Identification of arginine analogues as antagonists and agonists for the melanocortin-4 receptor.
In the present study, conducted to explore potent and small molecular melanocortin-4 (MC4) receptor ligands, we found that tripeptide 3a, containing a D-Phe-Arg-2-Nal (Nal; naphthylalanine) sequence, exhibited a moderate affinity for the MC4 receptor. Structural optimization led to the identification of a compound with a high affinity for the MC4 receptor, namely, tripeptide 3e, which showed a 70-fold higher affinity for the MC4 receptor than the lead compound 3a. Moreover, in an effort to further reduce the peptidic characters of tripeptide 3e, we found that dipeptide 3g exhibited a relatively high affinity for the MC4 receptor. Furthermore, in these analogues, the substituted position (1' vs. 2') of the naphthyl ring of Nal residue at position 7 was found to be important for the differentiation of agonist and antagonist activity. The synthesis and structure-activity relationships of the arginine analogues as MC4 receptor ligands were described in this paper.
Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., Saitama, Japan. dai.nozawa@po.rd.taisho.co.jp
Dai
D
Nozawa
Taketoshi
T
Okubo
Shigeyuki
S
Chaki
Shigeru
S
Okuyama
Atsuro
A
Nakazato
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008970:Molecular Weight; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
D008024:Ligands; D009842:Oligopeptides; D044105:Receptor, Melanocortin, Type 4; D011994:Recombinant Proteins; D001120:Arginine; D000242:Cyclic AMP