Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy

Published on 2018-08-10T08:18:57Z (GMT) by
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 <i>o-</i> or <i>m-</i>positions increased binding affinity to the kappa opioid receptor (KOR), whereas compounds containing methoxy or hydroxy groups in the <i>p</i>-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 <b>8c</b>, 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. (2018): Placement of Hydroxy Moiety on Pendant of Peptidomimetic

Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy. ACS Publications. Collection.