Common modes of action of gamma-butyrolactones and pentylenetetrazol on the GABAA receptor-ionophore complex.
The effects of pentylenetetrazol and bicyclic gamma-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the gamma-aminobutyric acid (GABAA) receptor-complex. Bicyclic gamma-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic gamma-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic gamma-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3 alpha-hydroxy-16-imino-5 beta,17-aza-androstan-11-one). A bicyclic gamma-butyrolactone and pentylenetetrazol accelerated the dissociation of [35S]TBPS, displaced [3H]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action on the GABAA receptor-ionophore complex.
Maksay
G
G
Department of Molecular Pharmacology, Hungarian Academy of Sciences, Budapest.
Molnár
P
P
Gruber
L
L
D015107:4-Butyrolactone / Q000494:pharmacology*; D000731:Androstanes / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001378:Azasteroids / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D004594:Electrophysiology; D005442:Flumazenil / Q000378:metabolism; D018756:GABA Antagonists / Q000378:metabolism / Q000494:pharmacology; D007476:Ionophores; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000494:pharmacology*; D016548:Prosencephalon / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013574:Synaptosomes / Q000378:metabolism
D000731:Androstanes; D001378:Azasteroids; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018756:GABA Antagonists; D007476:Ionophores; D011963:Receptors, GABA-A; D005442:Flumazenil; C037476:tert-butylbicyclophosphorothionate; D015107:4-Butyrolactone; C032061:RU 5135; D010433:Pentylenetetrazole