Design, synthesis, and opioid activity of arodyn analogs cyclized by ring-closing metathesis involving Tyr(allyl)

Kappa (kappa) opioid receptor selective antagonists are useful pharmacological tools in studying kappa opioid receptors and have potential to be used as therapeutic agents for the treatment of a variety of diseases including mood disorders and drug addiction. Arodyn (Ac[Phe(1-3), Arg(4), D-Ala(8)] Dyn A-(1-11) NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective kappa opioid receptor antagonist (Bennett et al. J Med Chem 2002; 45: 5617-5619) and prevents stress-induced reinstatement of cocaine-seeking behavior following central administration (Carey et al. Eur J Pharmacol 2007; 569: 84-89). To restrict its conformational mobility, explore possible bioactive conformations and potentially increase its metabolic stability we synthesized cyclic arodyn analogs on solid phase utilizing a novel ring-closing metathesis (RCM) reaction involving allyl-protected Tyr (Tyr(All)) residues. This approach preserves the aromatic functionality and directly constrains the side chains of one or more of the Phe residues. The novel cyclic arodyn analog 4 cyclized between Tyr(All) residues incorporated in positions 2 and 3 exhibited potent kappa opioid receptor antagonism in the [S-35] GTP gamma S assay (K-B = 3.2 nM) similar to arodyn. Analog 3 cyclized between Tyr(All) residues in positions 1 and 2 also exhibited nanomolar kappa opioid receptor antagonist potency (K-B = 27.5 nM) in this assay. These are the first opioid peptides cyclized via RCM involving aromatic residues, and given their promising pharmacological activity represent novel lead peptides for further exploration. (C) 2017 Elsevier Ltd. All rights reserved.