2,5-Dimethoxy-4-cyanoamphetamine

{{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | drug_name = DOCN | image = DOCN structure.svg | image_class = skin-invert-image | width = 225px | caption =

| legal_status =

| IUPAC_name = 4-(2-aminopropyl)-2,5-dimethoxybenzonitrile | C=12 | H=16 | N=2 | O=2 | SMILES = CC(CC1=CC(=C(C=C1OC)C#N)OC)N | StdInChI = 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 | StdInChIKey = ULNMEZQBQBLXMC-UHFFFAOYSA-N }}

'''2,5-Dimethoxy-4-cyanoamphetamine''' ('''DOCN''') is a serotonergic drug of the phenethylamine, amphetamine, and DOx families.<ref name="ShulginManningDaley2011">{{cite book | vauthors = Shulgin A, Manning T, Daley PF | chapter = #55. DOCN | pages = 105–106 | chapter-url = https://archive.org/details/shulgin-index-vol-1/page/105/mode/1up | title = The Shulgin Index, Volume One: Psychedelic Phenethylamines and Related Compounds | publisher = Transform Press | location = Berkeley, CA | volume = 1 | year = 2011 | isbn = 978-0-9630096-3-0 | oclc = 709667010 }}</ref><ref name="NelsonLucaitesWainscott1999">{{cite journal | vauthors = Nelson DL, Lucaites VL, Wainscott DB, Glennon RA | title = Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 359 | issue = 1 | pages = 1–6 | date = January 1999 | pmid = 9933142 | doi = 10.1007/pl00005315 }}</ref><ref name="SeggelYousifLyon1990">{{cite journal | vauthors = Seggel MR, Yousif MY, Lyon RA, Titeler M, Roth BL, Suba EA, Glennon RA | title = A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 3 | pages = 1032–1036 | date = March 1990 | pmid = 2308135 | doi = 10.1021/jm00165a023 }}</ref> It is a DOx derivative with a cyano group (–C≡N) at the 4{{nbsp}}position of the molecule.<ref name="ShulginManningDaley2011" /><ref name="NelsonLucaitesWainscott1999" /><ref name="SeggelYousifLyon1990" />

==Use and effects== The effects of DOCN in humans and whether it is a psychedelic are unknown.<ref name="ShulginManningDaley2011" />

==Interactions== {{See also|Psychedelic drug#Interactions|Trip killer#Serotonergic psychedelic antidotes}}

==Pharmacology== DON shows much lower affinities for the serotonin 5-HT2 receptors than other DOx drugs.<ref name="Trachsel2003">{{cite journal | vauthors = Trachsel D | title=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) | journal=Helvetica Chimica Acta | volume=86 | issue=8 | date=2003 | issn=0018-019X | doi=10.1002/hlca.200390224 | pages=2754–2759 | quote=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.}}</ref><ref name="NelsonLucaitesWainscott1999" /><ref name="SeggelYousifLyon1990" /> However, DOCN also showed by far the greatest degree of selectivity for the serotonin 5-HT2A receptor over the serotonin 5-HT2C receptor (22-fold) of any other assessed DOx drug.<ref name="Halberstadt2017">{{cite book | vauthors = Halberstadt AL | title = Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens | series = Current Topics in Behavioral Neurosciences| volume = 32 | pages = 283–311 | date = 2017 | pmid = 28097528 | doi = 10.1007/7854_2016_64 | isbn = 978-3-319-52442-9 | quote = 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 [...] }}</ref><ref name="BlaazerSmidKruse2008">{{cite journal | vauthors = Blaazer AR, Smid P, Kruse CG | title = Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors | journal = ChemMedChem | volume = 3 | issue = 9 | pages = 1299–1309 | date = September 2008 | pmid = 18666267 | doi = 10.1002/cmdc.200800133 | quote = 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] }}</ref><ref name="NelsonLucaitesWainscott1999" /> 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-HT2A receptor agonists discovered to date.<ref name="Halberstadt2017" /><ref name="PoulieJensenHalberstadt2020">{{cite journal | vauthors = Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL | title = DARK Classics in Chemical Neuroscience: NBOMes | journal = ACS Chemical Neuroscience | volume = 11 | issue = 23 | pages = 3860–3869 | date = December 2020 | pmid = 31657895 | pmc = 9191638 | doi = 10.1021/acschemneuro.9b00528 }}</ref>

==Chemistry== ===Analogues=== Related drugs include DON, 2C-N, DOA, 2C-CN, 25CN-NBOH, and 25CN-NBOMe.<ref name="CouttsMalicky1973">{{cite journal | vauthors = Coutts RT, Malicky JL | title=The Synthesis of Some Analogs of the Hallucinogen 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM) | journal=Canadian Journal of Chemistry | volume=51 | issue=9 | date=1 May 1973 | issn=0008-4042 | doi=10.1139/v73-210 | doi-access=free | pages=1402–1409 }}</ref><ref name="GlennonSeggel1989">{{cite book | vauthors = Glennon RA, Seggel MR | chapter=Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships | title=Probing Bioactive Mechanisms | publisher=American Chemical Society | publication-place=Washington, DC | volume=413 | date=14 November 1989 | isbn=978-0-8412-1702-7 | doi=10.1021/bk-1989-0413.ch018 | pages=264–280 | chapter-url=https://bitnest.netfirms.com/external/10.1021/bk-1989-0413.ch018 }}</ref><ref name="SeggelYousifLyon1990" /><ref name="JensenHalberstadtMärcher-Rørsted2020">{{cite journal | vauthors = Jensen AA, Halberstadt AL, Märcher-Rørsted E, Odland AU, Chatha M, Speth N, Liebscher G, Hansen M, Bräuner-Osborne H, Palner M, Andreasen JT, Kristensen JL | title = The selective 5-HT2A receptor agonist 25CN-NBOH: Structure-activity relationship, in vivo pharmacology, and in vitro and ex vivo binding characteristics of [3H]25CN-NBOH | journal = Biochemical Pharmacology | volume = 177 | issue = | article-number = 113979 | date = July 2020 | pmid = 32298690 | doi = 10.1016/j.bcp.2020.113979 }}</ref>

==History== DOCN was first described in the scientific literature by Richard Glennon and colleagues by 1989.<ref name="GlennonSeggel1989" /><ref name="SeggelYousifLyon1990" />

==Society and culture== ===Legal status=== ====Canada==== DOCN is a controlled substance in Canada under phenethylamine blanket-ban language.<ref name="CDSA">{{cite web | title=Controlled Drugs and Substances Act | website=Department of Justice Canada | url=https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html | access-date=19 January 2026}}</ref>

====United States==== DOCN is not a controlled substance in the United States as of 2011.<ref name="ShulginManningDaley2011" />

==See also== * DOx (psychedelics) * 2C-N * 2C-CN * 25CN-NBOH * 25CN-NBOMe

== References == {{Reflist}}

== External links == * [https://isomerdesign.com/pihkal/explore/2197 DOCN - isomer design]

Category:DOx (psychedelics) Category:Nitriles Category:Serotonin receptor modulators