The sarafotoxins (SRTXs) are a family of 21-amino acid bicyclic peptides that are structurally similar to the potent vasoconstrictors, the endothelins (ETs). SRTX-6c exhibits high selectivity for the ETB receptor subtype over the ETA subtype. This selectivity may be a result of a modification at positions 9 or 13, which are Glu9 and Asn13 in SRTX-6c and Lys9 and Tyr13 in ET-1. The truncated linear endothelin [Ala11,15]ET-18-21 was also on ETB receptor-selective ligand with 6-nM binding affinity. Therefore, a series of truncated endothelin/sarafotoxin (8-21) hybrid analogues were prepared, varying the amino acid at residues 9 and/or 13. These peptides were assayed for binding in tissues selectively expressing either the ETA or the ETB receptor subtypes. All linear analogues showed poor ETA binding, while ETB affinity was sequence dependent. Monocyclic 11-15 disulfide-containing analogues failed to bind to either ETA or ETB receptors at concentrations of up to 10 microM.