Placement of Hydroxy Moiety on Pendant of Peptidomimetic Scaffold Modulates Mu and Kappa Opioid Receptor Efficacy
| Autor: | Henry I. Mosberg, Aubrie A. Harland, Irina D. Pogozheva, Nicholas W. Griggs, John R. Traynor, Tyler J. Trask |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Protein Conformation Physiology Peptidomimetic Drug Evaluation Preclinical Receptors Opioid mu (+)-Naloxone Biochemistry Mixed-efficacy opioid ligands Mice 0302 clinical medicine Cricetinae Receptors Opioid delta Moiety mu opioid receptor agonist Naloxone Chemistry kappa opioid receptor agonist General Medicine Analgesics Opioid structure−activity relationships μ-opioid receptor Protein Binding Research Article medicine.drug Agonist medicine.drug_class Stereochemistry Cognitive Neuroscience CHO Cells κ-opioid receptor Structure-Activity Relationship 03 medical and health sciences Cricetulus Cell Line Tumor mental disorders medicine Animals Humans Structure–activity relationship Receptors Opioid kappa Cell Biology Enkephalin Ala(2)-MePhe(4)-Gly(5) Rats 030104 developmental biology Opioid Guanosine 5'-O-(3-Thiotriphosphate) peptidomimetics Enkephalin D-Penicillamine (2 5) 030217 neurology & neurosurgery |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| DOI: | 10.1021/acschemneuro.7b00284 |
| Popis: | 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: | OpenAIRE |
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