The Novel Neuropsychotropic Agent Milacemide Is a Specific Enzyme‐Activated Inhibitor of Brain Monoamine Oxidase B

Abstract

The novel neuropsychotropic agent milacemide hydrochloride (2-n-pentylaminoacetamide HCl) is a highly selective substrate of the B form of monoamine oxidase (EC 1.4.3.4; MAO). Under the in vitro conditions used in the present study, milacemide acts as an enzyme-activated, partially reversible inhibitor of MAO-B. A reversible inhibition of MAO-A activity is also observed at high concentrations. The inhibitory activity of milacemide is significantly greater for MAO-B. In vivo, after single or repeated oral administration, a specific inhibition of MAO-B is apparent in brain and liver, with a lack of inhibition of the MAO-A activity. In contrast to the irreversible inhibitory action of L-deprenyl, the recovery of MAO-B activity in vivo after milacemide administration is significantly faster, a result suggesting that it is a partially reversible inhibitor. The selective inhibitory effect of milacemide for MAO-B in vivo is confirmed by its potentiation of phenylethylamine-induced stereotyped behavior, whereas vasopressor responses to tyramine were not affected. These observations suggest that milacemide could enhance dopaminergic activity in the brain and could be used as therapy for Parkinson's disease in association with L-3,4-dihydroxyphenylalanine.

Novel substrates and products of amine oxidase-catalysed reactions

“…The secondary amine nature of milacemide, together with involvement of oxidative reaction in its Besides being a selective substrate of MAO-B with a relatively high affinity for this enzyme (Km=30-8O p~) as compared with MAO-A ( K , = 1200-1500 p~) , milacemide also acts as a time-dependent, enzyme-activated, partially-reversible specific inhibitor of MAO-B [13] (Fig. 1).…”

Letters to the editor

“…'Cerebellum' is neither synonym nor metaphor for incoordination. The Milacemide is a selective substrate (4) and a specific enzyme-activated reversible inhibitor of MAO-B in vitro and in vivo (5). Long-term chronic treatment with relatively large doses of milacemide in rhesus monkeys has resulted in a specific inhibition of brain MAO-B (5) and elevation of striatal dopamine, with concomitant decreases in dihydroxyphenylacetic acid and homovanilic acid (6).…”

A microdialysis study of glycinamide, glycine and other amino acid neurotransmitters in rat frontal cortex and hippocampus after the administration of milacemide, a glycine pro-drug

“…However, under normal physiological conditions the entry of glycine into the brain from blood is negligible (Oldendorf 1971) and thus numerous glycine derivatives, which readily pass the blood brain barrier have been developed (Christophe et al 1983;Abu Salach et al 1994). The most investigated, both experimentally and clinically, of these derivatives is milacemide (2-n-pentylaminoacetamide) which upon entry to the brain, after systemic administration, is rapidly metabolised by monoamine oxidase type B (MAO-B) firstly to glycinamide and then to glycine (de Varebeke et al 1989;.…”