Metabolism of 3-(p-chlorophenyl)pyrrolidine. Structural effects in conversion of a prototype gamma-aminobutyric acid prodrug to lactam and gamma-aminobutyric acid type metabolites.
By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.
Wall
G M
GM
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University 38677.
Baker
J K
JK
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001418:Baclofen / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007538:Isoniazid; D007769:Lactams / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000378:metabolism* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000596:Amino Acids; D007769:Lactams; D011355:Prodrugs; D011759:Pyrrolidines; C059971:3-(4-chlorophenyl)pyrrolidine; D005680:gamma-Aminobutyric Acid; D003577:Cytochrome P-450 Enzyme System; D008995:Monoamine Oxidase; D001418:Baclofen; D007538:Isoniazid