title: Design, synthesis, and structure-activity relationships of novel tetracyclic compounds as peripheral benzodiazepine receptor ligands.
abstract: The peripheral benzodiazepine receptor (PBR) is pharmacologically distinct from the central benzodiazepine receptor (CBR) and has been identified in a wide range of peripheral tissues as well as in the central nervous system. Although numerous studies have been performed of it, the physiological roles and functions of the PBR are still unclear. In the present study, in exploring new types of ligands for PBR, we found that a new series of compounds having a tetracyclic ring system, which were designed from FGIN-1-27, exhibited high affinities for PBR. We prepared and evaluated them for PBR affinities. The results of binding tests showed that 12e and 12f were the most potent PBR ligands among them (12e: IC(50)=0.44nM, 12f: IC(50)=0.37nM). In this paper, we present the design, synthesis, and structure-activity relationships (SARs) of novel tetracyclic compounds.
authors.affiliation: Medicinal Chemistry Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama-shi, Saitama 331-9530, Japan. t.okubo@po.rd.taisho.co.jp
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: D003500:Cyclization; D015195:Drug Design; D058787:GABA-A Receptor Antagonists; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D058787:GABA-A Receptor Antagonists; D008024:Ligands; D011963:Receptors, GABA-A