title: Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands.
abstract: Since the peripheral benzodiazepine receptor (PBR) has been primarily found as a high-affinity binding site for diazepam in rat kidney, numerous studies of it have been performed. However, the physiological role and functions of PBR have not been fully elucidated. Currently, we presented the pharmacological profile of two high and selective PBR ligands, N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl)acetamide (7-096, DAA1106) (PBR: IC(50)=0.28 nM) and N-(4-chloro-2-phenoxyphenyl)-N-(2-isopropoxybenzyl)acetamide (7-099, DAA1097) (PBR: IC(50)=0.92 nM). The compounds are aryloxyanilide derivatives, and identified with known PBR ligands such as benzodiazepine (1, Ro5-4864), isoquinoline (2, PK11195), imidazopyridine (3, Alpidem), and indole (5, FGIN-1-27) derivatives. The aryloxyanilide derivatives, which have been derived by opening the diazepine ring of 1, are a novel class as PBR ligands and have exhibited high and selective affinity for peripheral benzodiazepine receptors (PBRs). These novel derivatives would be useful for exploring the functions of PBR. In this paper, the design, synthesis and structure-affinity relationships of aryloxyanilide derivatives are described.
authors.affiliation: Medicinal Chemistry Laboratory, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Okubo
authors.forename: Ryoko
authors.initials: R
authors.lastname: Yoshikawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okuyama
authors.forename: Atsuro
authors.initials: A
authors.lastname: Nakazato
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000813:Anilides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology; D001671:Biochemistry / Q000379:methods; D015195:Drug Design; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D007210:Indoleacetic Acids / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017933:Peripheral Nervous System / Q000378:metabolism; D010647:Phenyl Ethers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000813:Anilides; C118941:DAA 1097; C118942:DAA 1106; D007093:Imidazoles; D007210:Indoleacetic Acids; D007546:Isoquinolines; D008024:Ligands; D010647:Phenyl Ethers; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; C081306:N,N-di-n-hexyl-2-(4-fluorophenyl)indole-3-acetamide; C052036:alpidem; C039109:isoquinoline