title: 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.
authors: Department of Chemistry "G. Ciamician", University of Bologna, via Selmi 2, 40126 Bologna, Italy. luca.gentilucci@unibo.it
authors: Luca
authors: L
authors: Gentilucci
authors: Alessandra
authors: A
authors: Tolomelli
authors: Rossella
authors: R
authors: De Marco
authors: Santi
authors: S
authors: Spampinato
authors: Andrea
authors: A
authors: Bedini
authors: Roberto
authors: R
authors: Artali
mesh_terms: D000465:Algorithms; D020816:Amino Acid Motifs; D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D004151:Dipeptides; D008024:Ligands; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105293:endomorphin 1; C028281:phenylalanyltryptophan