DOI-NBOMe
DOI-NBOMe, or NBOMe-DOI, also known as N--4-iodo-2,5-dimethoxyamphetamine, is a non-hallucinogenic serotonin 5-HT2A receptor biased agonist of the phenethylamine, DOx, and 25-NB families. It is the N- derivative of DOI and the amphetamine analogue of 25I-NBOMe.
Pharmacology
Pharmacodynamics
DOI-NBOMe is a potent serotonin 5-HT2A receptor partial agonist, with an affinity of 0.78 to 1.08nM, an of 36.1nM, and an of 43% in the employed assay. As an agonist of the serotonin 5-HT2A receptor, DOI-NBOMe had about half the affinity and potency of DOI and a little more than half the efficacy in comparison in vitro. Compared to 25I-NBOMe, the corresponding NBOMe analogue of 2C-I, DOI-NBOMe had about 14.4-fold lower potency as a serotonin 5-HT2A receptor agonist and slightly more than half the activational efficacy. Whereas the potency of 2Cs can be dramatically increased by N- substitution, this has not been the case with the DOx series of psychedelics, where activity has been negatively impacted.Besides the serotonin 5-HT2A receptor, DOI-NBOMe has also been shown to bind to the serotonin 5-HT2C receptor, with an affinity of 21.0nM. This was about 33-fold lower than the affinity of DOI. As such, DOI-NBOMe appears to show increased selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor compared to DOI. For comparison, 25I-NBOMe had increased affinities for both the serotonin 5-HT2A receptor and to a lesser extent the serotonin 5-HT2C receptor compared to 2C-I.
Subsequent to its earlier discovery and characterization, DOI-NBOMe was found to be a biased agonist of the serotonin 5-HT2A receptor, with robust Gq activation comparable to DOI but minor efficacy on Gi signaling. In addition, it was selective for the serotonin 5-HT2A receptor, with much less or no agonism of the 5-HT1A, 5-HT2B, or 5-HT2C receptors. The values were 10nM at the serotonin 5-HT2A receptor and 603nM at the serotonin 5-HT2C receptor. Values for Gq, Gi, and β-arrestin2 signaling at the serotonin 5-HT2A receptor were also reported. DOI-NBOMe failed to produce the head-twitch response in rodents. Moreover, DOI-NBOMe antagonized the head-twitch response induced by DOI or LSD. The drug was found to produce rapid and sustained antidepressant-like effects in the forced swim test in rodents. In addition, it produced sustained anxiolytic-like effects in the marble-burying test. It was concluded that serotonin 5-HT2A receptor Gi signaling and not Gq signaling is involved in the psychedelic-like effects of serotonergic psychedelics.