Novel highly potent μ-opioid receptor antagonist based on endomorphin-2 structure

Ligand-Directed Functional Selectivity at the Mu Opioid Receptor Revealed by Label-Free Integrative Pharmacology On-Target

“…In addition, we characterized the DMR response of HEK-MOR cells utilizing known MOR selective (CTOP and β-funaltrexamine), as well as opioid non-selective (naloxone) antagonists. We performed a dose response analysis and determined the EC 50 for each ligand tested and compared our results to the potency previously reported in the literature [28]–[30].…”

Novel Opioid Peptide Derived Antagonists Containing (2S)-2-Methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic Acid [(2S)-Mdcp]

“…It has 2-3-fold higher μ antagonist activity than Dcp-c[D-Cys-Gly-Phe( p NO 2 )-D-Cys]NH 2 7 and similar μ receptor binding selectivity, and is a more potent and more selective μ antagonist than Dhp-c[N ε ,N β -carbonyl-D-Lys 2 ,Dap 5 ]enkephalinamide (K i μ = 15.5 nM, K i δ = 273 nM) 4. Furthermore, compound 1 has higher μ antagonist potency and higher μ receptor binding selectivity than the endomorphin-derived μ antagonists antanal-1 ([Dmt 1 ,D-2-Nal 4 ]endomorphin-1; K i μ = 2.38 nM, K i δ = 17.4 nM) and antanal-2 ([Dmt 1 ,D-2-Nal 4 ]endomorphin-2; K i μ = 1.52 nM, K i δ = 7.74 nM)16, and higher μ antagonist potency but lower μ-selectivity than the tetrapeptide H-Dmt-Sar-Phe-D-Nal-NH 2 (K e μ = 2.34 nM, K e δ = 305 nM) 17. These various opioid peptide-derived μ antagonists are of interest because their mode of binding to the μ opioid receptor is likely to be different from that of the somatostatin-derived μ antagonists.…”

Design, Synthesis and Pharmacological Evaluation of Novel Endomorphin Analogues with Multiple Structural Modifications

“…These results confirm that each class of opioid peptides shows distinct chiral requirements for the spacers between the biologically important Tyr and Phe residues [47]. Introduction of a polar -OH group on the Pro 2 side chain and the extension of the backbone by a -CH 2 -group, while preserving the tertiary amide moiety of Pro has disadvantageous effects on µ-opioid receptor activity of EM-2 in general, regardless of different experimental conditions [142]. However, the observed effect of βPro 2 substitution may not be applicable generally for all µ-opioid receptor ligands, since in a previous study βPro-EM-1 exhibited µ-opioid receptor affinity, efficacy and agonist behavior similar to those of DAMGO and EM-1 [130].…”