title: Orally active and potent inhibitors of gamma-aminobutyric acid uptake.
abstract: 3-Pyrrolidineacetic acid (1a), certain piperidinecarboxylic acids--i.e., 3-piperidinecarboxylic acid (2a), 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid (3a), and cis-4-hydroxy-3-piperidinecarboxylic acid (4a)--cis-3-aminocyclohexanecarboxylic acid (5a, cis-3-ACHC), and gamma-aminobutyric acid (6a, GABA) itself are among the most potent inhibitors of [3H]GABA uptake by neurons and glia in vitro. These hydrophilic amino acids, however, do not readily enter the central nervous system in pharmacologically significant amounts following peripheral administration. We now report that N-(4,4-diphenyl-3-butenyl)-3-piperidinecarboxylic acid (2b) is a specific GABA-uptake inhibitor that is more potent, more lipophilic and, in limited testing, as selective as 2a. Similar results were obtained with the N-(4,4-diphenyl-3-butenyl) derivatives of 1a, 3a, and 4a. By contrast, N-(4,4-diphenyl-3-butenyl) derivatives of 5a and 6a were not more potent than the parent amino acids and appear to inhibit GABA uptake, at least in part, by a nonselective mechanism of action. The N-(4,4-diphenyl-3-butenyl)amino acids 1b-4b exhibit anticonvulsant activity in rodents following oral or intraperitoneal administration [Yunger, L.M.; et al. J. Pharmacol. Exp. Ther. 1984, 228, 109].
authors.forename: F E
authors.initials: FE
authors.lastname: Ali
authors.forename: W E
authors.initials: WE
authors.lastname: Bondinell
authors.forename: P A
authors.initials: PA
authors.lastname: Dandridge
authors.forename: J S
authors.initials: JS
authors.lastname: Frazee
authors.forename: E
authors.initials: E
authors.lastname: Garvey
authors.forename: G R
authors.initials: GR
authors.lastname: Girard
authors.forename: C
authors.initials: C
authors.lastname: Kaiser
authors.forename: T W
authors.initials: TW
authors.lastname: Ku
authors.forename: J J
authors.initials: JJ
authors.lastname: Lafferty
authors.forename: G I
authors.initials: GI
authors.lastname: Moonsammy
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000378:metabolism; D000284:Administration, Oral; D000478:Alkylation; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
chemical_list: D000596:Amino Acids; D002264:Carboxylic Acids; D014179:Neurotransmitter Uptake Inhibitors; D011963:Receptors, GABA-A; D017981:Receptors, Neurotransmitter; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D005968:Glutamate Decarboxylase; D009638:Norepinephrine