Gentilucci, Luca; Tolomelli, Alessandra; De Marco, Rossella; Spampinato, Santi; Bedini, Andrea; Artali, Roberto
The Inverse Type II beta-Turn on D-Trp-Phe, a Pharmacophoric Motif for MOR Agonists
CHEMMEDCHEM, 6:1640-1653, SEP 5 2011

Herein we propose the D-Trp-Phe sequence within an inverse type II beta-turn as a new kind of pharmacophoric motif for mu-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-NH(2)) lacking the crucial protonatable amino group of Tyr1, 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 beta-turn. These efforts led to c[Tyr-Gly-D-Trp-Phe-Gly] (14) and to the cyclote-trapeptide c[D-Asp-1-amide-beta-Ala-d-Trp-Phe] (15), showing improved nanomolar affinity. Both 14 and 15 selectively bind MOR, as they have negligible affinity for the kappa- and delta-opioid receptors. Both 14 and 15 behave as partial MOR agonists in functional assays. Conformational and docking analyses confirm the role of the inverse b-turn in binding. These results indicate that the D-Trp-Phe inverse b-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.

DOI:10.1002/cmdc.201100169

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