Placement of Hydroxy Moiety on Pendant of Peptidomimetic
Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy
Version 2 2018-08-10, 08:18
Version 1 2017-08-24, 20:43
Posted on 2018-08-10 - 08:18
In
an effort to expand the structure–activity relationship (SAR)
studies of a series of mixed-efficacy opioid ligands, peptidomimetics
that incorporate methoxy and hydroxy groups around a benzyl or 2-methylindanyl
pendant on a tetrahydroquinoline (THQ) core of the peptidomimetics
were evaluated. Compounds containing a methoxy or hydroxy moiety in
the o- or m-positions increased
binding affinity to the kappa opioid receptor (KOR), whereas compounds
containing methoxy or hydroxy groups in the p-position
decreased KOR affinity and reduced or eliminated efficacy at the mu
opioid receptor (MOR). The results from a substituted 2-methylindanyl
series aligned with the findings from the substituted benzyl series.
Our studies culminated in the development of 8c, a mixed-efficacy
MOR agonist/KOR agonist with subnanomolar binding affinity for both
MOR and KOR.
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Harland, Aubrie A.; Pogozheva, Irina D.; Griggs, Nicholas W.; Trask, Tyler J.; Traynor, John R.; Mosberg, Henry I. (2017). Placement of Hydroxy Moiety on Pendant of Peptidomimetic
Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy. ACS Publications. Collection. https://doi.org/10.1021/acschemneuro.7b00284
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AUTHORS (6)
AH
Aubrie A. Harland
IP
Irina D. Pogozheva
NG
Nicholas W. Griggs
TT
Tyler J. Trask
JT
John R. Traynor
HM
Henry I. Mosberg