Chemistry:2,5-Dimethoxy-4-hexylamphetamine

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2,5-Dimethoxy-4-hexylamphetamine (DOHx or DOHE) is a non-hallucinogenic serotonin receptor modulator of the phenethylamine, amphetamine, and DOx families.[1][2][3][4]

Pharmacology

Pharmacodynamics

DOHx has shown the highest affinity for the serotonin 5-HT2A and 5-HT2C receptors of any other assessed DOx drug in multiple studies.[2][3][5][6] In one study, its affinities for the human serotonin 5-HT2 receptors were 0.1 nM for the 5-HT2A receptor, 30 nM for the 5-HT2B receptor, and 0.7 nM for 5-HT2C receptor.[3][4][5] In the case of the serotonin 5-HT2A receptor, this was 6- to 14-fold higher than DOB, DOI, and DOC and was 9-fold higher than DOPR.[3][5] In another study, DOHx showed 25-fold higher affinity for the serotonin 5-HT2A receptor than DOM or DOET, 23- to 28-fold higher affinity than DOPR and DOBU, and 2.8-fold higher affinity than DOAM.[6] Conversely, it showed only slightly higher or roughly the same affinity for the receptor relative to DOCT (2.5 nM vs. 3.0 nM, respectively).[6]

In contrast to many other DOx drugs, DOHx, as well as related drugs like DOCT, have been found to act as serotonin 5-HT2 receptor antagonists rather than as an agonists, and hence would not be expected to be serotonergic psychedelics.[1][2] In accordance, DOHx, DOCT, and other related drugs do not produce DOM-like effects in rodent drug discrimination tests.[2] DOHx has also been assessed and found to act as a silent antagonist of the serotonin 5-HT2B receptor (Emax = 0%).[7]

Chemistry

DOHx is part of the series of 4-alkylated DOx drugs that includes DOM (methyl), DOET (ethyl), DOPR (propyl), DOBU (butyl), and DOAM (amyl/pentyl), with DOHx having a hexyl substitution and hence the longest alkyl chain of the preceding drugs.[1][3][4] Following DOHx in the series are DOHP (heptyl) and then DOCT (octyl).[2][6]

Synthesis

The chemical synthesis of DOHx has been described.[8]

History

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

Society and culture

Canada

DOHx is a controlled substance in Canada under phenethylamine blanket-ban language.[10]

See also

  • DOx (psychedelics)

