2-(甲基氨基)-1-(4-甲基苯基)-1-丙酮盐酸盐 | 1189726-22-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 2-(甲基氨基)-1-(4-甲基苯基)-1-丙酮盐酸盐
• 中文别名: 2-甲基氨基-1-对甲苯-1-丙酮盐酸盐
• 英文名称: mephedrone hydrochloride
• 英文别名: 4-methylmethcathinone hydrochloride；mephedrone；mephedrone·HCl；2-(methylamino)-1-(4-methylphenyl)propan-1-one;hydrochloride
• CAS: 1189726-22-4
• 化学式: C₁₁H₁₅NO*ClH
• 分子量: 213.707
• InChiKey: DLQZFTUKJGRPLZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.21
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  29.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(甲基氨基)-1-(4-甲基苯基)-1-丙酮盐酸盐 在 potassium carbonate 作用下， 以 水 为溶剂， 生成 甲氧麻黄酮
  参考文献：
  名称：

  X-ray structures and computational studies of several cathinones

  摘要：

  2-(Ethylamino)-1-(4-methylphenyl)propan-l-one (shortly named 4-MEC) (1a), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (shortly named methylone or 3,4-methylenedioxymethcathinone) (1b), 1-(3,4-dimethylphenyl)-2-(methylamino)propan-1-one (1c), 2-methylamino-1-(4-methylphenyl)propan-1 -one (shortly named mephedrone; 4-MMC or 4-methylmethcathinone) (1d) and 2-(methylamino)-1-phenylbutan-1 -one (shortly named buphedrone) (1e) and their aminium salts (2a-e), are examples of cathinones which were characterized by FTIR, UV-Vis, multinuclear NMR spectroscopy. By single crystal X-ray diffraction method structures of 2a, 2h, 2c and 2d were determined. NMR solution spectra showed readily diagnostic H-1 and C-13 signals from methyl, ethyl, N-methyl or N-ethyl groups. The diastereotopic methylene protons of la appear as an ABX(3), and le and 2e appear as an ABMX(3) system. The geometries of the studied compounds were optimized in singlet states using the density functional theory (OFT) method with B3LYP functional. Electronic spectra were calculated by TDDFT method. In general, the predicted bond lengths and angles are in good agreement with the values based on the X-ray crystal structure data. (C) 2011 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.molstruc.2011.06.030
• 作为产物：
  描述：

  对甲基苯丙酮 在 溴 、 溶剂黄146 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 17.0h， 生成 2-(甲基氨基)-1-(4-甲基苯基)-1-丙酮盐酸盐
  参考文献：
  名称：

  Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats

  摘要：

  Background and PurposeSynthetic cathinones, commonly referred to as ‘bath salts’, are a group of amphetamine‐like drugs gaining popularity worldwide. 4‐Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate‐type releaser at monoamine transporters. Similar to other cathinone‐related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R‐mephedrone (R‐MEPH) and S‐mephedrone (S‐MEPH).Experimental ApproachHere, we provide the first investigation into the neurochemical and behavioural effects of R‐MEPH and S‐MEPH. We analysed both enantiomers in rat brain synaptosome neurotransmitter release assays and also investigated their effects on locomotor activity (e.g. ambulatory activity and repetitive movements), behavioural sensitization and reward.Key ResultsBoth enantiomers displayed similar potency as substrates (i.e. releasers) at dopamine transporters, but R‐MEPH was much less potent than S‐MEPH as a substrate at 5‐HT transporters. Locomotor activity was evaluated in acute and repeated administration paradigms, with R‐MEPH producing greater repetitive movements than S‐MEPH across multiple doses. After repeated drug exposure, only R‐MEPH produced sensitization of repetitive movements. R‐MEPH produced a conditioned place preference whereas S‐MEPH did not. Lastly, R‐MEPH and S‐MEPH produced biphasic profiles in an assay of intracranial self‐stimulation (ICSS), but R‐MEPH produced greater ICSS facilitation than S‐MEPH.Conclusions and ImplicationsOur data are the first to demonstrate stereospecific effects of MEPH enantiomers and suggest that the predominant dopaminergic actions of R‐MEPH (i.e. the lack of serotonergic actions) render this stereoisomer more stimulant‐like when compared with S‐MEPH. This hypothesis warrants further study.

