The Inverse Type II β‐Turn on D‐Trp‐Phe, a Pharmacophoric Motif for MOR Agonists

Abstract

Herein we propose the D-Trp-Phe sequence within an inverse type II β-turn as a new kind of pharmacophoric motif for μ-opioid receptor (MOR) cyclopeptide agonists. Initially, we observed that c[Tyr-D-Pro-D-Trp-Phe-Gly] (4), an analogue of endomorphin-1 (H-Tyr-Pro-Trp-Phe-NH₂) lacking the crucial protonatable amino group of Tyr 1, is a MOR agonist with 10⁻⁸ M affinity. Molecular docking analysis suggested that the relevant interactions with the receptor involve D-Trp-Phe. The bioactive conformation of this region was investigated by selected derivatives of 4 designed to adopt an inverse type II β-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclotetrapeptide c[D-Asp-1-amide-β-Ala-D-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the κ- and δ-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse β-turn in binding. These results indicate that the D-Trp-Phe inverse β-turn structure can be used for designing non-endomorphin-like peptidomimetic opioid agonists in general, characterized by an atypical mechanism of interaction between ligand and receptor.

Molecular Docking of Opiates and Opioid Peptides, a Tool for the Design of Selective Agonists and Antagonists, and for the Investigation of Atypical Ligand-Receptor Interactions

“…Among the new cyclopeptides, c[Tyr-Gly-D-Trp-PheGly], CycloEM/3, proved to be a selective ligand of MOR with nanomolar affinity, almost as good as the reference DAMGO, and about 10-fold better compared to the parent CycloEM/1 (18), a very good result for a compound lacking of the cationic amino group [126]. Another compound c[Tyr-Ala-D-Trp-Ala-Gly] was a selective, modest ligand of the DOR, and c[Tyr-Gly-D-Trp-AlaGly] had a significant affinity and selectivity for the KOR.…”

Macrocyclic Inhibitors of GPCR's, Integrins and Protein–Protein Interactions

“…Molecular docking investigations suggest an inverse type II b-turn geometry centered on D TrpPhe to be important for activity. 142 This model is corroborated by the synthesis of cyclopeptide 72, which was not based on endomorphin-1 and which showed high affinity at the m-receptor and partial agonist activity. Peptide 72 was found to adopt an inverse type II b-turn conformation around the D TrpPhe residues in solution, stabilized by an H-bond between the b-Ala carbonyl and the D Asp NH group.…”

“…Peptide 72 was found to adopt an inverse type II b-turn conformation around the D TrpPhe residues in solution, stabilized by an H-bond between the b-Ala carbonyl and the D Asp NH group. 142 …”

Cyclic side-chain-linked opioid analogs utilizing cis - and trans -4-aminocyclohexyl- d -alanine

“…We utilized the models of hMOR and hDOR previously reported by us 18 and subsequently validated using the crystallographic structure obtained in 2012. 19 The initial structures of the ligands were the ROESY-derived structures of the cyclopeptides shown in Figure 1.…”

“…Docking studies with MOR and DOR 17 were performed for the most representative peptides 1, 2c and 2t. In the docking experiments, our models of human MOR (hMOR) and DOR (hDOR), 18 obtained by homology modelling and subsequently validated using the crystallographic structure obtained in 2012, 19 were used as targets. Initially we explored the possible binding positions and binding modes of the ligands within each rigid receptor environment.…”