Subtleties of structure-agonist versus antagonist relationships of opioid peptides and peptidomimetics

The development of novel delta opioid antagonists and delta opioid agonists structurally derived from the prototype delta antagonist TIPP (H-Tyr-Tic P he-Phe-OH), is reviewed. Both delta antagonists and delta agonists with ext raordinary potency and unprecedented delta receptor selectivity were discov ered. Some of them are already widely used as pharmacological tools and are also of interest as potential therapeutic agents for use in analgesia. The results of the performed structure-activity studies revealed that the delt a antagonist versus delta agonist behavior of this class of compounds depen ded on very subtle structural differences in diverse locations of the molec ule. These observations can be best explained with a receptor model involvi ng a number of different inactive and active receptor conformations.