  DOI：

  10.1111/bph.12951

文献信息

• Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
  作者：F P Mayer、L Wimmer、O Dillon‐Carter、J S Partilla、N V Burchardt、M D Mihovilovic、M H Baumann、H H Sitte

  DOI：10.1111/bph.13547

  日期：2016.9

  Background and Purpose4‐Methyl‐N‐methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate‐type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5‐HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N‐demethylated metabolite, 4‐methylcathinone (nor‐mephedrone); the ring‐hydroxylated metabolite, 4‐hydroxytolylmephedrone (4‐OH‐mephedrone); and the reduced keto‐metabolite, dihydromephedrone.Experimental ApproachWe used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter‐mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3 mg·kg−1) on extracellular dopamine and 5‐HT levels in rat nucleus accumbens.Key ResultsIn cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor‐mephedrone and 4‐OH‐mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor‐mephedrone produced elevations in extracellular dopamine and 5‐HT, whereas 4‐OH‐mephedrone did not. Mephedrone and nor‐mephedrone, but not 4‐OH‐mephedrone, induced locomotor activity.Conclusions and ImplicationsOur results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor‐mephedrone increases extracellular dopamine and 5‐HT in the brain whereas 4‐OH‐mephedrone does not, suggesting the latter metabolite does not penetrate the blood–brain barrier. Future studies should examine the pharmacokinetics of nor‐mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
• Is the 3,4-methylendioxypyrovalerone/mephedrone combination responsible for enhanced stimulant effects? A rat study with investigation of the effect/concentration relationships
  作者：Nadia Benturquia、Lucie Chevillard、Christophe Poiré、Olivier Roussel、Camille Cohier、Xavier Declèves、Jean-Louis Laplanche、Mélanie Etheve-Quelquejeu、Huixiong Chen、Bruno Mégarbane

  DOI：10.1007/s00213-018-4962-0

  日期：2019.3

  RationaleThe use of synthetic cathinones as recreational drugs frequently sold in combination has been increasing exponentially. However, the consequences of combining cathinones on the resulting stimulant effects and the pharmacokinetics have been poorly investigated.Objective and methodsTo study 3,4-methylenedioxypyrovalerone (MDPV; 3mg/kg) and mephedrone (4-MMC; 30mg/kg)-induced effects on rat locomotor activity and pharmacokinetics, administered alone or in combination by the intragastric route. The pharmacokinetic parameters were determined using non-compartmental analysis and the relationships between the locomotor activity and drug concentrations using sigmoidal E-max modeling.ResultsLocomotor activity significantly increased during the first hour post-administration with the MDPV/4-MMC combination in comparison to MDPV (p<0.001) and 4-MMC (p<0.01) alone. The pharmacokinetic profile of MDPV, but not 4-MMC, was significantly modified with the combination resulting in decreases in C-max (16.45.5 versus 62.2 +/- 14.2g/L, p<0.05) and AUC(0) (708 +/- 91 versus 3316 +/- 682g/L/min, p<0.01) and increases in V/F (582.6 +/- 136.8 versus 115.9 +/- 42.7L/kg, p<0.05) and Cl/F (4.6 +/- 0.7 versus 1.2 +/- 0.4L/kg/min, p<0.01) in comparison to MDPV alone. The sigmoidal E-max model fitted the observed data well; MDPV being markedly more potent than 4-MMC (EC50, 0.043 versus 0.7mol/L). The enhancing factor representing the MDPV contribution to the alteration in the relationships between locomotor activity and 4-MMC concentrations was 0.3.Conclusion An MDPV/4-MMC combination results in enhanced stimulant effects in the rat, despite significant reduction in MDPV bioavailability. Enhanced effects could be explained by increased MDPV distribution and/or possible complementation at the brain dopaminergic targets. However, the exact consequences of the MDPV/4-MMC combination in humans remain to be clarified.
• Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats
  作者：Ryan A Gregg、Michael H Baumann、John S Partilla、Julie S Bonano、Alexandre Vouga、Christopher S Tallarida、Venkata Velvadapu、Garry R Smith、M Melissa Peet、Allen B Reitz、S Stevens Negus、Scott M Rawls

