d-Opioid Receptor Antagonists  are a novel class of synthetic opioid peptide ligands with enhanced potency and selectivity toward d -opioid receptors1.

Related Peptides
The original structure of TIPP, i.e., H-Tyr-Tic-Phe-Phe-OH, was further modi?ed by systematic side-chain replacements with nonconventional amino acids to produce novel d-opioid receptor antagonists. These unnatural amino acids were selected on the basis of their capability to possess well-de?ned side-chain conformations1.

The discovery of the prototype d-opioid antagonists TIPP (H-Tyr-Tic-Phe-Phe-OH) and TIP (H-Tyr-Tic-Phe-OH) in 1992 by Schiller and coworkers 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 d-opioid antagonists with subnanomolar delta receptor binding affinity and extraordinary delta receptor selectivity include TIPP[?] (H-Tyr-Tic?[CH2NH]Phe-Phe-OH] and TICP[?] (H-Tyr-Tic? [CH2NH]Cha-Phe-OH); Cha: cyclohexylalanine), which are widely used in opioid research2.

Structural Characteristics
The development of the prototype synthetic d-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe- Phe-OH); Tic: tetrahydroisoquinoline-3-carboxylic acid] and TIPP ? (H-Tyr- ? Tic-Phe-Phe-OH) by Schiller and coworkers was followed by extensive structure-activity relationship studies, leading to the emergence of numerous analogs that are of pharmacological interest. Eight novel diastereomeric compounds in this peptide family were designed, prepared, and tested biologically to gain structure-activity relationship information. The new multisubstituted tetrapeptide analogs contain both a 2', 6’-dimethyltyrosine residue at the N-terminus and ß-methyl-cyclohexylalanine at the third position as replacements for the original first tyrosine and the third phenylalanine, respectively. These derivatives wear either free acidic (-COOH) or amidated (-CONH2) C-terminal. The analogs show d-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed µ-agonist/ d-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. The identification of potent and very selective dipeptide µ-agonists of the general formula H-Tyr-Tic-NH-arylalkyl are of interest for drug development because of their low molecular weight and their lipophilic character. The conformational constraints imposed by the Tic residue eventuates the d-antagonist properties. Addition of methyl groups at the second and sixth position of the tyrosine moiety forming 2-6-dimethyltyrosine (Dmt) and combining it with the Tic pharmacophore resulted in Dmt-Tic dipeptide with enhanced/remarkable d-antagonist potency and unprecedented d-receptor selectivity1.

Mode of Action
These peptide antagonists mediate their action by competing with the normal opioid substances for the d-opioid receptor sites 1.

These novel tetrapeptide opioid ligands may serve as useful pharmacological and therapeutic agents and they can represent valuable experimental tools in research and probably in medicine2.



1.     Ioja E, Tóth G, Benyhe S, Tourwe D, Péter A, Tömböly C, Borsodi A (2005). Opioid Receptor Binding Characteristics and Structure-Activity Studies of Novel Tetrapeptides in the TIPP (Tyr-Tic-Phe-Phe) series. Neurosignals, 14(6):317-328.

2.     Schiller PW, Nguyen TM, Weltrowska G, Wilkes BC, Marsden BJ, Lemieux C (1992). Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists. PNAS, 89(24):11871-11875.

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