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Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy
journal contribution
posted on 2017-08-10, 00:00 authored by Aubrie A. Harland, Irina D. Pogozheva, Nicholas W. Griggs, Tyler J. Trask, John R. Traynor, Henry I. MosbergIn
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.