alpha -Melanotropin (alpha MSH) and several of its derivatives are potent but not selective agonists at melanocortin receptors 3, 4, and 5 present in the brain (MC3-5R). To differentiate between the physiological role of hMC-4R (believed to be involved in regulation of energy balance) from those of melanocortin receptors 3 and 5, potent and receptor-specific agonists are needed. Therefore, the cyclic derivatives of aMSH of a general structure, cyclo(X-His-D-Phe-Arg-Trp-Y)-NH2, where X is succinic acid or an omega -amino-carboxylic acid, and Y is an alpha,omega -di-amino-carboxylic acid or an omega -carboxy-alpha -amino acid, were prepared and tested in binding assays and in cAMP assays on CHO cells expressing hMC3-5R. Several of the 21-membered or larger lactams turned out to be potent and hMC-4R-selective agonists. For instance, cyclo(CO-CH2-CH2-CO-His-D-Phe-Axg-Trp-Dab)-NH2 (Dab: 2,4-di-aminobutyric acid) was a potent agonist at hMC-4R (EC50 = 4 nM) with 55-fold selectivity over hMC-3R and greater than 1000-fold selectivity over hMC-5R. Another potent and selective compound was cyclo(NH-CH2-CH2-CO-His-D-Phe-Arg-Trp-Glu)-NH2: EC50 about 1 nM at hMC-4R, with 90-fold selectivity over hMC-3R and greater than 2000-fold selectivity over hMC-5R.