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DeutschDMBMPP
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| Other names | Juncosamine; 2-(2,5-Dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine |
| Drug class | Selective serotonin 5-HT2A receptor agonist; Serotonergic psychedelic; Hallucinogen |
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| Chemical and physical data | |
| Formula | C21H26BrNO3 |
| Molar mass | 420.347 g·mol−1 |
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DMBMPP, also known as juncosamine or as 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is a highly selective serotonin 5-HT2A receptor agonist and 2-benzylpiperidine analogue of the serotonergic psychedelic 25B-NBOMe which is used in scientific research.[1][2][3][4]
Use
[edit]Research
[edit]Despite its uniquely high selectivity for the serotonin 5-HT2A receptor, it has been said that DMBMPP is not widely used as a pharmacological tool in scientific research, presumably due to its chemical synthesis being relatively inaccessible.[5] Consequently, 25CN-NBOH, another highly selective serotonin 5-HT2A receptor agonist, has been proposed as an alternative to DMBMPP for use in scientific research.[5] DMBMPP and 25CN-NBOH are the two most selective serotonin 5-HT2A receptor agonists known as of 2020.[6]
Pharmacology
[edit]The (S,S)-isomer ((2S,6S)-DMBMPP) is the most selective agonist for the human serotonin 5-HT2A receptor yet discovered, with a affinity (Ki) of 2.5 nM at the human serotonin 5-HT2A receptor and with 124-fold selectivity for the serotonin 5-HT2A receptor over the structurally similar serotonin 5-HT2C receptor.[4][7] Together with 25CN-NBOH,[8] (2S,6S)-DMBMPP is the only known 5-HT2A agonist to exhibit this level of selectivity.[5] In contrast to the case of the serotonin 5-HT2A receptor, no functional data has been reported for DMBMPP at the serotonin 5-HT2C receptor as of 2023.[9][5]
| Ligand | Ki ± SEM (nM) | Ki ± SEM (nM) | Ki ± SEM (nM) |
|---|---|---|---|
| [3H] ketanserin | [3H] mesulergine | fold selectivity | |
| h5-HT2A | h5-HT2C | h5-HT2C/h5-HT2A | |
| 2C-B | 6.0 ± 0.3 | 23.8 ± 2.6 | 9.5 |
| 25B-NBOMe | 0.19 ± 0.01 | 4.0 ± 0.4 | 21 |
| (±)-DMBMPP | 5.3 ± 0.3 | 520 ± 22 | 98 |
| (S,S)-(−)-DMBMPP | 2.5 ± 0.1 | 310 ± 42 | 124 |
| (R,R)-(+)-DMBMPP | 2,100 ± 171 | 28,600 ± 4700 | 27 |
(S,S)-DMBMPP was assessed and found to fully substitute for the psychedelic drug LSD in rodent drug discrimination tests.[10][11][4] As such, DMBMPP may be expected to have hallucinogenic effects in humans.[10][11][4]
Chemistry
[edit]DMBMPP, also known as 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is a cyclized phenethylamine, 2C, and NBOMe derivative of 2C-B and 25B-NBOMe.[2] It differs from 25B-NBOMe by incorporating the amine within a piperidine ring, making for a more conformationally restrained or rigid molecular structure than that of the open-chain 25B-NBOMe.[2] The presence of the piperidine ring introduces two stereocenters, thus, four stereoisomers of this compound can be made.[2]
History
[edit]DMBMPP was first described in the scientific literature by Jose Juncosa of the lab of David E. Nichols at Purdue University in 2011.[3][4]
See also
[edit]References
[edit]- ^ Trachsel, D.; Lehmann, D.; Enzensperger, C. (2013). Phenethylamine: von der Struktur zur Funktion [Phenethylamines: From Structure to Function]. Nachtschatten-Science (in German) (1 ed.). Solothurn: Nachtschatten-Verlag. pp. 866–867. ISBN 978-3-03788-700-4. OCLC 858805226. Retrieved 31 January 2025.
- ^ a b c d Halberstadt AL (2017). "Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens". Curr Top Behav Neurosci. 32: 283–311. doi:10.1007/7854_2016_64. PMID 28097528.
NBOMes exhibit a high degree of conformational flexibility and could potentially adopt a range of active binding poses. In order to identify the active conformation, Nichols and colleagues synthesized a series of rigid analogues of 25B-NBOMe [54]. Of the nine structurally constrained compounds tested, ()-trans-DMBMPP (Fig. 7) was the most potent, binding to human 5-HT2A receptors with a Ki of 5.3 nM. Interestingly, the affinity of ()-trans-DMBMPP for human 5-HT2C sites is significantly lower in comparison, making it 98-fold selective for 5-HT2A receptors. The (S,S) enantiomer of DMBMPP, resolved by derivatization with a chiral auxiliary, has even higher 5-HT2A affinity (Ki ¼ 2.5 nM) and is reportedly 124-fold selective for 5-HT2A vs. 5-HT2C receptors. By contrast, (R,R)-DMBMPP has μM affinity for 5-HT2A receptors (Fig. 7). It appears that the structural configuration of (S,S)-DMBMPP closely mirrors the active binding conformation of NBOMes. [...] Fig. 7 Structures of racemic trans-2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine (-trans-DMBMPP) and its S,S and R,R enantiomers. Binding affinities were assessed at human 5-HT2A and 5-HT2C receptors labeled with [3 H]ketanserin and [3 H]mesulergine, respectively [54].
