Pyrrolines as prodrugs of gamma-aminobutyric acid analogues.
delta 1-Pyrroline, 5-methyl-delta 1-pyrroline, and 5,5-dimethyl-delta 1-pyrroline have been identified as substances metabolized to gamma-aminobutyric acid (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-pyrroline 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 intraperitoneal injection of 5-methyl-delta 1-pyrroline (200 mg/kg), methylGABA was detected in mouse brain (0.27 mumol/g). DimethylGABA (1.21 mumol/g) was determined in mouse brain 30 min after intraperitoneal administration of 5,5-dimethyl-delta 1-pyrroline (200 mg/kg). Neither methylGABA nor dimethylGABA penetrated into the central nervous system when administered in the periphery. The present studies suggest that pyrrolines may represent a chemical class of brain-penetrating precursors of pharmacologically active analogues of GABA.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011758:Pyrroles / Q000378:metabolism*; D011817:Rabbits; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism
D011758:Pyrroles; D005680:gamma-Aminobutyric Acid