Orally active and potent inhibitors of gamma-aminobutyric acid uptake
| Autor: | Fadia E. Ali, William E. Bondinell, Penelope A. Dandridge, James S. Frazee, Eleanor Garvey, Gerald R. Girard, Carl Kaiser, Thomas W. Ku, John J. Lafferty, George I. Moonsammy, Hye-Ja Oh, Julia A. Rush, Paulette E. Setler, Orum D. Stringer, Joseph W. Venslavsky, Beth W. Volpe, Libby M. Yunger, Charles L. Zirkle |
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| Rok vydání: | 1985 |
| Předmět: |
Male
Alkylation medicine.medical_treatment Central nervous system Carboxylic Acids Administration Oral In Vitro Techniques Norepinephrine Drug Discovery medicine Animals Gamma-aminobutyric acid uptake Neurotransmitter Uptake Inhibitors Amino Acids gamma-Aminobutyric Acid chemistry.chemical_classification Chemistry Glutamate Decarboxylase Brain Rats Inbred Strains Stereoisomerism Receptors GABA-A In vitro Amino acid Rats Receptors Neurotransmitter Orally active Anticonvulsant medicine.anatomical_structure Biochemistry Mechanism of action 4-Aminobutyrate Transaminase Molecular Medicine GABA Uptake Inhibitors medicine.symptom Synaptosomes |
| Zdroj: | Journal of medicinal chemistry. 28(5) |
| ISSN: | 0022-2623 |
| Popis: | 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]. |
| Databáze: | OpenAIRE |
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