Chemical space screening around Phe3 in opioid peptides: Modulating µ versus δ agonism by Suzuki-Miyaura cross-couplings. Issue 13 (15th July 2018)

• Record Type: Journal Article
• Authors: Willemse, Tom; Eiselt, Emilie; Hollanders, Karlijn; Schepens, Wim; van Vlijmen, Herman W.T.; Chung, Nga N.; Blais, Véronique; Holleran, Brain; Longpré, Jean-Michel; Schiller, Peter W.; Maes, Bert U.W.; Sarret, Philippe; Gendron, Louis; Ballet, Steven
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 13(2018)
• Page Start: 2320
• Page End: 2323
• Publication Date: 2018-07-15
• Subjects: BRET bioluminescence resonance energy transfer -- cAMP cyclic adenosine monophosphate -- Dmt 2, 6-dimethyltyrosine -- DOP δ-opioid receptor -- EC50 half maximal effective concentration -- EPAC exchange protein directly activated by cAMP -- GPI guinea pig ileum -- IC50 half maximal inhibitory concentration -- Ki inhibitory constant -- KOP κ-ipioid receptor -- MOP µ-opioid receptor -- MVD mouse vas deferens -- P.A. partial agonist -- TES triethylsilane; Opioid peptides -- GPCR ligands -- Non-natural amino acids -- Suzuki-Miyaura cross coupling -- Receptor selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.05.015
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Dmt-dermorphin[1–4] analogs were tested at the opioid receptors. Solid-phase and solution-phase Suzuki-Miyaura cross-couplings. Chemical space screening around the Phe 3 side chain in Dmt-dermorphin[1–4] analogs. Abstract: In this study, affinities and activities of derivatized analogues of Dmt-dermorphin[1–4] (i.e. Dmt-d -Ala-Phe-GlyNH2, Dmt = 2′, 6′-dimethyl-( S )-tyrosine) for the µ opioid receptor (MOP) and δ 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.