Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias

While
mu opioid receptor (MOR) agonists are especially effective
as broad-spectrum pain relievers, it has been exceptionally difficult
to achieve a clear separation of analgesia from many problematic side
effects. Recently, many groups have sought MOR agonists that induce
minimal βarrestin-mediated signaling because MOR agonist-treated
βarrestin2 knockout mice were found to display enhanced antinociceptive
effects with significantly less respiratory depression and tachyphylaxis.
Substantial data now exists to support the premise that G protein
signaling biased MOR agonists can be effective analgesic agents. We
recently showed that, within a chemical series, the degree of bias
correlates linearly with the magnitude of the respiratory safety index.
Herein we describe the synthesis and optimization of piperidine benzimidazolone
MOR agonists that together display a wide range of bias (G/βarr2).
We identify structural features affecting potency and maximizing bias
and show that many compounds have desirable properties, such
as long half-lives and high brain penetration.