DOHx has shown the highest affinity for the serotonin5-HT2A and 5-HT2C receptors of any other assessed DOx drug in multiple studies. In one study, its affinities for the human serotonin 5-HT2 receptors were 0.1nM for the 5-HT2A receptor, 30nM for the 5-HT2B receptor, and 0.7nM for 5-HT2C receptor. 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. 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. Conversely, it showed only slightly higher or roughly the same affinity for the receptor relative to DOCT (2.5nM vs. 3.0nM, respectively).
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. In accordance, DOHx, DOCT, and other related drugs do not produce DOM-like effects in rodent drug discrimination tests. DOHx has also been assessed and found to act as a silent antagonist of the serotonin 5-HT2B receptor (EmaxTooltip maximal efficacy = 0%).
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 hexylsubstitution and hence the longest alkyl chain of the preceding drugs. Following DOHx in the series are DOHP (heptyl) and then DOCT (octyl).
123Glennon RA, Dukat M (June 2024). "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. doi:10.1021/acsptsci.4c00157. PMC11184610. PMID38898956. 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.
12345Glennon RA, Teitler M, Sanders-Bush E (1992). "Hallucinogens and Serotonergic Mechanisms"(PDF). NIDA Res Monogr. 119: 131–135. PMID1435968. Archived from the original(PDF) on August 5, 2023. 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).
12345Blaazer 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. PMID18666267. 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]
123Duan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants". Chem Rev. 124 (1): 124–163. doi:10.1021/acs.chemrev.3c00375. PMID38033123. 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.
123Nelson 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 Schmiedebergs Arch Pharmacol. 359 (1): 1–6. doi:10.1007/pl00005315. PMID9933142.
↑Shulgin A, Shulgin A (September 1991). PiHKAL: A Chemical Love Story. Berkeley, California: Transform Press. ISBN0-9630096-0-5. OCLC25627628. "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."
