Refinement of the pharmacophore of an agonist ligand of the secretin receptor using conformationally constrained cyclic hexapeptides

There is a compelling need for the development of small molecule agonists acting at family B G protein-coupled receptors. A possible lead for the development of such drugs was reported when it was recognized that sequences endogenous to the amino terminus of the secretin receptor and certain other receptors in this family possess weak full agonist activity (Dong et al. Mol Pharmacol 2006;70:206–213). In the current report, we extended those observations by building the active dipeptide motif found in the secretin receptor (WD) into each position around a conformationally constrained d-amino acid-containing cyclic hexapeptide, and determining the biological activity of each peptide at the secretin receptor. Indeed, only two positions for WD around this constrained ring resulted in biological activity at the receptor, providing further insights into the structural specificity of this phenomenon. Molecular modeling supported the presence of a unique WD backbone conformation shared only by these active peptides, and provided a more constrained template for future receptor-active agonist drug development.