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DOI-NBOMe

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DOI-NBOMe
Clinical data
Other namesNBOMe-DOI; N-(2-Methoxybenzyl)-4-iodo-2,5-dimethoxyamphetamine; 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)amphetamine
Drug classSerotonin 5-HT2A receptor partial agonist; Serotonin 5-HT2C receptor ligand; Possible serotonergic psychedelic or hallucinogen
ATC code
  • None
Identifiers
  • 1-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]propan-2-amine
PubChem CID
Chemical and physical data
FormulaC19H24INO3
Molar mass441.309 g·mol−1
3D model (JSmol)
  • COc1cc(I)c(cc1CC(NCc1ccccc1OC)C)OC
  • InChI=1S/C19H24INO3/c1-13(21-12-14-7-5-6-8-17(14)22-2)9-15-10-19(24-4)16(20)11-18(15)23-3/h5-8,10-11,13,21H,9,12H2,1-4H3
  • Key:XRQNUXKKHOVYIR-UHFFFAOYSA-N

DOI-NBOMe, or NBOMe-DOI, also known as N-(2-methoxybenzyl)-4-iodo-2,5-dimethoxyamphetamine, is a serotonin 5-HT2A receptor agonist and possible psychedelic drug of the phenetylamine, DOx, and 25-NB (NBOMe) families.[1][2][3][4][5] It is the N-(2-methoxybenzyl) derivative of DOI and the amphetamine (i.e., α-methyl) analogue of 25I-NBOMe.[4][3][5]

Pharmacology

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The drug is a potent serotonin 5-HT2A receptor partial agonist, with an affinity (Ki) of 0.78 to 1.08 nM, an EC50Tooltip half-maximal effective concentration of 36.1 nM, and an EmaxTooltip half-maximal effective concentration of 43% in the employed assay.[4][3] 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 (with DOI having a Ki of 0.58–0.64 nM, an EC50 of 19.2 nM, and an Emax of 77%).[4][3] 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.[4][3] Whereas the potency of 2Cs can be dramatically increased by N-(2-methoxybenzyl) substitution, this has not been the case with the DOx series of psychedelics, where activity has been negatively impacted.[2][4][3][5][6][7]

Besides the serotonin 5-HT2A receptor, DOI-NBOMe has also been shown to bind to the serotonin 5-HT2C receptor, with an affinity (Ki) of 21.0 nM.[3] This was about 33-fold lower than the affinity of DOI.[3] As such, DOI-NBOMe appears to show increased selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor compared to DOI.[3] 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.[3]

Discovery

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DOI-NBOMe was first described in the scientific literature by Ralf Heim by 2003.[5] However, Heim only synthesized DOI-NBOMe without reporting its pharmacology.[5] The pharmacological interactions of DOI-NBOMe were subsequently reported by Michael Braden and colleagues, from the lab of David E. Nichols, by 2006.[4][3]

See also

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References

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  1. ^ Trachsel D, Lehmann D, Enzensperger C (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 837–838, 841. ISBN 978-3-03788-700-4. OCLC 858805226.
  2. ^ a b Halberstadt AL (2017). "Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens". Current Topics in Behavioral Neurosciences. 32: 283–311. doi:10.1007/7854_2016_64. ISBN 978-3-319-52442-9. PMID 28097528. Differences exist between the structure–activity relationships (SAR) of hallucinogens in the NBOMe and phenylalkylamine classes. First, there is a difference in the effect of α-methyl substitution. Compared to their α-desmethyl congeners, phenylisopropylamine hallucinogens have higher intrinsic activities at 5-HT2A, which is thought to be the reason why the phenylisopropylamines have higher potency in vivo [41, 42]. With NBOMes, however, the presence of an α-methyl group reduces intrinsic activity and 5-HT2A affinity [23]. According to Braden et al., adding an α-methyl group to 25I-NBOMe reduced its efficacy (Emax) from 78% to 43% and produced a 12-fold reduction of affinity for rat 5-HT2A receptors labeled with [125I]DOI.
  3. ^ a b c d e f g h i j k Braden MR (2007). Towards a biophysical understanding of hallucinogen action (Ph.D. thesis). Purdue University. ProQuest 304838368. With the exceptions of the N-(2-methoxy)benzyl analogue of DOI (DOI-NBOMe), and the N-(2-napthyl)methyl analogue of 25I (25I-NNap) all N-arylmethyl analogues of phenylalkylamines followed this trend of increased binding affinity at the rat 5-HT2A receptor. [...] All compounds tested were relatively potent agonists at the cloned rat 5-HT2A receptor and possessed robust intrinsic activities, with the exception of DOI-NBOMe, 25I-NB 25I-NNap, and 25I-NBF, which were weak partial agonists. [...] Table 4.3 Effect of N-alkyl or N-aryl phenylalkylamine substitution on binding and functional activity at the rat 5-HT2A receptor. [...] Table A.1 Binding affinities at wild type human and rat 5-HT receptors. [...]
  4. ^ a b c d e f g Braden MR, Parrish JC, Naylor JC, Nichols DE (December 2006). "Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists". Molecular Pharmacology. 70 (6): 1956–1964. doi:10.1124/mol.106.028720. PMID 17000863.
  5. ^ a b c d e Heim R (25 March 2003). "Synthese und Pharmakologie potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur. Entwicklung eines neuen Struktur-Wirkungskonzepts" [Synthesis and pharmacology of potent 5-HT2A receptor agonists with an N-2-methoxybenzyl partial structure. Development of a new structure-activity concept.] (in German). diss.fu-berlin.de. Archived from the original on 2012-04-16. Retrieved 2013-05-10.
  6. ^ Silva M (2009). Theoretical study of the interaction of agonists with the 5-HT2A receptor (PhD.). Universität Regensburg. Table 5.1: Agonistic potency (pEC50) and intrinsic activity (Emax) of 5-HT2AR partial agonistic arylethylamines (indole, methoxybenzene and quinazolinedione derivatives) used in the study. [...] [Compound] 234 [...]
  7. ^ Silva ME, Heim R, Strasser A, Elz S, Dove S (January 2011). "Theoretical studies on the interaction of partial agonists with the 5-HT2A receptor". Journal of Computer-aided Molecular Design. 25 (1): 51–66. doi:10.1007/s10822-010-9400-2. PMID 21088982. Table 1 Structure, agonistic potency (pEC50) and efficacy (Emax) of r5-HT2AR partial agonistic arylethylamines [...] [Compound] 25 [...] On average, methyl groups in a-position of the ethyl side chain decrease activity. However, the effect of a-Me depends on the nature of the amino group: if one considers the pEC50 values and residuals (see Table 1), it becomes obvious that the methyl branch is favourable in primary amines (cpds. 11 and 12) and unfavourable in secondary benzylamines (cpds. 17 and 25). This different behavior may be simply due to a potential interaction of the a-Me group with the receptor which is not possible in the case of a bulky RN moiety because of restricted degrees of freedom for fit. A methyl group as part of a tertiary amine strongly lowers activity.
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