title: Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
abstract: Novel N-substituted indol-3-ylglyoxylamides (10-37) were synthesized and evaluated as ligands of the benzodiazepine receptor (BzR). In an effort to achieve affinity-based selectivity among BzR subtypes, these compounds were designed to probe the LDi and L2 lipophilic regions. Taking the alpha1-selective benzylindolylglyoxylamides Ia and Ib as leads, we varied the substituent on the benzylamide phenyl ring (compounds 10-23) or replaced the benzyl moiety with alkyl groups (compounds 24-37). The above structural changes gave no shift of selectivity from the alpha1 toward the alpha2 or alpha5 subtypes, thus confirming that a ligand which occupies the LDi region probably exhibits alpha1 selectivity, despite its interactions with other lipophilic areas in the receptor binding cleft. Compound 11 (N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide), which selectively binds with a full agonist efficacy at the alpha1 receptor subtype and displays sedative action, can be regarded as an interesting potential zolpidem-like sedative-hypnotic agent.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. primofiore@farm.unipi.it
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Primofiore
authors.forename: Sabrina
authors.initials: S
authors.lastname: Taliani
authors.forename: Federico
authors.initials: F
authors.lastname: Da Settimo
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Marini
authors.forename: Concettina
authors.initials: C
authors.lastname: La Motta
authors.forename: Francesca
authors.initials: F
authors.lastname: Simorini
authors.forename: Maria Paola
authors.initials: MP
authors.lastname: Patrizi
authors.forename: Valentina
authors.initials: V
authors.lastname: Sergianni
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Greco
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Marina
authors.initials: M
authors.lastname: Montali
authors.forename: François
authors.initials: F
authors.lastname: Besnard
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D058785:GABA-A Receptor Agonists; D006038:Glyoxylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009043:Motor Activity / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D058785:GABA-A Receptor Agonists; D006038:Glyoxylates; D006993:Hypnotics and Sedatives; D007211:Indoles; D008024:Ligands; C519518:N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide