2,5-Dimethoxy-4-cyanoamphetamine

Pharmaceutical compound From Wikipedia, the free encyclopedia

2,5-Dimethoxy-4-cyanoamphetamine (DOCN) is a serotonergic drug of the phenethylamine, amphetamine, and DOx families.^[1]^[2]^[3] It is a DOx derivative with a cyano group (–C≡N) at the 4 position of the molecule.^[1]^[2]^[3]

Other namesDOCN; 2,5-Dimethoxy-4-cyanoamphetamine; 4-Cyano-2,5-dimethoxyamphetamine

Drug classSerotonergic agent; Serotonin 5-HT₂ receptor modulator

ATC code

None

CAS Number

125903-74-4

Quick facts Clinical data, Other names ...

DOCN
Clinical data

Other names	DOCN; 2,5-Dimethoxy-4-cyanoamphetamine; 4-Cyano-2,5-dimethoxyamphetamine
Drug class	Serotonergic agent; Serotonin 5-HT₂ receptor modulator
ATC code	None
Identifiers
IUPAC name 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile
CAS Number	125903-74-4
PubChem CID	23900148
ChemSpider	23108720
ChEMBL	ChEMBL8336
CompTox Dashboard (EPA)	DTXSID80635930
Chemical and physical data
Formula	C₁₂H₁₆N₂O₂
Molar mass	220.272 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CC(CC1=CC(=C(C=C1OC)C#N)OC)N
InChI InChI=1S/C12H16N2O2/c1-8(14)4-9-5-12(16-3)10(7-13)6-11(9)15-2/h5-6,8H,4,14H2,1-3H3 Key:ULNMEZQBQBLXMC-UHFFFAOYSA-N

Use and effects

The effects of DOCN in humans and whether it is a psychedelic are unknown.^[1]

Interactions

Pharmacology

DON shows much lower affinities for the serotonin 5-HT₂ receptors than other DOx drugs.^[4]^[2]^[3] However, DOCN also showed by far the greatest degree of selectivity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor (22-fold) of any other assessed DOx drug.^[5]^[6]^[2] Applying this strategy (i.e., cyano substitution) to the 25-NB series resulted in the discovery of 25CN-NBOH, one of the most selective serotonin 5-HT_2A receptor agonists discovered to date.^[5]^[7]

Chemistry

Analogues

Related drugs include DON, 2C-N, DOA, 2C-CN, 25CN-NBOH, and 25CN-NBOMe.^[8]^[9]^[3]^[10]

History

DOCN was first described in the scientific literature by Richard Glennon and colleagues by 1989.^[9]^[3]

Society and culture

Legal status

Canada

DOCN is a controlled substance in Canada under phenethylamine blanket-ban language.^[11]

United States

DOCN is not a controlled substance in the United States as of 2011.^[1]

References

[1]
Shulgin A, Manning T, Daley PF (2011). "#55. DOCN". The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds. Vol. 1. Berkeley, CA: Transform Press. pp. 105–106. ISBN 978-0-9630096-3-0. OCLC 709667010.
[2]
Nelson DL, Lucaites VL, Wainscott DB, Glennon RA (January 1999). "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 359 (1): 1–6. doi:10.1007/pl00005315. PMID 9933142.
[3]
Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, et al. (March 1990). "A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors". Journal of Medicinal Chemistry. 33 (3): 1032–1036. doi:10.1021/jm00165a023. PMID 2308135.
[4]
Trachsel D (2003). "Synthesis of Novel (Phenylalkyl)amines for the Investigation of Structure–Activity Relationships, Part 3: 4-Ethynyl-2,5-dimethoxyphenethylamine (=4-Ethynyl-2,5-dimethoxybenzeneethanamine; 2C-YN)". Helvetica Chimica Acta. 86 (8): 2754–2759. doi:10.1002/hlca.200390224. ISSN 0018-019X. The Table summarizes some physicochemical data for the ethynyl group compared to other 4-substituents resulting in some of the most-potent 4-substituted 2,5-dimethoxy-α-methylbenzeneethanamines 2a ± d investigated in in vitro and in vivo studies [3j] [6] (compound 2d had considerably lower affinity at 5-HT2A2) sites [4 f] [6] but is used for structural comparison). [...] A Hansch analysis of a series of 4-substituted 2,5-dimethoxyamphetamines [6] gave a significant correlation between 5-HT2A affinity and the hydrophobicity of the 4- substituents. The measured 5-HT2A binding data for compound 2d bearing the 4-CN substituent showed an affinity of approximately two orders of magnitude lower than that of 2a,b [4f] [6]. For the binding affinity at the 5-HT2A receptor, the comparison of the physicochemical data for 4-substituents (Table) suggests that compound 1 should have substantially higher affinity than 4-cyano-2,5-dimethoxyamphetamine (2d; DOCN) or the α-demethyl congener thereof.
[5]
Halberstadt AL (2017). Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. Current Topics in Behavioral Neurosciences. Vol. 32. pp. 283–311. doi:10.1007/7854_2016_64. ISBN 978-3-319-52442-9. PMID 28097528. Similar to other classes of hallucinogens, NBOMes act as 5-HT2C receptor agonists and are relatively nonselective for 5-HT2A vs. 5-HT2C sites [39]. Given their high affinity and efficacy at 5-HT2A receptors, NBOMes have been developed as 5-HT2A agonist radioligands [50] and as PET tracers [51, 52]. Such work has also encouraged development of NBOMes exhibiting selectivity for 5-HT2A receptors compared with 5-HT2C sites. In contrast to other phenylisopropylamines, 2,5-dimethoxy4-cyanoamphetamine (DOCN, Fig. 6) exhibits moderate (22-fold) selectivity for human 5-HT2A (Ki = 45.7 nM) vs. 5-HT2C (Ki = 1,011 nM) sites labeled with [125I]DOI [46], indicating that 4-cyano substitution represents a potential strategy to augment 5-HT2A selectivity. Applying this strategy to the NBOMe class led to the discovery of N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenethylamine (25CN-NBOH), which is reportedly 100-fold selective for 5-HT2A receptors (Ki = 1.3 nM vs. [3H]ketanserin) compared with 5-HT2C receptors (Ki = 132 nM vs. [3H]mesulergine) [25]. However, according to a more recent investigation using the same antagonist radioligands, 25CN-NBOH is only 23-fold selective for 5-HT2A receptors (Ki = 2.2 nM) relative to 5-HT2C sites (Ki = 49.8 nM) [38]. Although the selectivity of 25CN-NBOH may be less than was initially believed, it still exhibits moderate 5-HT2A selectivity. [...] Fig. 6 Structures of the 4-cyano-substituted phenylalkylamines DOCN and 25CN-NBOH [...]
[6]
Blaazer AR, Smid P, Kruse CG (September 2008). "Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors". ChemMedChem. 3 (9): 1299–1309. doi:10.1002/cmdc.200800133. PMID 18666267. A near unity slope was found for 5-HT2A and 5-HT2C receptor affinity correlations, revealing a close correspondence. The only exception was the 4-cyano analogue 24 (DOCN), with a 22-fold higher affinity for 5-HT2A (Ki=45.7 nm) over 5-HT2C (Ki=1011 nm).[63]
[7]
Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL (December 2020). "DARK Classics in Chemical Neuroscience: NBOMes". ACS Chemical Neuroscience. 11 (23): 3860–3869. doi:10.1021/acschemneuro.9b00528. PMC 9191638. PMID 31657895.
[8]
Coutts RT, Malicky JL (1 May 1973). "The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM)". Canadian Journal of Chemistry. 51 (9): 1402–1409. doi:10.1139/v73-210. ISSN 0008-4042.
[9]
Glennon RA, Seggel MR (14 November 1989). "Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships". Probing Bioactive Mechanisms. Vol. 413. Washington, DC: American Chemical Society. pp. 264–280. doi:10.1021/bk-1989-0413.ch018. ISBN 978-0-8412-1702-7.
[10]
Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, et al. (July 2020). "The selective 5-HT_2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [³H]25CN-NBOH". Biochemical Pharmacology. 177 113979. doi:10.1016/j.bcp.2020.113979. PMID 32298690.
[11]
"Controlled Drugs and Substances Act". Department of Justice Canada. Retrieved 19 January 2026.