Conformational Constraint between Aromatic Residue Side Chains in the “Message” Sequence of the Peptide Arodyn Using Ring Closing Metathesis Results in a Potent and Selective Kappa Opioid Receptor Antagonist

Kappa
opioid receptor (KOR) antagonists have recently shown potential
for treating drug addiction and mood disorders. The linear acetylated
dynorphin A analog arodyn (Ac­[Phe1,2,3,Arg4,d-Ala8]­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 (KB = 15 nM) similar to arodyn. These promising
cyclized analogs with constrained aromatic residues represent novel
leads for further exploration of KOR pharmacology.