2,5-DDM-DOM

vanc 6 2,5-DDM-DOM.svg skin-invert-image 200px Neurotoxin None 52336-50-2 148574 130968 3247439 2-O-,5-O-Didesmethyl-DOM; 2,5-Didesmethyl-DOM; 2,5-DES-Me-DOM; 2,5-Dihydroxy-4-methylamphetamine; 4-Methyl-2,5-dihydroxyamphetamine; 1-(2,5-Dihydroxy-4-methylphenyl)-2-aminopropane 2-(2-aminopropyl)-5-methylbenzene-1,4-diol 10 15 1 2 CC1=CC(=C(C=C1O)CC(C)N)O 1S/C10H15NO2/c1-6-3-10(13)8(4-7(2)11)5-9(6)12/h3,5,7,12-13H,4,11H2,1-2H3 ISJCIACBPBDNKH-UHFFFAOYSA-N 2,5-DDM-DOM, also known as 2-O-,5-O-didesmethyl-DOM or as 2,5-dihydroxy-4-methylamphetamine, is a neurotoxin of the phenethylamine and amphetamine families related to the DOx psychedelic DOM (2,5-dimethoxy-4-methylamphetamine; STP). Shulgin AT Burger A, Wolf ME Hallucinogens Burger's Medicinal Chemistry New York 3 1109–1137 1980 https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=6ac0c892ee380436f614d3aae0686ef617b2e0c5 4 Wiley 978-0-471-01572-7 219960627 https://books.google.com/books?id=2b3wAAAAMAAJ The third principal metabolic route common to the hallucinogenic drugs is oxidation. Benzylic oxidation had been reported with both DOM (60.22aa) and DOET (60.22bb) (61, 62). Of greater theoretical interest is oxidative cyclization to form an indole species, reminiscent of the conversion of epinephrine to adrenochrome. Many of the hallucinogens are in fact indoles, and since the phenethylamine chain has the exact atom composition of indole itself, there has been frequent speculation that there might be some metabolic conversion from one family to the other. It has been shown (63) that one of the metabolites of DOM (2,5-dihydroxy[-4-methyl]phenylisopropylamine, 60.17), which bears a close chemical and pharmacological resemblance to the potent neurodegenerative agent 6-hydroxydopamine (60.18) (64), can undergo a facile oxidative cyclization to form a 5-hydroxyindole. The intermediate iminoquinone is potentially very reactive with nucleophilic agents found in normal body chemistry, and may be important in any explanation of biological activity. Castagnoli N Drug Metabolism: Review of Principles and the Fate of One-Ring Psychotomimetics Stimulants 335–387 1978 10.1007/978-1-4757-0510-2_7 Springer US Boston, MA 978-1-4757-0512-6 http://link.springer.com/10.1007/978-1-4757-0510-2_7 3 February 2026 FIG. 9. Metabolic pathways for amine III (DOM). [...] The third general metabolic pathway for 111 is oxidative O-demethylation of the methyl phenyl ether groups. All three possible O-demethylated metabolites, compounds 118-120, have been characterized in rabbit liver homogenates (Zweig and Castagnoli, 1975, 1977). The p-hydroquinone 120 is an analog of the sympatholytic agent 6-hydroxydopamine (107) and has been shown to possess some of the neurodegenerative properties of 6-hydroxydopamine (Butcher, 1975). Similar to 6-hydroxydopamine (Blank et ai., 1972), hydroquinone 120 undergoes facile oxidation to form the quinone 129 (Fig. 10), which cyclizes to the iminoquinone 130 (Zweig and Castagnoli, 1974). In the absence of nucleophiles, 130 is relatively stable at pH 7.4. As the pH is raised, however, proton rearrangements take place, eventually leading to the indole 132 via the indolinine 131. In view of the ease with which the hydroquinone 120 undergoes oxidation at pH 7.4, it is somewhat surprising that this compound survives the one hour pH 7.4 incubation. This stabilization may be analogous to the inhibition by liver constituents of hydroxylamine auto-oxidation. It should prove of interest to determine the nature and significance of the protection of these substances from air oxidation. [...] FIG. 10. Oxidative cyclization of p-hydroquinone metabolite derived from