has been shown to be an effective neural rescue/antiapoptotic agent in vitro (see 90 for review), in vivo R-deprenyl shows a markedly decreased efficacy on chronic administration (22,33) at best. In a large part, this is related to the metabolism of R-deprenyl, which in addition to a desmethyl metabolite also yields amphetamine and methamphetamine derivatives (5,37,78). These amphetaminergic metabolites have been shown to be proapoptotic (63), and as such the in vivo efficacy of R-deprenyl is self-limiting. We have developed a number of compounds which, like R-deprenyl, show potent, irreversible inhibition of MAO-B, and a MAO-B-independent antiapoptotic effect. Unlike R-deprenyl, however, these compounds show excellent in vivo efficacy in a number of animal models and are devoid of toxic metabolites. Indeed, at least one of the metabolites of our lead compound appears to be responsible for the antiapoptotic effect while being essentially devoid of MAO-B-inhibitory activity. The present review will describe the development and known activity of our lead compound R-N-(2heptyl)-N-methylpropargylamine hydrochloride (R-2HMP) (Fig. 1).