References

  1. ↑ 1.0 1.1 1.2 "1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI): From an Obscure to Pivotal Member of the DOX Family of Serotonergic Psychedelic Agents - A Review". ACS Pharmacol Transl Sci 7 (6): 1722–1745. June 2024. doi:10.1021/acsptsci.4c00157. PMID 38898956. "Due to the incredibly large number of possible analogues, it is common to simply refer to this as the DOX series wherein the aryl 2,5-dimethoxy groups have been retained and the 4-position substituent has been varied. For example, DOHX is DOX where the 4-position substituent is an n-hexyl group. [...] A large number of DOX-related phenylalkylamines was examined and structure−activity and QSAR studies were conducted.51,144 Although 5-HT2 receptor affinity could be accounted for by the lipophilic and electronic character of the 4-position substituent of DOX compounds, affinity and agonist action were not synonymous. That is, some high-affinity DOX analogues with sterically large/extended 4-position substituents unexpectedly resulted in antagonist action. For example, where the X substituent was benzyl (DOBZ, Ki = 7 nM), n-hexyl (DOHX, Ki = 2.5 nM), or n-octyl (Ki = 3 nM)] the compounds acted as antagonists, whereas DOM (4), DOET (5), DOPR (6), DOB (7), and DOI (1) displayed agonist action in a 5-HT2-mediated inositol phosphate assay.51,145 It would appear that there is a "sweet spot" for agonist action with compounds such as DOI and DOB (as well as DOET and DOPR) bearing 4-position substituents being among the optimal. In contrast, DOPP (11; Figure 4) is a high-affinity 5- HT2A receptor antagonist,51 and the 2,5-dimethoxy substitution pattern of DOX compounds was not required for high affinity.". 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Hallucinogens and Serotonergic Mechanisms". NIDA Res Monogr 119: 131–135. 1992. PMID 1435968. https://archives.nida.nih.gov/sites/default/files/monograph119.pdf#page=161. "Novel lipophilic derivatives, predicted to bind with Ki values of between 1 and 15 nM, were subsequently prepared and evaluated. For example, the 4-hexyl and 4-octyl derivatives DOHX and DOCT (Ki = 2.5 and 3 nM, respectively) bind with greater affinity than DOM (Ki = 100 nM) and represent some of the highest affinity [phenylalkylamines (PAAs)] reported to date. Discordant with these findings, however, is that neither DOHX nor DOCT (nor several other related agents) produce DOM-like stimulus effects in DOM-trained animals. [Figure 1 shows the relationship between the chain length of several 4-alkyl-substituted derivatives and both their 5-HT2 affinity and relative potency in the drug discrimination assay using 1 mg/kg of DOM as the training drug. Note that the derivatives where the chain length is 5, 6 (DOHX), and 8 (DOCT) carbon atoms lack agonist activity.] Because these highly lipophilic high-affinity agents lack agonist activity, the possibility existed that they constitute a novel class of 5-HT2 antagonists; several have now been shown to antagonize the contractile effects of 5-HT in the rat aorta preparation (Seggel et al., 1990).". 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT(2A) receptors". ChemMedChem 3 (9): 1299–1309. September 2008. doi:10.1002/cmdc.200800133. PMID 18666267. "Using [125I]DOI labeled human receptor data, the highest binding affinity at 5-HT2A receptors was found for the 4-n-hexyl analogue DOHx (21, Ki=0.1 nm), followed by the 4-benzyl analogue DOBz (22, Ki=0.4 nm), DOB (16, Ki=0.6 nm), DOI (17, Ki=0.7 nm), and the 4-n-propyl analogue DOPR (23, Ki=0.9 nm).[63]". 
  4. ↑ 4.0 4.1 4.2 "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev 124 (1): 124–163. January 2024. doi:10.1021/acs.chemrev.3c00375. PMID 38033123. "Similarly, based on compounds 2C-C, 2C-B, and 2C-I, the introduction of an α-methyl group to the aminoalkyl chain resulted in a novel series of compounds known as DOXs (Figure 11B), including DOC (88), DOB (89), and DOI (90). These compounds are among the most potent phenethylamines at the 5-HT2AR (Ki = 1.4, 0.6, and 0.7 nM, respectively; [ 125I]-DOI).172 Replacing the halogen on the 4-position with a methyl group led to significantly reduced activity (91, DOM, Ki = 100 nM), but the activity could be restored with longer linear alkyl chains and the benzyl group, such as compounds DOPR (92, Ki = 0.9 nM), DOHx (93, Ki = 0.1 nM), and DOBz (94, Ki = 0.4 nM).172 Interestingly, these DOXs compounds also exhibited some selectivity against the 5- HT2BR and 5-HT2CR.172 [...] Besides 25CN-NBOH, a small number of other abovementioned 5-HT2AR agonists have also been reported to be subtype-selective for 5-HT2AR, which are summarized in Table 3. [...] DOHx and DOBz also have high binding selectivity for 5-HT2AR against 5- HT2BR (303-fold and 87.5-fold, respectively). However, because the degree of sequence identity between 5-HT2AR and 5-HT2CR is extremely high, achieving 5-HT2AR versus 5-HT2CR selectivity is more challenging.". 
  5. ↑ 5.0 5.1 5.2 "Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, -HT(2B) and 5-HT2C receptors". Naunyn Schmiedebergs Arch Pharmacol 359 (1): 1–6. January 1999. doi:10.1007/pl00005315. PMID 9933142. 
  6. ↑ 6.0 6.1 6.2 6.3 "A structure-affinity study of the binding of 4-substituted analogues of 1-(2,5-dimethoxyphenyl)-2-aminopropane at 5-HT2 serotonin receptors". J Med Chem 33 (3): 1032–1036. March 1990. doi:10.1021/jm00165a023. PMID 2308135. https://www.erowid.org/archive/rhodium/pdf/glennon.sar.4-subst.pea.pdf. 
  7. ↑ "Binding and functional structure-activity similarities of 4-substituted 2,5-dimethoxyphenyl isopropylamine analogues at 5-HT2A and 5-HT2B serotonin receptors". Front Pharmacol 14. 2023. doi:10.3389/fphar.2023.1101290. PMID 36762110. 
  8. ↑ Shulgin, Alexander; Shulgin, Ann (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN 0-9630096-0-5. OCLC 25627628. http://www.erowid.org/library/books_online/pihkal/pihkal.shtml.  "The work was started towards two additional compounds but these never got past the first “ketone and phenol” stage. p-Dimethoxybenzene was brought into reaction with n-caproic acid with polyphosphoric acid (aiming towards 2,5-dimethoxy-4-n-hexylamphetamine, DOHE) but this was dropped when DOAM proved to be down in potency. And the reaction between p-dimethoxybenzene and benzoyl chloride with anh. aluminum chloride went well (aiming towards 2,5-dimethoxy-4-benzylamphetamine, DOBZ). A goodly amount of the phenol (2-hydroxy-5-methoxybenzophenone) was obtained as fine yellow crystals, but this line of inquiry was also dropped."
  9. ↑ "Interaction of Phenylisopropylamines with Central 5-HT2 Receptors: Analysis by Quantitative Structure—Activity Relationships". Probing Bioactive Mechanisms. 413. Washington, DC: American Chemical Society. 14 November 1989. pp. 264–280. doi:10.1021/bk-1989-0413.ch018. ISBN 978-0-8412-1702-7. https://bitnest.netfirms.com/external/10.1021/bk-1989-0413.ch018. 
  10. ↑ "Controlled Drugs and Substances Act". https://laws-lois.justice.gc.ca/eng/acts/c-38.8/FullText.html. 



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