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

Abstract

Milacemide is a glycinamide derivative which readily enters the brain and is metabolised to glycine. As its mechanism of action as an anticonvulsant drug is unknown we used the technique of microdialysis to study the temporal inter-relationship of glycinamide, glycine and other amino acid neurotransmitters in the extracellular fluid of rat hippocampus and frontal cortex. After milacemide administration (400 or 800 mg/kg i.p.), glycinamide concentrations rose linearly and dose-dependently in both hippocampus and frontal cortex. In contrast, whilst glycine concentrations rose in the hippocampus, glycine was unaffected in the frontal cortex. Concomitant increases in taurine hippocampal concentrations were observed. An increase in serine and a decrease in alanine concentrations was only observed at the highest milacemide dose (800 mg/kg). Other amino acids were affected. Thus, while glycinamide appears to be universally distributed throughout the brain, its metabolism to glycine and its effects on brain amino acids appear to be region specific.

Clozapine and glycinamide prevent MK-801-induced deficits in the novel object recognition (NOR) test in the domestic rabbit (Oryctolagus cuniculus)

“…Previous clinical studies had tested the effectiveness of milacemide (2-n-pentylaminoacetamide) as a possible antipsychotic, but with negative results [53,54]. Milacemide enters the brain and is converted to glycinamide by monoamine oxidase, and then glycinamide is converted to glycine [7,12,24,49,57,70]. Glycine itself, when given orally at high doses (800 mg/kg) as an adjunct therapy with olanzapine or risperidone, has been shown to reduce negative symptoms [18][19][20][21]25].…”

Amino Acids in the Development of Prodrugs

“…The potential therapeutic use of glycine as an analgesic has been hindered by its limited penetrability into CNS [ 193 ], as a large amount of the amino acid is being required to produce significant levels in CNS [ 194 ]. Some percursors like melacemide (2- n -pentyaminoacetamide) ( 143 , Figure 60 ), readily penetrate into the CNS and elevate glycine concentrations in the brain [ 195 ]. This precursor is used as an antiepileptic drug and interferes with the production of allodynia by strychnine, and is metabolized primarily by monoamine oxidase (MAO-B) to glycinamide ( 144 , Figure 60 ), which is the immediate precursor of glycine.…”