MOR modulator-1 (compound 6) is a potent and selective modulator of the μ opioid receptor (MOR). Compared to NAT (6α-configuration), MOR modulator-1 demonstrates improved opioid receptor selectivity, enhanced antagonistic effects in vivo, and overall reduced withdrawal symptoms. It connects to the μ, δ, and γ receptors with carboxamide linkers, showing Ki values of 0.25, 41.1, and 1.30 nM respectively.

δ opioid receptor:41.1 nM(Ki)

MOR modulator-1 exhibits sub-nanomolar binding affinity at MOR and nanomolar binding affinity at KOR (kappa opioid receptor), with significantly lower binding affinity for DOR (delta opioid receptor), maintaining reasonable selectivity for MOR over DOR [1]. The compound shows the highest δ/μ selectivity, surpassing NAT by approximately 3-fold [1]. MOR modulator-1 connects carboxamide linker μ, δ, γ with Ki values of 0.25, 41.1, and 1.30 nM respectively [1]. It binds MOR [35S]GTPγS with an EC50 of 2.16 nM [1]. The EC50 for MOR modulator-1 binding to KOR [35S]GTPγS is 3.83 and 23.6 nM [1]. It has low efficacy with potencies ranging from nanomolar to sub-nanomolar and a %Emax value of 11.3 [1]. The compound significantly antagonizes DAMGO-induced increases in intracellular calcium in Gαqi5-transfected mMORCHO cells [1] and inhibits calcium ions with an IC50 of 5.64 nM [1].

MOR modulator-1 (10 mg/kg, warm-water tail immersion, 20 min) is the most potent antagonist of morphine-mediated analgesia among this series of NAT analogs [1]. The AD 50 of MOR modulator-1 is 0.043 mg/kg, which is 10 times more potent than NAT [1]. Among MOR modulators based on epoxy morphinan molecules, MOR modulator-1 is the most active [1]. At all tested doses (0.05-10 mg/kg, s.c., 20 min), it showed less wet-dog shakes and paw tremors compared to 1 mg/kg naloxone (NLX), even at the highest doses of 5 mg/kg and 10 mg/kg [1]. The average values for wet-dog shakes, jumps, and paw tremors at 5 mg/kg, s.c., 20 min were 9.8, 36.8, and 30.2, respectively [1]. Following administration, brain concentrations of MOR modulator-1 were 0.187, 0.235, and 0.264 μg/g at 5, 10, and 30 minutes, respectively, indicating rapid brain penetration and prolonged retention [1].