6 Development of Receptor-Specific Opioid Peptide Analogues

Abstract

This chapter discusses the development of receptor-specific opioid peptide analogs. The development of receptor-specific opioids is of great importance, not only for the elucidation of the physiological roles of the various opioid receptor types but also for the development of potential drugs with minimal side-effects. Considerable progress has been made in recent years in the development of receptor-selective nonpeptide opioid agonists, and antagonists and some of the most selective ones are mentioned. In the opioid peptide field, most of the analogs prepared to date are structurally derived from the enkephalins; however, interesting analogs of the bcasomorphins, dermorphins, dynorphins, and pendorphin have also been developed. Various approaches have been taken to develop receptor-selective opioid peptide analogs, and the following design principles are discussed in the chapter: (a) Substitution, deletion or addition of natural or artificial (nonproteinogenic) amino acids, (b) Design of bivalent ligands containing two opioid peptide moieties separated by a spacer of appropriate length and interacting simultaneously with two receptor-binding sites, (c) The concept of conformational restriction as achieved primarily through appropriate peptide cyclizations, and (d) Peptide bond replacements.