Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR.

ABSTRACT: The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named C6guano. Presently, to improve systemic activity of this ligand, we used structure-based design, identifying a new ligand named RO76 where the flexible alkyl linker and polar guanidine guano group is swapped with a benzyl alcohol, and the sodium site is targeted indirectly through waters. A cryoEM structure of RO76 bound to the μOR-G_i complex confirmed that RO76 interact

SUBMITTER: Ople RS 

PROVIDER: S-EPMC11363324 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature