The discovery of the prototype ␦ opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 was followed by extensive structure-activity relationship studies, leading to the development of analogues that are of interest as pharmacological tools or as potential therapeutic agents. Stable TIPP-derived ␦ opioid antagonists with subnanomolar ␦ receptor binding affinity and extraordinary ␦ receptor selectivity include TIPP [⌿]
(H-Tyr-Tic⌿[CH 2 NH]Phe-Phe-OH] and TICP[⌿] (H-Tyr-Tic⌿[CH 2 NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research. Theoretical conformational analyses in conjunction with the pharmacological characterization of conformationally constrained TIPP analogues led to a definitive model of the receptor-bound conformation of H-Tyr-Tic-(Phe-Phe)-
OH-related ␦ opioid antagonists, which is characterized by all-trans peptide bonds. Further structure-activity studies revealed that the ␦ antagonist vs ␦ agonist behavior of TIP(P)-derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a ␦ receptor model involving a number of different inactive receptor conformations. A further outcome of these studies was the identification of a new class of potent and very selective dipeptide ␦ agonists of the general formula H-Tyr-Tic-NH-X (X ϭ arylalkyl), which are of interest for drug development because of their low molecular weight and lipophilic character. Most interestingly, TIPP analogues containing a C-terminal carboxamide group displayed a mixed agonist/␦ antagonist profile, and thus were expected to be analgesics with a low propensity to produce tolerance and physical dependence. This turned out to be the case with the TIPP-derived agonist/␦ antagonist DIPP-NH 2 [⌿] (H-Dmt-Tic⌿[CH 2 NH]Phe-Phe-NH 2 ); Dmt: 2Ј,6Јdimethyltyrosine).