The development of the prototype synthetic δ-opioid receptor antagonist peptides TIPP [(H-Tyr-Tic-Phe-Phe-OH); Tic: tetrahydroisoquinoline-3- carboxylic acid] and TIPPψ (H-Tyr-ψTic-Phe-Phe-OH) by Schiller and co-workers 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 β-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 δ- versus μ-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]GTPγS-binding assays using rat brain membranes or Chinese hamster ovary cells stably expressing μ- or δ-opioid receptors. The analogs showed δ-antagonist selectivity with differences regarding their isomeric forms, and these analogs containing a C-terminal carboxamide group displayed a mixed μ-agonist/δ-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 β-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.
ASJC Scopus subject areas
- Developmental Neuroscience
- Cellular and Molecular Neuroscience