Synthesis and Biological Activity of Terlipressin and its Putative Metabolites

Introduction Terlipressin (H-Gly3-LVP, GLYPRESSIN ® [1]), 1, is a peptide drug approved in some European and Asian countries for the treatment of bleeding esophageal varices and in France for hepatorenal syndrome. It presumably acts on the vasopressin 1a receptor (V1a-R), whose endogenous ligand is arginine vasopressin (AVP), to increase peripheral vascular resistance leading to increase in arterial blood pressure (ABP). Although 1 and AVP have both been used clinically to correct syndromes of inappropriate vasodilatation, 1 has much longer onset and duration of action [2,3]. It is hypothesized that 1 acts as a pro-drug and that its onset and duration of action are due to successive cleavage of the glycine N-terminal moieties to ultimately produce lysine vasopressin (LVP, 4). Each of the putative metabolites 2-4 would be biologically active. To determine the biological activity of the metabolites and further investigate the mechanism of action of 1, the peptides 1-4 were synthesized and tested both in vivo and in vitro.