Developments in the Structure-Activity Relationships for the o-Selective Opioid Peptides of Amphibian Skin

Abstract

As endogenous chemical messengers of biological information, peptides represent a promising class of compounds for the preliminary stages of pharmaceutical development. Amphibian skin has proven to be a valuable source of opioid peptides which demonstrate remarkable specificity for 1-L or 8 opioid receptors. The deltorphin family, opiate-like analgesic heptapeptides consisting of deltorphin I, deltorphin II and dermenkephalin, bind with high affinity and inherent selectivity at 8 sites. These parent peptide compounds have been investigated extensively, primarily by modifi­cation of amino acid residues to vary physicochemical (steric, electronic, hydrophobic) and conformational properties. Examination of receptor binding and bioactivity data has allowed the development of structure-activity relationships, which have shed some light on the characteristics that are important in the binding interaction at each receptor type. Since the 1-L and 8 receptors appear to mediate different pharmacological effects, factors influencing receptor discrimination also have been studied. In this way, both the exact physiological role and the ligand preferences of each receptor type may be probed. The ultimate goal is the rational design of an opiate peptidomimetic drug with analgesic properties, yet devoid of the addictive and other adverse side effects currently associated with opiate treatment. This review · summarizes current knowledge of deltorphin structure-activity relationships for each residue, both for elements which are part of the binding pharmacophore and for those that play a conformational role.