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

ABSTRACT: Kappa (?) opioid receptor selective antagonists are useful pharmacological tools in studying ? 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[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective ? 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 ? opioid receptor antagonism in the [35S]GTP?S assay (KB?=?3.2?nM) similar to arodyn. Analog 3 cyclized between Tyr(All) residues in positions 1 and 2 also exhibited nanomolar ? opioid receptor antagonist potency (KB?=?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.

SUBMITTER: Fang WJ

PROVIDER: S-EPMC6005658 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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

Fang Wei-Jie WJ Murray Thomas F TF Aldrich Jane V JV

Bioorganic & medicinal chemistry 20171121 6

Kappa (κ) opioid receptor selective antagonists are useful pharmacological tools in studying κ 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[Phe1-3,Arg4,d-Ala8]Dyn A-(1-11)NH2) is a linear acetylated dynorphin A (Dyn A) analog that is a potent and selective κ opioid receptor antagonist (Bennett et al. J Med Chem 2002;45:5617-5619) a ...[more]

PMID: 29273415

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Project description:Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

Dataset Information

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

Publications

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

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