Structure-activity relationships of the potent combined endothelinA/endothelinB receptor antagonist Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893): development of endothelinB receptor selective antagonists

The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His(16)-Leu(17)-Asp(18)-Ile(19)-Ile(20)-Trp(21)) to the development of Potent antagonists at both receptor subtypes (ET(A) and ET(B)). In particular, it has been shown that Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip(16)-Leu-Asp-Ile-Ile-Trp(21) (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ET(B) receptor selective ligands and the pharmacological differences that exist between species ET(B) receptors with respect to their affinity for C-terminal hexapeptide antagonists.