title: Synthesis of new molecular probes for investigation of steroid biosynthesis induced by selective interaction with peripheral type benzodiazepine receptors (PBR).
abstract: In the present study, we have synthesized and tested novel pyridopyrrolo- and pyrrolobenzoxazepine derivatives, as novel and selective peripheral type benzodiazepine receptor (PBR) ligands, and their ability to modulate steroid biosynthesis has been investigated. A subset of new ligands bind the PBR (rat brain and testis) with picomolar affinity, representing the most potent ligands that have been identified to date, and elicited effects on endogenous rate of steroidogenesis in MA10 Leydig cells, having similar potency and effect as PK11195. Several compounds, differently substituted at C-7, were used as molecular yardsticks to probe the spatial dimension of the lipophilic pocket L4 in the receptor binding site.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universita' degli Studi di Siena, via Aldo Moro, 53100 Siena, Italy. campiani@unisi.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Anna
authors.initials: A
authors.lastname: Ramunno
authors.forename: Isabella
authors.initials: I
authors.lastname: Fiorini
authors.forename: Vito
authors.initials: V
authors.lastname: Nacci
authors.forename: Elena
authors.initials: E
authors.lastname: Morelli
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Mara
authors.initials: M
authors.lastname: Goegan
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Stephen
authors.initials: S
authors.lastname: Sullivan
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Clive D
authors.initials: CD
authors.lastname: Williams
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010077:Oxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011374:Progesterone / Q000096:biosynthesis; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D013256:Steroids / Q000096:biosynthesis*; D013329:Structure-Activity Relationship; D013737:Testis / Q000166:cytology / Q000648:ultrastructure
chemical_list: D001381:Azepines; D008024:Ligands; D015335:Molecular Probes; D010077:Oxazepines; D011963:Receptors, GABA-A; D013256:Steroids; D011374:Progesterone