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| Other names | Juncosamine; 2-(2,5-Dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine |
| Drug class | Selectiveserotonin5-HT2A receptoragonist;Serotonergic psychedelic;Hallucinogen |
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| Chemical and physical data | |
| Formula | C21H26BrNO3 |
| Molar mass | 420.347 g·mol−1 |
| 3D model (JSmol) | |
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DMBMPP, also known asjuncosamine or as2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is a highlyselectiveserotonin5-HT2A receptoragonist and2-benzylpiperidineanalogue of theserotonergic psychedelic25B-NBOMe which is used inscientific research.[1][2][3][4]
Despite its uniquely highselectivity for theserotonin5-HT2A receptor, it has been said that DMBMPP is not widely used as apharmacological tool inscientific research, presumably due to itschemical 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]
The (S,S)-isomer ((2S,6S)-DMBMPP) is the mostselectiveagonist for the humanserotonin5-HT2A receptor yet discovered, with aaffinity (Ki) of 2.5 nM at the human serotonin 5-HT2A receptor and with 124-foldselectivity for the serotonin 5-HT2A receptor over the structurally similar serotonin5-HT2C receptor.[4][7] Together with25CN-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 thepsychedelic drugLSD in rodentdrug discrimination tests.[10][11][4] As such, DMBMPP may be expected to havehallucinogenic effects in humans.[10][11][4]
DMBMPP, also known as 2-(2,5-dimethoxy-4-bromobenzyl)-6-(2-methoxyphenyl)piperidine, is acyclized phenethylamine,2C, andNBOMederivative of2C-B and25B-NBOMe.[2] It differs from 25B-NBOMe by incorporating theamine within apiperidinering, making for a moreconformationally restrained, rigidmolecular structure than that of theopen-chain 25B-NBOMe.[2] The presence of the piperidine ring introduces twostereocenters, thus, fourstereoisomers of this compound can be made.[2]
DMBMPP was first described in thescientific literature by Jose Juncosa of the lab ofDavid E. Nichols atPurdue University in 2011.[3][4]
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].
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 former 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.
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%).
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.
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. [...]
