The TIPP opioid peptide family: Development of ? antagonists, ? agonists, and mixed ? agonist/? antagonists

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Abstract
The discovery of the prototype δ 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 δ opioid antagonists with subnanomolar δ receptor binding affinity and extraordinary δ receptor selectivity include TIPP[Ψ] (H–Tyr–TicΨ[CH2NH]Phe–Phe–OH] and TICP[Ψ] (H–Tyr–TicΨ[CH2NH]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 δ opioid antagonists, which is characterized by all‐trans peptide bonds. Further structure–activity studies revealed that the δ antagonist vs δ agonist behavior of TIP(P)‐derived compounds depended on very subtle structural differences in diverse locations of the molecule and suggested a δ 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 δ agonists of the general formula H–Tyr–Tic–NH–X (X = 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 μ agonist/δ 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 μ agonist/δ antagonist DIPP‐NH2[Ψ] (H–Dmt–TicΨ[CH2NH]Phe–Phe–NH2); Dmt: 2′,6′‐ dimethyltyrosine). © 2000 John Wiley & Sons, Inc. Biopoly 51: 411–425, 1999