title: New 1,5-benzodiazepine compounds: activity at native GABA(A) receptors.
abstract: Various new 1,5-benzodiazepine compounds were synthesized and tested for their biological activity in terms of effects on GABA(A) receptors of rat cerebellar granules in culture. Their effects were compared to those of a 1,4-benzodiazepine agonist, flunitrazepam and the already known 1,5-benzodiazepine antiepileptic clobazam. The effects were evaluated for the two different GABA(A) receptor populations present in these neurons, one mediating phasic inhibition and the other one mediating tonic inhibition. Many such compounds display a profile of inverse agonist to both GABA(A) receptor populations. One of them presents a profile of full agonist at the component mediating phasic inhibition. Interestingly, substitution of just one oxygen atom in that compound with sulphur in a specific position of a morpholine ring resulted in a remarkable change of activity from full agonist to a probable inverse agonist. This indicates such a position as a proton accepting one for the ligand within the benzodiazepine binding pocket of the relevant GABA(A) receptors. In addition, that position appears to be critical for the pharmacological activity.
authors.affiliation: Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Italy.
authors.forename: E
authors.initials: E
authors.lastname: Gatta
authors.forename: A
authors.initials: A
authors.lastname: Cupello
authors.forename: M
authors.initials: M
authors.lastname: Di Braccio
authors.forename: G
authors.initials: G
authors.lastname: Grossi
authors.forename: R
authors.initials: R
authors.lastname: Ferruzzi
authors.forename: G
authors.initials: G
authors.lastname: Roma
authors.forename: M
authors.initials: M
authors.lastname: Robello
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D054314:Drug Inverse Agonism; D018757:GABA Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D013329:Structure-Activity Relationship
chemical_list: D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines