Recently, noribogaine has been determined to act as a biased agonist of the κ-opioid receptor (KOR). It activates the G protein (GDP-GTP exchange) signaling pathway with 75% the efficacy of dynorphin A (EC50 = 9 μM), but it is only 12% as efficacious at activating the β-arrestin pathway. Moreover, due to its very low efficacy on the β-arrestin pathway, noribogaine blocked dynorphin A activation of the pathway (IC50 = 1 μM) and hence functioned as an antagonist of it.
The β-arrestin pathway is thought to be responsible for the dysphoric and aversive effects of KOR activation, and its lack of activation by noribogaine may be the reason for the lack of dysphoric effects of the drug. This biased agonist/antagonist action of noribogaine at the KOR is unique to it relative to other iboga alkaloids and related compounds such as ibogaine and 18-methoxycoronaridine (18-MC). Moreover, it has been hypothesized that it may give noribogaine unique properties such that it may have the analgesic and antiaddictive effects of KOR agonists without the anxiogenic, dysphoric, or anhedonic effects that are typical of them.
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