Opioid receptor binding characteristics and structure-activity studies of novel tetrapeptides in the TIPP (Tyr-Tic-Phe-Phe) series.

Abstract

The development of the prototype synthetic delta-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe- Phe-OH); Tic: tetrahydroisoquinoline-3-carboxylic acid] and TIPPpsi (H-Tyr-psiTic-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 beta-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 potency and delta- versus mu-opioid receptor selectivity were evaluated by in vitro radioreceptor-binding assays, while the intrinsic G-protein-activating efficacy of these analogs was tested in [35S]GTPgammaS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing mu- or delta-opioid receptors. The analogs showed delta-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed mu-agonist/delta-antagonist profile, thus they are expected to be safer analgesics with a low propensity to produce tolerance and physical dependence. These results constitute further examples of the influence of beta-methyl substitution and C-terminal amidation on potency, selectivity, and signal transduction properties of TIPP-related peptides as well as they represent valuable pharmacological tools for opioid research.

• Authors: Eniko Ioja, Géza Tóth, Sándor Benyhe, Dirk Tourwe, Antal Péter, Csaba Tömböly, Anna Borsodi
• Journal: Neuro-Signals (Neurosignals) Vol. 14 Issue 6 Pg. 317-28 ( 2005) ISSN: 1424-862X [Print] Switzerland
• PMID: 16772734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2005 S. Karger AG, Basel.

Chemical References

• Analgesics, Opioid
• Oligopeptides
• Receptors, Opioid
• Receptors, Opioid, delta
• Receptors, Opioid, mu
• Tetrahydroisoquinolines
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine
• Guanosine 5'-O-(3-Thiotriphosphate)

Topics

• Analgesics, Opioid (pharmacology)
• Animals
• CHO Cells
• Cell Membrane (drug effects, metabolism)
• Cells, Cultured
• Cricetinae
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (pharmacology)
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• In Vitro Techniques
• Molecular Conformation
• Oligopeptides (chemistry, metabolism, pharmacology)
• Radioligand Assay
• Rats
• Rats, Wistar
• Receptors, Opioid (drug effects, metabolism)
• Receptors, Opioid, delta (drug effects)
• Receptors, Opioid, mu (drug effects)
• Structure-Activity Relationship
• Tetrahydroisoquinolines (chemistry, metabolism, pharmacology)