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Pyrrolines as Prodrugs of γ‐Aminobutyric Acid Analogues
Author(s) -
Callery Patrick S.,
Geelhaar Linda A.,
Nayar M. S. Balachandran,
Stogniew Martin,
Rao K. Gurudath
Publication year - 1982
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1982.tb05348.x
Subject(s) - pyrroline , intraperitoneal injection , aminooxyacetic acid , chemistry , biochemistry , acetaldehyde , gamma aminobutyric acid , stereochemistry , enzyme , biology , pharmacology , receptor , ethanol
Δ′‐Pyrroline, S‐methyl‐Δ′‐pyrroline, and 5.5‐dimethyl‐Δ′‐pyrroline have been identified as substances metabolized to γ‐aminobutyric acid (GABA), 4‐aminopentanoic acid (raethyl GABA), and 4‐amino‐4‐methylpen‐tanoic acid (dimethyl GABA), respectively. An enzyme system residing in the soluble fraction of rabbit liver catalyzes the conversion of Δ′‐pyrroline to GABA and its lactam, 2‐pyrrolidinone. Acetaldehyde, allopurinol, and cyanide inhibited the reaction. Incubation of deuterium‐labeled Δ′‐pyrroline with mouse brain homogenates produced deuterated GABA. Mouse liver 10,000 g supernatant and mouse brain homogenates converted S‐methyl‐Δ′‐pyrroline to methyl GABA, and 5,5‐dimethyl‐Δ′‐pyrroline to dimethyl GABA. Four hours after intraperitoneal injection of 5‐methyl‐Δ′‐pyrroline (200 mg/kg), methyl GABA was detected in mouse brain (0.27 μ‐mol/g). Dimethyl GABA (1.21 μmol/g) was determined in mouse brain 30 min after intraperitoneal administration of 5.5‐dimethyl‐Δ′‐pyrroline (200 mg/kg). Neither methyl GABA nor dimethyl GABA 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.