We synthesized a new series of small cyclic melanocyte-stimulating hormone (MSH) analogues and screened them for binding affinity at the four MSH binding melanocortin (MC) receptors. We identified a novel substance HS131, with about 20-fold higher affinity for the MC4 receptor than the MC3 receptor. This substance proved to be antagonist for all the four MC receptors in a cAMP assay. HS131 is a six amino acid long peptide, has a molecular weight below 1000, and has only two amino acids in common with the natural MSH peptides. HS131 potently and dose dependently increased food intake after i.c.v. administration. Moreover, s.c. administration of HS131 (1.0 mg/kg) increased food intake, suggesting that HS131 may be able to pass the blood brain barrier. This cyclic low molecular weight peptidomimetic will enable studies of the functional role of the MC4 receptors by peripheral administration and it may be used as a template for further development of low molecular weight substances for the MC receptors. (C) 2003 Elsevier Science (USA). All rights reserved.