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

Autor:	Harland AA; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States., Pogozheva ID; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States., Griggs NW; Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States., Trask TJ; Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States., Traynor JR; Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States., Mosberg HI; Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , Ann Arbor, Michigan 48109, United States.; Interdepartmental Program in Medicinal Chemistry, University of Michigan , Ann Arbor, Michigan 48109, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2017 Nov 15; Vol. 8 (11), pp. 2549-2557. Date of Electronic Publication: 2017 Aug 25.
DOI:	10.1021/acschemneuro.7b00284
Abstrakt:	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.
Databáze:	MEDLINE
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