Chemical space screening around Phe(3) in opioid peptides: Modulating mu versus delta agonism by Suzuki-Miyaura cross-couplings

In this study, affinities and activities of derivatized analogues of Dmt-dermorphin[1-4] (i.e. Dmt-D-Ala-Phe-GIyNH(2), Dmt = 2',6'-dimethyl-(S)-tyrosine) for the mu opioid receptor (MOP) and delta opioid receptor (DOP) were evaluated using radioligand binding studies, functional cell-based assays and isolated organ bath experiments. By means of solid-phase or solution-phase Suzuki-Miyaura cross-couplings, various substituted regioisomers of the phenylalanine moiety in position 3 of the sequence were prepared. An 18-membered library of opioid tetrapeptides was generated via screening of the chemical space around the Phe(3) side chain. These substitutions modulated bioactivity, receptor subtype selectivity and highly effective ligands with subnanomolar binding affinities, contributed to higher functional activities and potent analgesic actions. In search of selective peptidic ligands, we show here that the Suzuki-Miyaura reaction is a versatile and robust tool which could also be deployed elsewhere. (C) 2018 Elsevier Ltd. All rights reserved.