Synthesis, pharmacology, and structural analysis of opioid peptides: Cyclic somatostatin analogs which include unusual amino acids with conformationally restricted side-chain groups

Abstract

This work relates the activities of Somatostatin-derived opioid peptides to their 3-dimensional structures. Due to the flexability of peptides, they adopt multiple conformations. This flexibility leads to ambiguity in the development of structure-activity profiles. Here flexibility is reduced by incorporation of amino acids with conformationally restricted side-chain groups. These groups are restricted to certain topographies by cyclization or biased through substitution at the beta carbon. The opioid activities of these peptides are determined by brain binding radioligand competition assay, in vitro activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) smooth muscle twitch-height inhibition assays, and in vivo in the mouse warm water tail-flick latency assay. Their 3-dimensional structures were determined through a variety of 2D 1H NMR including TOCSY, ROESY, DQF-COSY, and COSY-35, as well as molecular modeling including energy minimization and molecular dynamics. By knowing the activity of the peptides, and their preferred conformations, a reasonably confident structure-activity profile was generated.