Novel selective human melanocortin-3 receptor ligands: use of the 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffold.

Abstract In search of new selective antagonists and/or agonists for the human melanocortin receptor subtypes h MC1R to h MC5R to elucidate the specific biological roles of each GPCR, we modified the structures of the superagonist MT-II (Ac-Nle-c[Asp-His- d -Phe-Arg-Trp-Lys]-NH 2 ) and the h MC3R/ h MC4R antagonist SHU9119 (Ac-Nle-c[Asp-His- d -Nal(2′)-Arg-Trp-Lys]-NH 2 ) by replacing the His- d -Phe and His- d -Nal(2′) fragments in MT-II and SHU9119, respectively, with Aba-Xxx (4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one-Xxx) dipeptidomimetics (Xxx =  d -Phe/pCl- d -Phe/ d -Nal(2′)). Employment of the Aba mimetic yielded novel selective high affinity h MC3R and h MC3R/ h MC5R antagonists.