title: A behaviorally selective class of thiophene-containing benzodiazepine receptor ligands.
abstract: In a continued effort to probe the role of the aromatic rings in classical 1,4-benzodiazepine (BDZ) ligand pharmacology, a series of new thiophene-containing benzodiazepine receptor (BDZR) ligands were synthesized. As a first step in determining the binding profile and selectivity to BDZR functional subtypes, the affinities in two central nervous system (CNS) regions, cerebellum, in which a single 'Type I' BDZR could be labeled; and spinal cord, in which we have previously demonstrated some receptor heterogeneity, were determined. These compounds were also assessed for their compliance with a recently developed three dimensional pharmacophore for recognition and activation of the 'Type I' BDZR, using the techniques of computational chemistry. The computations showed all ligands synthesized fulfilled the minimum requirements for recognition, further validating the current pharmacophore. Using the criteria for activation, the new ligands were all predicted to be agonists at the cerebellar 'Type I' BDZR. Since the compounds showed reasonable affinity, the behavioral profile of one of them at five in vivo endpoints was determined. This compound demonstrated more behavioral selectivity than the typical 1,4-BDZ ligand. While they fulfilled the requirements for agonist activity at the 'Type I' BDZR, these ligands showed significantly greater delocalization in the electron density distribution in the lowest unoccupied molecular orbital (LUMO), so that either aromatic ring could serve as an electron accepting site, not just the one comparable to the more classical BDZR agonist, flunitrazepam. It is possible that the ability of the second ring in the tested compound (5a) to also function as an electron acceptor can affect the recognition and activation of other receptor types leading to the more discriminate behavioral profile of this thiophene analog compared to flunitrazepam.
authors.affiliation: Molecular Research Institute, Palo Alto, CA 94304, USA.
authors.forename: L T
authors.initials: LT
authors.lastname: Schove
authors.forename: S W
authors.initials: SW
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Beatty
authors.forename: P A
authors.initials: PA
authors.lastname: Maguire
authors.forename: M F
authors.initials: MF
authors.lastname: Davies
authors.forename: G H
authors.initials: GH
authors.lastname: Loew
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002531:Cerebellum / Q000378:metabolism; D005445:Flunitrazepam / Q000031:analogs & derivatives; D058785:GABA-A Receptor Agonists; D008024:Ligands; D008297:Male; D051381:Rats; D012995:Solubility; D013116:Spinal Cord / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes
chemical_list: D058785:GABA-A Receptor Agonists; D008024:Ligands; D013876:Thiophenes; D005445:Flunitrazepam