Pyrrolines as Prodrugs of γ‐Aminobutyric Acid Analogues

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Abstract
.DELTA.1-Pyrroline, 5-methyl-.DELTA.1-pyrroline and 5,5-dimethyl-.DELTA.1-pyrroline were identified as substances metabolized to GABA, 4-aminopentanoic acid (methylGABA) and 4-amino-4-methylpentanoic acid (dimethylGABA), respectively. An enzyme system residing in the soluble fraction of rabbit liver catalyzes the conversion of .DELTA.1-pyrolline to GABA and its lactam, 2-pyrrolidinone. Acetaldehyde, allopurinol and cyanide inhibited the reaction. Incubation of deuterium-labeled .DELTA.1-pyrroline with mouse brain homogenates produced deuterated GABA. Mouse liver 10,000 g supernatant and mouse brain homogenates converted 5-methyl-.delta.1-pyrroline to methylGABA and 5,5-dimethyl-.DELTA.1-pyrroline to dimethylGABA. Four hours after i.p. injection of 5-methyl-.DELTA.1-pyrroline (200 mg/kg), methylGABA was detected in mouse brain (0.27 .mu.mol/g). DimethylGABA (1.21 .mu.mol/g) was determined in mouse brain 30 min after i.p. administration of 5,5-dimethyl-.DELTA.1-pyrroline (200 mg/kg). Neither methylGABA nor dimethylGABA penentrated into the CNS when administered in the periphery. Evidently, pyrrolines may represent a chemical class of brain-penetrating precursors of pharmacologically active GABA analogs.