A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects

Mitragynine and 7-hydroxymitragynine
(7OH) are the major alkaloids
mediating the biological actions of the psychoactive plant kratom.
To investigate the structure–activity relationships of mitragynine/7OH
templates, we diversified the aromatic ring of the indole at the C9,
C10, and C12 positions and investigated their G-protein and arrestin
signaling mediated by mu opioid receptors (MOR). Three synthesized
lead C9 analogs replacing the 9-OCH3 group with phenyl
(4), methyl (5), or 3′-furanyl [6 (SC13)] substituents demonstrated partial agonism
with a lower efficacy than DAMGO or morphine in heterologous G-protein
assays and synaptic physiology. In assays limiting MOR reserve, the
G-protein efficacy of all three was comparable to buprenorphine. 6 (SC13) showed MOR-dependent analgesia with
potency similar to morphine without respiratory depression, hyperlocomotion,
constipation, or place conditioning in mice. These results suggest
the possibility of activating MOR minimally (G-protein Emax ≈ 10%) in cell lines while yet attaining maximal
antinociception in vivo with reduced opioid liabilities.