Analogs of lactam derivatives of alpha-melanotropin with basic and acidic residues

A role of the aromatic and of the basic residues of the potent agonist (MTI I) and antagonist (SHU9119) at the human melanocortin receptors 4 in the fo rmation and stabilization of ligand-receptor complexes was examined. Analog s of MTII and SHU9119 with glutamic acid replacing one amino acid at a time were synthesized and tested for their ability to bind to and activate huma n melanocortin receptors 3, 4, and 5. Replacement of Phe (Na1) or Trp with Glu resulted in analogs of MTII and SHU9119 which were practically inactive at the receptors studied. The rather large (and unexpected) tolerance towa rd the presence of Glu in the position of His or Arg of MTII and SHU9119 cl early suggested that in the ligand receptor complexes these basic residues are not in contact with the receptors but probably face the extracellular e nvironment. This identified the aromatic residues of MTII and SHU9119 as th e primary structural features determining interactions of the agonist/antag onist with hMCR3-5. (C) 2000 Academic Press.