Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 6, Pages 3153-3164Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01984
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- National Institute on Drug Abuse [R01 DA018832]
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Kappa opioid receptor (KOR) antagonists, such as the newly synthesized cyclized analogs, have shown promising potential in treating drug addiction and mood disorders by stabilizing bioactive conformation and enhancing metabolic stability. This cyclization strategy provides novel leads for further exploration of KOR pharmacology.
Kappa opioid receptor (KOR) antagonists have recently shown potential for treating drug addiction and mood disorders. The linear acetylated dynorphin A analog arodyn (Ac[Phe(1,2,3),Arg(4),D-Ala(8)]dynorphin A-(1-11)NH2), synthesized in our laboratory, demonstrated potent and selective KOR antagonism. Cyclization of arodyn could potentially stabilize the bioactive conformation and enhance its metabolic stability. The cyclization strategy employed involved ring closing metathesis between adjacent meta- or para-substituted Tyr(allyl) residues in the message sequence that were predicted in a docking study to yield analogs that would bind to the KOR with binding poses similar to arodyn. Consistent with the modeling, the resulting analogs retained KOR affinity similar to arodyn; the peptides involving cyclization between para O-allyl groups also retained high KOR selectivity, with one analog exhibiting KOR antagonist potency (K-B = 15 nM) similar to arodyn. These promising cyclized analogs with constrained aromatic residues represent novel leads for further exploration of KOR pharmacology.
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