Probing Opioid Receptor Interactions with Azacycloalkane Amino Acids. Synthesis of a Potent and Selective ORL1 Antagonist

Azacycloalkane turn mimics 6−9 were used to explore the relationship between conformation and biological activity of peptide ligands to the opioid receptor-like (ORL1) receptor. Three azabicyclo[x.y.0]alkane amino acids and a 5-tBuPro type VI β-turn mimic were introduced into peptides 10−13 by solid-phase synthesis on MBHA resin. Biological examination of peptides 10−13 showed two new antagonists (10 and 12) exhibiting increased selectivity for the ORL1 receptor.