DOM. [...] Glennon RA The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse Journal of Medicinal Chemistry 60 7 2605–2628 April 2017 28244748 10.1021/acs.jmedchem.7b00085 5824997 However, there was some concern that 2-DM-DOM and 5-DM-DOM might undergo further O-demethylation in vivo to a hydroquinone. It had been shown years earlier that DOM can undergo metabolic bis-demethylation to a hydroquinone, and that the hydroquinone undergoes oxidation to a para-quinone (and/or a cyclic iminoquinone) that reacts irreversibly with various proteins.44 As a consequence, this approach was not pursued because of potential risks of neurotoxicity. [...] 44. Jacob P. 3rd; Kline, T., Castagnoli, N. Jr. Chemical and biological studies of 1-(2,5-dihydroxy-4- methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine. J Med Chem. 1979; 22:662– 671. [PubMed: 458821] Jacob P, Kline T, Castagnoli N Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine Journal of Medicinal Chemistry 22 6 662–671 June 1979 458821 10.1021/jm00192a011 It is a metabolite of DOM formed by O-desmethylation, with 2-DM-DOM and 5-DM-DOM serving as metabolic intermediates. Anderson GM, Castagnoli N, kollman PA Quantitative structure-activity relationships in the 2,4,5-ring substituted phenylisopropylamines NIDA Research Monograph 22 199–217 1978 101881 A potentially important consequence of the electronic and distribution properties of the “rearranged” isomers concerns their susceptibility to biotransformation in vivo. Investigation of the metabolic fate of DOM (5) (Zweig and Castagnoli 1977) had established the conversion of this compound into the bis-O-demethylated metabolite (15), a close analogue of the selective noradrenergic toxin 6-hydroxydopamine (16). The chemical behavior of the hydroquinone (15) and 6-hydroxydopamine (16) is analogous in that both readily undergo spontaneous oxidation leading to electrophilic intermediates (Zweig and Castagnoli 1974) which in the case of 6-hydroxydopamine are likely to be responsible for the observed destruction of noradrenergic terminals (Malnifors and Thoenen 1971). Zweig JS, Castagnoli N In vitro O-demethylation of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane Journal of Medicinal Chemistry 20 3 414–421 March 1977 845874 10.1021/jm00213a020 DOM might produce neurotoxicity via metabolism into 2,5-DDM-DOM followed by subsequent transformation. Blank CL, Lewis RJ, Lehr RE 6-Hydroxydopamine and Related Catecholaminergic Neurotoxins: Molecular Mechanisms Highly Selective Neurotoxins 1–18 1998 10.1007/978-1-59259-477-1_1 Humana Press Totowa, NJ 978-1-61737-047-2 http://link.springer.com/10.1007/978-1-59259-477-1_1 3 February 2026 A number of agents structurally similar to the original 6-HDA have been demonstrated, or are strongly suspected, to possess neurodegenerative properties. These include: 1. The 16 trisubstituted phenethylamines or α-methylphenethylamines in which the trisubstitution pattern on the ring is of the 2,3,5- or 2,4,5- variety with respect to the side chain, and involves either trihydroxy or aminodihydroxy functional group entities (15-18); [...] For example, in regard to CNS noradrenergic effects, the seven other derivatives implicated in Fig. 2 have been shown equipotent or more potent than the standard 6-HDA while simultaneously being equally or more selective (13,15-17,19,24,25). [...] Pharmacology 2,5-DDM-DOM can undergo facile oxidation to form a quinone, which then cyclizes to the iminoquinone. 