Ballet, Steven

Blais, V\ue9ronique

Chung, Nga N.

Eiselt, Emilie

Gendron, Louis

Hollanders, Karlijn

Holleran, Brain

Longpr\ue9, Jean-Michel

Maes, Bert

Sarret, Philippe

Schepens, Wim

Schiller, Peter W.

van Vlijmen, Herman W.T.

Willemse, Tom

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 \ub5 opioid receptor (MOP) and \u3b4 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 Phe3 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

Institutional Repository Universiteit Antwerpen

Chemical space screening around <tex>Phe^{3}$</tex> in opioid peptides : modulating \ub5 versus \u3b4 agonism by Suzuki-Miyaura cross-couplings

Chemical space screening around <tex>Phe^{3}$</tex> in opioid peptides : modulating \ub5 versus \u3b4 agonism by Suzuki-Miyaura cross-couplings

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Institutional Repository Universiteit Antwerpen