MOR antagonist 2 hydrochloride

MOR antagonist 2 hydrochloride is a μ-opioid receptor (MOR) antagonist that can cross the blood-brain barrier. It exhibits an IC50 of 28.37 nM, an EC50 of 4.25 nM, and a Ki of 0.18 nM at MOR. This compound stabilizes the inactive conformation of MOR, thereby reducing receptor activation levels. In mice, MOR antagonist 2 hydrochloride counteracts analgesic effects in the warm-water tail-flick test and induces fewer opioid withdrawal symptoms, such as wet-dog shakes and paw tremors. It is applicable in researching opioid use disorder.

μ Opioid Receptor/MOR:28.37 nM

MOR antagonist 2 hydrochloride (Compound 7) (1.5 h) demonstrates high binding affinity for MOR with a K i value of 0.18 nM. In CHO cell membrane preparations, its selectivity for KOR (K i = 2.93 nM) is 16 times greater and for DOR (K i = 30.44 nM) is 169 times greater. It acts as a low-efficacy partial agonist for MOR, with an EC 50 of 4.25 nM in [35 S]-GTPγS binding assays. Additionally, MOR antagonist 2 hydrochloride exhibits high metabolic stability in human liver S9 fractions and shows high plasma protein binding in both human and mouse plasma. It also displays good passive intestinal permeability, low baseline efflux, and functions as a substrate for P-gp and BCRP transport proteins in Caco-2 cells.

MOR antagonist 2 hydrochloride (10 mg/kg; s.c.; once) reduces MPE in mice subjected to warm water tail immersion, proving to be a potent μ-opioid receptor antagonist with an AD 50 of 0.09 mg/kg. Compound 7 (0.1-5 mg/kg; s.c.; once) significantly diminishes opioid withdrawal symptoms (wet-dog shakes and paw tremors) in opioid-withdrawn mice, compared to equivalent or higher doses of Naloxone, while maintaining similar μ-opioid receptor antagonist activity.