2,5-DDM-DOM has been found to be an alkylating agent and a potent neurotoxin similarly to 6-hydroxydopamine. Butcher LL Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine Journal of Neural Transmission 37 3 189–203 1975 1185165 10.1007/BF01670128 Similarly, 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane was not a more potent cytotoxin than 6-OHDA even though this new neurotoxin has a propane side chain which renders it immune to monoamine oxidase. [...] The neurotoxin 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane-HC1 (DIMPAP) was synthesized by Dr. Nell Castagnoli, University of California Medical Center, San Francisco, CA, U.S.A. [...] Fig. 28. Chemical structure of 1-(2, 5-dihydroxy-4-methylphenyl)-2-aminopropaneHC1 (DIMPAP) [...] The extent of zone-3 damage: after intrastriatal infusion of various doses of DIMPAP is depicted in figures 29–33. No significant difference exists between the non-selective damage produced by DIMPAP and similar doses of 6-OHDA (e.g., compare Figs. 29–33 with Figs. 25–30 in Butcher et al., 1974). Furthermore, nialamide pre-treatment does not alter the destructive potency of either 6-OHDA or DIMPAP (compare Figs. 34–38 with Figs. 39–43 and Figs. 44–47). 2,5-DDM-DOM and its iminoquinone have been found to produce hyperthermia in rabbits. They are both far less potent than DOM in this regard. 2,5-DDM-DOM is polar and unlikely to cross the blood–brain barrier, but its iminoquinone metabolite is highly lipophilic and has been found to readily cross the blood–brain barrier. Chemistry The chemical synthesis of 2,5-DDM-DOM has been described. Zweig JS, Castagnoli N Chemical conversion of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane to 5-hydroxy-2,6-dimethylindole Journal of Medicinal Chemistry 17 7 747–749 July 1974 4836406 10.1021/jm00253a019 Anderson GM Structure activity relationships in one-ring psychotomimetics 1982 eScholarship https://escholarship.org/uc/item/7z78s45q 3 February 2026 The log P of 2,5-DDM-DOM is 1.04, compared to 2.08 to 2.24 in the case of DOM. The chemical structure of 2,5-DDM-DOM is very similar to that of 6-hydroxydopamine. Various analogues of 2,5-DDM-DOM have been studied and some have also been found to be neurotoxic. Cheng AC, Castagnoli N Synthesis and physicochemical and neurotoxicity studies of 1-(4-substituted-2,5-dihydroxyphenyl)-2-aminoethane analogues of 6-hydroxydopamine Journal of Medicinal Chemistry 27 4 513–520 April 1984 6423824 10.1021/jm00370a014 History 2,5-DDM-DOM was first described in the scientific literature by 1974. Its neurotoxic properties were described in 1975. It was once hypothesized, for instance by Alexander Shulgin and others, that the hallucinogenic effects of serotonergic psychedelics like DOM might be due to formation of neurotoxic metabolites like 2,5-DDM-DOM. Shulgin AT Profiles of Psychedelic Drugs: 5. STP Journal of Psychedelic Drugs 9 2 171–172 1977 10.1080/02791072.1977.10472044 0022-393X https://bibliography.maps.org/resources/download/9495 https://web.archive.org/web/20250712225853/https://bibliography.maps.org/resources/download/9495 2025-07-12 This structural feature permits a metabolic demethylation to a hydroquinone which has been proven, in the case of STP, to be easily air-oxidized in vitro to a quinone. There can thus be generated an intermediate capable of reacting with any of several biological systems, or with itself intramolecularly, to form an indole. No in vivo evidence has yet supported either of these processes as being involved in the mechanism of action of STP in man. See also DOx (psychedelics) Monoamine neurotoxin 2,4,5-Trihydroxyamphetamine References External links 2,5-DES-Me-DOM - Isomer Design Category:Hydroxyarenes Category:Methyl compounds Category:Monoaminergic neurotoxins Category:Peripherally selective drugs Category:Psychedelic drug metabolites