title: Neurosteroid analogues. 11. Alternative ring system scaffolds: gamma-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes.
abstract: Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate gamma-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.
authors.affiliation: Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Scaglione
authors.forename: Brad D
authors.initials: BD
authors.lastname: Manion
authors.forename: Ann
authors.initials: A
authors.lastname: Benz
authors.forename: Amanda
authors.initials: A
authors.lastname: Taylor
authors.forename: Gregory T
authors.initials: GT
authors.lastname: DeKoster
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.forename: Alex S
authors.initials: AS
authors.lastname: Evers
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007814:Larva / Q000187:drug effects / Q000502:physiology; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D011083:Polycyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D018757:GABA Modulators; D007192:Indenes; D011083:Polycyclic Compounds; D011963:Receptors, GABA-A; D013256:Steroids