Formation of the Neurotransmitter Glycine from the Anticonvulsant Milacemide Is Mediated by Brain Monoamine Oxidase B

Abstract

Milacemide (2-n-pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO-A and -B (rat brain and liver), MAO-A (human placenta), and MAO-B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO-B rather than MAO-A oxidize (H2O2 production and glycinamide formation) milacemide. The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM). In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO-A) and beta-phenylethylamine (MAO-B) by brain mitochondria prepared from rats pretreated with clorgyline (0.5-10 mg/kg) and l-deprenyl (0.5-10 mg/kg). Furthermore, in vivo experiment demonstrated that l-deprenyl selectively increased the urinary excretion of [14C]milacemide and the total radioactivity with a concomitant decrease of [14C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO-B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.

Disposition and Metabolism of Safinamide, a Novel Drug for Parkinson's Disease, in Healthy Male Volunteers

“…These values (>100 litres independently of the F value) exceed the actual subjects' BWs and indicate an extensive organ(s)/tissue(s) distribution of the drug. For the parent compound, the organ/tissue drug is in equilibrium with the blood drug according to a one-compartment open model, corroborated by the observed mono-exponential elimination of unchanged safinamide (t 1/2 22 h), confirming results obtained in previous clinical studies [17]. Differently, 14 C radioactivity decreased in a biphasic manner (terminal t 1/2 80 h), indicating a multi-component and, probably, multi-compartmental model.…”

“…The presence of this metabolite indicates N-dealkylation as a major pathway of safinamide metabolism, characterized by safinamide oxidation by MAO followed by further oxidation to the acid. This metabolic pathway is characteristic of other MAO-B inhibitors, a typical example being milacemide, an anticonvulsant drug which is metabolized by MAO-B [17,18], giving rise to the N-dealkylated pentanoic acid plus glycinamide, the latter then transformed into glycine. It is possible that N-dealkylation of safinamide might lead to the formation of alaninamide (and then alanine) in the same way.…”

Simultaneous delivery of valproic acid and glycine to the brain

“…Recently, MAO has been found to be involved in the conversion of an antiepileptic prodrug, 2-n-pentylaminoacetamide (milacemide") (de Varebeke et al, 1988). Milacemide can cross the blood-brain barrier and then be oxidized by MAO to form glycinamide, which is subsequently cleaved to glycine.…”

Microionophoretic study with milacemide, a glycine precursor, on mammalian central nervous system cells

“…Milacemide is transformed, through a monoamine oxidase B inhibitor (IMAO-B)-sensitive process, into glycinamide and glycine (Janssens de Varebeke et al, 1988). Following its administration, the glycine content of the brain is significantly increased (Christophe et al, 1983).…”

“…Following its administration, the glycine content of the brain is significantly increased (Christophe et al, 1983). The action of milacemide is believed to be indirectly due, at least in part, to its degradation into glycine (Hunter et al, 1986;Roba et al, 1986; de Varebeke et al, 1988;Youdim et al, 1988). However, milacemide does not appear very potent against convulsions induced by strychnine (Van Dorsser et al, 1983;Roba et al, 1986), which is a known glycine antagonist (Curtis & Johnston, 1974).…”