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2,5-DDM-DOM

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2,5-DDM-DOM
Clinical data
Other names2-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
Drug classNeurotoxin
ATC code
  • None
Identifiers
  • 2-(2-aminopropyl)-5-methylbenzene-1,4-diol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC10H15NO2
Molar mass181.235 g·mol−1
3D model (JSmol)
  • CC1=CC(=C(C=C1O)CC(C)N)O
  • InChI=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
  • Key: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).[1][2][3][4] It is a metabolite of DOM formed by O-desmethylation, with 2-DM-DOM and 5-DM-DOM serving as metabolic intermediates.[3][4][2][5][6] DOM might produce neurotoxicity via metabolism into 2,5-DDM-DOM followed by subsequent transformation.[7][1][3][4]

Pharmacology

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2,5-DDM-DOM can undergo facile oxidation to form a quinone, which then cyclizes to the iminoquinone.[1][3][2][4] 2,5-DDM-DOM has been found to be an alkylating agent and a potent neurotoxin similarly to 6-hydroxydopamine.[1][3][4][8] 2,5-DDM-DOM and its iminoquinone have been found to produce hyperthermia in rabbits.[9] They are both far less potent than DOM in this regard.[9] 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.[4]

Chemistry

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The chemical synthesis of 2,5-DDM-DOM has been described.[10][9] The log P of 2,5-DDM-DOM is 1.04, compared to 2.08 to 2.24 in the case of DOM.[9] The chemical structure of 2,5-DDM-DOM is very similar to that of 6-hydroxydopamine.[1][4][2][10][6][8] Various analogues of 2,5-DDM-DOM have been studied and some have also been found to be neurotoxic.[11]

History

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2,5-DDM-DOM was first described in the scientific literature by 1974.[10] Its neurotoxic properties were described in 1975.[8] 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.[1][4][6][12]

See also

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References

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  1. ^ a b c d e f Shulgin AT (1980). "Hallucinogens". In Burger A, Wolf ME (eds.). Burger's Medicinal Chemistry. Vol. 3 (4 ed.). New York: Wiley. pp. 1109–1137. ISBN 978-0-471-01572-7. OCLC 219960627. 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.
  2. ^ a b c d Castagnoli, Neal (1978). "Drug Metabolism: Review of Principles and the Fate of One-Ring Psychotomimetics". Stimulants. Boston, MA: Springer US. p. 335–387. doi:10.1007/978-1-4757-0510-2_7. ISBN 978-1-4757-0512-6. Retrieved 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. [...]
  3. ^ a b c d e Glennon RA (April 2017). "The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse". J Med Chem. 60 (7): 2605–2628. doi:10.1021/acs.jmedchem.7b00085. PMID 28244748. 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]
  4. ^ a b c d e f g h Jacob P, Kline T, Castagnoli N (June 1979). "Chemical and biological studies of 1-(2,5-dihydroxy-4-methylphenyl)-2-aminopropane, an analogue of 6-hydroxydopamine". J Med Chem. 22 (6): 662–671. doi:10.1021/jm00192a011. PMID 458821.
  5. ^ Anderson GM, Castagnoli N, Kollman PA (1978). "Quantitative structure-activity relationships in the 2,4,5-ring substituted phenylisopropylamines". NIDA Res Monogr (22): 199–217. PMID 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).
  6. ^ a b c Zweig JS, Castagnoli N (March 1977). "In vitro O-demethylation of the psychotomimetic amine, 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane". J Med Chem. 20 (3): 414–421. doi:10.1021/jm00213a020. PMID 845874.
  7. ^ Blank, C. LeRoy; Lewis, Russell J.; Lehr, Roland E. (1998). "6-Hydroxydopamine and Related Catecholaminergic Neurotoxins: Molecular Mechanisms". Highly Selective Neurotoxins. Totowa, NJ: Humana Press. p. 1–18. doi:10.1007/978-1-59259-477-1_1. ISBN 978-1-61737-047-2. Retrieved 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). [...]
  8. ^ a b c Butcher LL (1975). "Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine". J Neural Transm. 37 (3): 189–203. doi:10.1007/BF01670128. PMID 1185165. 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).
  9. ^ a b c d Anderson, George M. (1982). "Structure activity relationships in one-ring psychotomimetics". eScholarship. Retrieved 3 February 2026.
  10. ^ a b c Zweig JS, Castagnoli N (July 1974). "Chemical conversion of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane to 5-hydroxy-2,6-dimethylindole". J Med Chem. 17 (7): 747–749. doi:10.1021/jm00253a019. PMID 4836406.
  11. ^ Cheng AC, Castagnoli N (April 1984). "Synthesis and physicochemical and neurotoxicity studies of 1-(4-substituted-2,5-dihydroxyphenyl)-2-aminoethane analogues of 6-hydroxydopamine". J Med Chem. 27 (4): 513–520. doi:10.1021/jm00370a014. PMID 6423824.
  12. ^ Shulgin, Alexander T. (1977). "Profiles of Psychedelic Drugs: 5. STP". Journal of Psychedelic Drugs. 9 (2): 171–172. doi:10.1080/02791072.1977.10472044. ISSN 0022-393X. Archived from the original on 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.
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