title: Structure-activity studies on the activity of a series of cyclopentane GABA analogues on GABAA receptors and GABA uptake.
abstract: A series of analogues of gamma-aminobutyric acid (GABA) has been investigated for GABA mimetic activity on the isolated guinea-pig ileum, facilitation of [3H]diazepam binding in rat brain membranes and inhibition of [3H]GABA uptake from rat brain cortical slices. The derivatives tested include six racemic amino acids, all of which contain a 'GABA backbone' with the conformation restricted by a cyclopentane or cyclopentene ring system. From the more potent analogues, five optically pure compounds, including (+)-(4S)-4-aminocyclopent-1-ene-1-carboxylic acid and its (-)-4R enantiomer, have also been assessed as GABA agonists. Of the racemic analogues, 4-aminocyclopent-1-ene-1-carboxylic acid and trans-3-aminocyclopentane-1-carboxylic acid were the most potent at GABAA receptors, while most of the analogues had considerable activity on GABA uptake. The individual resolved isomers of 4-aminocyclopent-1-ene-carboxylic acid and of trans-3-aminocyclopentane-1-carboxylic acid displayed great specificity for GABA receptor and GABA uptake sites. For example (+)-(4S)-4-aminocyclopent-1-ene-1-carboxylic acid was approximately twice as potent as GABA and about 600 times more active than the (-)-4R isomer on the guinea-pig ileum, while it was not significantly active as a GABA uptake inhibitor at 500 microM. On the other hand, its (-)-4R isomer was selective for inhibiting GABA uptake with an IC50 equal to that of racemic nipecotic acid.
mesh_terms: D000818:Animals; D003975:Diazepam / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D003975:Diazepam