  DOI：10.1111/bph.12951

  日期：2015.2

  Background and PurposeSynthetic cathinones, commonly referred to as ‘bath salts’, are a group of amphetamine‐like drugs gaining popularity worldwide. 4‐Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate‐type releaser at monoamine transporters. Similar to other cathinone‐related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R‐mephedrone (R‐MEPH) and S‐mephedrone (S‐MEPH).Experimental ApproachHere, we provide the first investigation into the neurochemical and behavioural effects of R‐MEPH and S‐MEPH. We analysed both enantiomers in rat brain synaptosome neurotransmitter release assays and also investigated their effects on locomotor activity (e.g. ambulatory activity and repetitive movements), behavioural sensitization and reward.Key ResultsBoth enantiomers displayed similar potency as substrates (i.e. releasers) at dopamine transporters, but R‐MEPH was much less potent than S‐MEPH as a substrate at 5‐HT transporters. Locomotor activity was evaluated in acute and repeated administration paradigms, with R‐MEPH producing greater repetitive movements than S‐MEPH across multiple doses. After repeated drug exposure, only R‐MEPH produced sensitization of repetitive movements. R‐MEPH produced a conditioned place preference whereas S‐MEPH did not. Lastly, R‐MEPH and S‐MEPH produced biphasic profiles in an assay of intracranial self‐stimulation (ICSS), but R‐MEPH produced greater ICSS facilitation than S‐MEPH.Conclusions and ImplicationsOur data are the first to demonstrate stereospecific effects of MEPH enantiomers and suggest that the predominant dopaminergic actions of R‐MEPH (i.e. the lack of serotonergic actions) render this stereoisomer more stimulant‐like when compared with S‐MEPH. This hypothesis warrants further study.
• X-ray structures and computational studies of several cathinones
  作者：Jacek E. Nycz、Grzegorz Malecki、Marcin Zawiazalec、Tadeusz Pazdziorek

  DOI：10.1016/j.molstruc.2011.06.030

  日期：2011.9

  2-(Ethylamino)-1-(4-methylphenyl)propan-l-one (shortly named 4-MEC) (1a), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (shortly named methylone or 3,4-methylenedioxymethcathinone) (1b), 1-(3,4-dimethylphenyl)-2-(methylamino)propan-1-one (1c), 2-methylamino-1-(4-methylphenyl)propan-1 -one (shortly named mephedrone; 4-MMC or 4-methylmethcathinone) (1d) and 2-(methylamino)-1-phenylbutan-1 -one (shortly named buphedrone) (1e) and their aminium salts (2a-e), are examples of cathinones which were characterized by FTIR, UV-Vis, multinuclear NMR spectroscopy. By single crystal X-ray diffraction method structures of 2a, 2h, 2c and 2d were determined. NMR solution spectra showed readily diagnostic H-1 and C-13 signals from methyl, ethyl, N-methyl or N-ethyl groups. The diastereotopic methylene protons of la appear as an ABX(3), and le and 2e appear as an ABMX(3) system. The geometries of the studied compounds were optimized in singlet states using the density functional theory (OFT) method with B3LYP functional. Electronic spectra were calculated by TDDFT method. In general, the predicted bond lengths and angles are in good agreement with the values based on the X-ray crystal structure data. (C) 2011 Elsevier B.V. All rights reserved.