title: Novel ligands specific for mitochondrial benzodiazepine receptors: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. Synthesis, structure-activity relationships, and molecular modeling studies.
abstract: A novel class of ligands specific for MBR receptors has been identified: 6-arylpyrrolo[2,1-d][1,5]benzothiazepine derivatives. The majority of newly synthesized esters 37-64 as well as some intermediate ketones showed micro- or nanomolar affinity for [3H]PK 11195 binding inhibition. A SAR study on 42 compounds and a molecular modeling approach led to a preliminary structural selectivity profile: the 6,7-double bond, the carbamoyloxy, alcanoyloxy, and mesyloxy side chains at the 7-position, and the prospective chloro substitution at the 4-position seemed to be the most important structural features improving affinity. Therefore, 7-[(dimethylcarbamoyl)oxy]- and 7-acetoxy-4-chloro-6-phenylpyrrolo[2,1-d][1,5]benzothiazepine (43 and 57) were synthesized. With 7-[(dimethylcarbamoyl)oxy]-6-(p-methoxyphenyl)pyrrolo[2,1- d][1,5]benzothiazepine (65), these were the most promising compounds with IC50s of respectively 9, 8, and 9 nM, under conditions where PK 11195 had an IC50 of 2 nM.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università di Siena, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Fiorini
authors.forename: V
authors.initials: V
authors.lastname: Nacci
authors.forename: S M
authors.initials: SM
authors.lastname: Ciani
authors.forename: A
authors.initials: A
authors.lastname: Garofalo
authors.forename: G
authors.initials: G
authors.lastname: Campiani
authors.forename: L
authors.initials: L
authors.lastname: Savini
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: P
authors.initials: P
authors.lastname: Bernasconi
authors.forename: T
authors.initials: T
authors.lastname: Mennini
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D008024:Ligands; D011758:Pyrroles; D011963:Receptors, GABA-A; D013841:Thiazepines