While mu opioid receptors are the primary therapeutic target for treatment of pain and drug abuse, kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and depression. Arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]Dyn A(1-11)-NH2), an acetylated dynorphin A (Dyn A) analog synthesized in our laboratory, demonstrated potent and selective KOR antagonism but is rapidly metabolized by proteases. Cyclization of arodyn could enhance metabolic stability and potentially stabilize the bioactive conformation. Accordingly, a cyclization strategy involving ring closing metathesis (RCM) of O-allyl groups was pursued. However, side reactions involving olefin isomerization limited the scope of the RCM reactions, especially their use to probe how modification of important aromatic residues affects the peptide’s pharmacological activity. The optimization of the synthetic methodology (including employing microwave heating and isomerization suppressants) using a model dipeptide and its application to the synthesis of arodyn analogs will be presented. The resulting analogs were evaluated for their opioid receptor binding affinities, and promising cyclized analogs that retained high KOR affinity and selectivity were identified.

Conformational constraint of aromatic residues of the kappa opioid receptor antagonist arodyn using ring closing metathesis

2019 Spring National Meeting

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