title: Novel piperazines: potent melanocortin-4 receptor antagonists with anxiolytic-like activity.
abstract: In the present study, we found that a novel piperazine compound, 11a, showed a moderate affinity (IC(50)=333nM) for the MC4 receptor. We developed the new type of piperazine compounds and found that mono-piperazine 11b exhibited a high-affinity (IC(50)=40.3nM) for the MC4 receptor. We also found that a series of biphenyl analogues exhibited a high-affinity for the receptor, and in particular, compound 11j exhibited the highest affinity for the MC4 receptor with an IC(50) value of 14.5nM. Furthermore, some of these compounds, when administered orally, significantly reversed the stress-induced anxiety-like behavior in rats. In this paper, we report the synthesis, structure-activity relationships, and oral activity of the novel mono-piperazines as MC4 receptor antagonists.
authors.affiliation: Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. dai.nozawa@po.rd.taisho.co.jp
authors.forename: Dai
authors.initials: D
authors.lastname: Nozawa
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Okubo
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ishii
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takamori
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: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D019556:COS Cells / Q000187:drug effects; D002522:Chlorocebus aethiops; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D014151:Anti-Anxiety Agents; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4