title: Synthesis, structure-activity relationships, and molecular modeling studies of N-(indol-3-ylglyoxylyl)benzylamine derivatives acting at the benzodiazepine receptor.
abstract: A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Da Settimo
authors.forename: G
authors.initials: G
authors.lastname: Primofiore
authors.forename: F
authors.initials: F
authors.lastname: Da Settimo
authors.forename: A M
authors.initials: AM
authors.lastname: Marini
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.forename: G
authors.initials: G
authors.lastname: Greco
authors.forename: C
authors.initials: C
authors.lastname: Martini
authors.forename: G
authors.initials: G
authors.lastname: Giannaccini
authors.forename: A
authors.initials: A
authors.lastname: Lucacchini
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011963:Receptors, GABA-A; C103089:N-(indol-3-ylglyoxylyl)benzylamine