TY - JOUR
T1 - Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the ΰ Opioid Receptor
AU - Ramos-Colon, Cyf N.
AU - Lee, Yeon Sun
AU - Remesic, Michael
AU - Hall, Sara M.
AU - Lavigne, Justin
AU - Davis, Peg
AU - Sandweiss, Alexander J.
AU - McIntosh, Mary I.
AU - Hanson, Jessica
AU - Largent-Milnes, Tally M.
AU - Vanderah, Todd W.
AU - Streicher, John
AU - Porreca, Frank
AU - Hruby, Victor J.
N1 - Funding Information:
This work has been supported by U.S. Public Health Services, NIH, and NIDA (Grants RO1 DA 13449 and PO1 DA 006284).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/11/23
Y1 - 2016/11/23
N2 - Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the ΰ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.
AB - Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the ΰ opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.
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U2 - 10.1021/acs.jmedchem.6b01411
DO - 10.1021/acs.jmedchem.6b01411
M3 - Article
C2 - 27797517
AN - SCOPUS:84999700097
VL - 59
SP - 10291
EP - 10298
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 22
ER -