- ^ a b Juncosa JI (2011-05-07). Organic synthesis combined with molecular modeling: A powerful approach to map the functional topography of dopamine and serotonin receptors (Ph.D. thesis). Purdue University.
- ^ a b c d e Juncosa JI, Hansen M, Bonner LA, Cueva JP, Maglathlin R, McCorvy JD, Marona-Lewicka D, Lill MA, Nichols DE (January 2013). "Extensive rigid analogue design maps the binding conformation of potent N-benzylphenethylamine 5-HT2A serotonin receptor agonist ligands". ACS Chemical Neuroscience. 4 (1): 96–109. doi:10.1021/cn3000668. PMC 3547484. PMID 23336049.
- ^ a b c d Märcher Rørsted E, Jensen AA, Kristensen JL (November 2021). "25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor". ChemMedChem. 16 (21): 3263–3270. doi:10.1002/cmdc.202100395. PMID 34288515.
In the quest for more sub-type selective tool agonists for the 5- HT2AR medicinal chemistry exploration has yielded several subtype selective scaffolds most notably the Benzylpiperidines and the N-Benzylphenethylamines. 2-(2,5-dimethoxy-4- bromobenzyl)-6-(2-methoxyphenyl)piperidine (DMBMPP, see Scheme 1.) represents the fomer and is one the most selective agonists reported to date, with high binding affinity to 5-HT2AR (Ki = 2.5 nM) and 124-fold selectivity towards the 5-HT2CR, although functional data is yet to be reported. [28] DMBMPP is not widely used as a pharmacological tool, presumably due to its relative inaccessibility from a synthetic standpoint.
- ^ Poulie CB, Jensen AA, Halberstadt AL, Kristensen JL (December 2020). "DARK Classics in Chemical Neuroscience: NBOMes" (PDF). ACS Chem Neurosci. 11 (23): 3860–3869. doi:10.1021/acschemneuro.9b00528. PMC 9191638. PMID 31657895.
- ^ Duan 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. PMID 38033123.
Structural rigidification of the ethyl chain has also led to the discovery of DMBMPP (158, Figure 13B),193 which displayed high affinity for the h5-HT2AR (Ki = 2.5 nM, [3 H]- mesulergine), more potent than that of its parental compound DOB. Notably, DMBMPP had a significant 124-fold 5- HT2AR/5-HT2CR selectivity, being one of the most selective 5-HT2AR agonists reported. DMBMPP exhibited potent partial agonist activity at the 5-HT2AR in the PI hydrolysis assay (EC50 = 74 nM, Emax = 73%).
- ^ Hansen M, Phonekeo K, Paine JS, Leth-Petersen S, Begtrup M, Bräuner-Osborne H, Kristensen JL (March 2014). "Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists". ACS Chemical Neuroscience. 5 (3): 243–9. doi:10.1021/cn400216u. PMC 3963123. PMID 24397362.
- ^ Marcher-Rørsted E, Nykodemová J, Harpsøe K, Jensen AA, Kristensen JL (March 2023). "Introducing Conformational Restraints on 25CN-NBOH: A Selective 5-HT2A Receptor Agonist". ACS Med Chem Lett. 14 (3): 319–325. doi:10.1021/acsmedchemlett.3c00014. PMC 10009789. PMID 36923922.
In order to probe the optimal spacial orientation of the highly flexible benzylethylamine chain of the NBOMe scaffold, Nichols in 2013 reported conformationally restricted NBOMe analogs and found 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2- methoxyphenyl)piperidine (DMPMBB, 2, Scheme 1) to be ∼100-fold more selective for 5-HT2AR over 5-HT2CR in a binding assay.11 Moreover, 2 displayed an EC50 value of 74 nM and an Rmax value of 73% at 5-HT2AR in a phosphoinositol hydrolysis assay,11 whereas no functional data for 2 at 5- HT2CR has been reported to date.
- ^ a b Halberstadt AL (January 2015). "Recent advances in the neuropsychopharmacology of serotonergic hallucinogens" (PDF). Behav Brain Res. 277: 99–120. doi:10.1016/j.bbr.2014.07.016. PMC 4642895. PMID 25036425.
- ^ a b Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Curr Top Behav Neurosci. 36: 1–43. doi:10.1007/7854_2017_475. PMID 28401524.
In an attempt to identify the active binding conformation of the N-benzylphenethylamines, a series of nine of conformationally constrained analogues of 76 was prepared (Juncosa et al. 2013). The most potent of these analogues was S,S enantiomer 77. This compound, as the racemate, had an EC50 of 74 nM and an Emax of 73% for PI hydrolysis through activation of the human 5-HT2A receptor. In drug discrimination experiments in rats trained to discriminate LSD from saline, 77 had an ED50 of 0.41 μmol/kg. Furthermore, (S,S)-(−)-77 had 124-fold selectivity for the 5-HT2A receptor versus the 5-HT2C receptor, using antagonist radioligands to measure affinity. [...]