Novel piperazines: potent melanocortin-4 receptor antagonists with anxiolytic-like activity.
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.
Nozawa
Dai
D
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
Okubo
Taketoshi
T
Ishii
Takaaki
T
Takamori
Kazuaki
K
Chaki
Shigeyuki
S
Okuyama
Shigeru
S
Nakazato
Atsuro
A
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
D014151:Anti-Anxiety Agents; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4