DOB-NBOMe

DOB-NBOMe
Clinical data
Other names	NBOMe-DOB; N-(2-Methoxybenzyl)-4-bromo-2,5-dimethoxyamphetamine; 4-Bromo-2,5-dimethoxy-N-(2-methoxybenzyl)amphetamine
Drug class	Serotonin 5-HT2A receptor partial agonist; Possible serotonergic psychedelic or hallucinogen
ATC code	None;
Identifiers
	IUPAC name 1-(4-bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]propan-2-amine;
PubChem CID	169776410;
Chemical and physical data
Formula	C19H24BrNO3
Molar mass	394.309 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES COc1cc(Br)c(cc1CC(NCc1ccccc1OC)C)OC;
	InChI InChI=1S/C19H24BrNO3/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:VIURPEKIEYLSKF-UHFFFAOYSA-N;

DOB-NBOMe, or NBOMe-DOB, also known as N-(2-methoxybenzyl)-4-bromo-2,5-dimethoxyamphetamine, is a serotonin 5-HT_2A receptor agonist and possible psychedelic drug of the phenethylamine, DOx, and 25-NB (NBOMe) families.^[1]^[2]^[3] It is the N-(2-methoxybenzyl) derivative of DOB and the amphetamine (i.e., α-methyl) analogue of 25B-NBOMe.^[1]^[2]^[3]

Pharmacology

The drug is a potent serotonin 5-HT_2A receptor partial agonist, with an EC₅₀Tooltip half-maximal effective concentration of 7.94 nM and an E_maxTooltip half-maximal effective concentration of 20% in the employed assay.^[1]^[2]^[3] As an agonist of the serotonin 5-HT_2A receptor, DOB-NBOMe had about the same potency as DOB but had greatly reduced efficacy in comparison in vitro (with DOB having an EC₅₀ of 10.2 nM and an E_max of 71%).^[1]^[2]^[3] Compared to 25B-NBOMe, the corresponding NBOMe analogue of 2C-B, DOB-NBOMe had about 30-fold lower potency as a serotonin 5-HT_2A receptor agonist and about half the activational efficacy.^[1]^[2]^[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.^[4]^[5]^[6]^[1]^[2]^[3]

Discovery

DOB-NBOMe was first described in the scientific literature by Ralf Heim by 2003.^[1]

References

^ ^a ^b ^c ^d ^e ^f ^g Heim R (25 March 2003). "Synthese und Pharmakologie potenter 5-HT_2A-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. Tab. 3-11. 5-HT2A-Rezeptoraktivität N-benzylierter 1-(2,5-Dimethoxyphenyl)-2-aminoalkan-Derivate, untersucht an 5-HT2ARezeptoren der isolierten Rattenschwanzarterie. [...] [Compound] 234 [...] Im Unterschied zum primären 4-Brom-2,5-Dimethoxyphenylethylamin (41) bewirkt eine α-Methylverzweigung im (N-2-Methoxybenzyl)phenylethylamin-Derivat 231 eine Verringerung der 5-HT2AAktivität des resultierenden Phenylisopropyl-Analogons 234 um 1.5 log-Einheiten auf pEC50 = 8.10 (vs. 9.58 für 231). Auch die beobachtete agonistische Wirkung an 5-HT2A-Rezeptoren geht beim Übergang von 231 nach 234 von Emax = 40 % auf Emax = 20 % zurück. Im Vergleich hierzu wird bei der Einführung einer α-Methylgruppe innerhalb der primären Amine (41 → 35) eine sechsfache Steigerung der 5-HT2A-Aktivität und ein ca. 10%iger Anstieg der intrinsischen Aktivität registriert. Offensichtlich übt die Methylgruppe in α-Position zur sekundären Aminfunktion im N-2-Methoxybenzyl-Derivat 234 einen erheblich größeren sterischen Einfluß auf dieses potentielle kationische Wechselwirkungsareal aus, als dies bei der primären Aminfunktion in 35 der Fall ist. Eine mögliche Erklärung für diese experimentellen Befunde könnte die stark eingeschränkte konformative Flexibilität der Phenylisopropyl-Seitenkette innerhalb der Rezeptorbindungsstelle infolge der zusätzlichen Wechselwirkung des 2-Methoxybenzylrestes liefern.
^ ^a ^b ^c ^d ^e ^f 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 [...]
^ ^a ^b ^c ^d ^e ^f 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.
^ 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.
^ 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. [...]
^ 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.

External links

DOB-NBOMe - Isomer Design

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[Heim_2003-1] ^ ^a ^b ^c ^d ^e ^f ^g Heim R (25 March 2003). "Synthese und Pharmakologie potenter 5-HT_2A-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. Tab. 3-11. 5-HT2A-Rezeptoraktivität N-benzylierter 1-(2,5-Dimethoxyphenyl)-2-aminoalkan-Derivate, untersucht an 5-HT2ARezeptoren der isolierten Rattenschwanzarterie. [...] [Compound] 234 [...] Im Unterschied zum primären 4-Brom-2,5-Dimethoxyphenylethylamin (41) bewirkt eine α-Methylverzweigung im (N-2-Methoxybenzyl)phenylethylamin-Derivat 231 eine Verringerung der 5-HT2AAktivität des resultierenden Phenylisopropyl-Analogons 234 um 1.5 log-Einheiten auf pEC50 = 8.10 (vs. 9.58 für 231). Auch die beobachtete agonistische Wirkung an 5-HT2A-Rezeptoren geht beim Übergang von 231 nach 234 von Emax = 40 % auf Emax = 20 % zurück. Im Vergleich hierzu wird bei der Einführung einer α-Methylgruppe innerhalb der primären Amine (41 → 35) eine sechsfache Steigerung der 5-HT2A-Aktivität und ein ca. 10%iger Anstieg der intrinsischen Aktivität registriert. Offensichtlich übt die Methylgruppe in α-Position zur sekundären Aminfunktion im N-2-Methoxybenzyl-Derivat 234 einen erheblich größeren sterischen Einfluß auf dieses potentielle kationische Wechselwirkungsareal aus, als dies bei der primären Aminfunktion in 35 der Fall ist. Eine mögliche Erklärung für diese experimentellen Befunde könnte die stark eingeschränkte konformative Flexibilität der Phenylisopropyl-Seitenkette innerhalb der Rezeptorbindungsstelle infolge der zusätzlichen Wechselwirkung des 2-Methoxybenzylrestes liefern.

[Silva_2009-2] ^ ^a ^b ^c ^d ^e ^f 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 [...]

[Silva_2011-3] ^ ^a ^b ^c ^d ^e ^f 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.

[Halberstadt_2017-4] 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.

[Braden_2007-5] 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. [...]

[Braden_2006-6] 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.

[1]

[2]

[3]

[4]

[5]

[6]

Pharmacology

Discovery

See also

References

External links