Abstract：
:With the hope of discovering effective analgesics with fewer side effects, attention has recently shifted to allosteric modulators of the opioid receptors. In the past two years, the first chemotypes of positive or silent allosteric modulators (PAMs or SAMs, respectively) of μ- and δ-opioid receptor types have been reported in the literature. During a structure-guided lead optimization campaign with μ-PAMs BMS-986121 and BMS-986122 as starting compounds, we discovered a new chemotype that was confirmed to display μ-PAM or μ-SAM activity depending on the specific substitutions as assessed by endomorphin-1-stimulated β-arrestin2 recruitment assays in Chinese Hamster Ovary (CHO)-μ PathHunter cells. The most active μ-PAM of this series was analyzed further in competition binding and G-protein activation assays to understand its effects on ligand binding and to investigate the nature of its probe dependence.
journal_name
J Chem Inf Modeljournal_title
Journal of chemical information and modelingauthors
Bisignano P,Burford NT,Shang Y,Marlow B,Livingston KE,Fenton AM,Rockwell K,Budenholzer L,Traynor JR,Gerritz SW,Alt A,Filizola Mdoi
10.1021/acs.jcim.5b00388subject
Has Abstractpub_date
2015-09-28 00:00:00pages
1836-43issue
9eissn
1549-9596issn
1549-960Xjournal_volume
55pub_type
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