Syntheses, analytical and pharmacological characterizations of the ‘legal high’ 4‐[1‐(3‐methoxyphenyl)cyclohexyl]morpholine (3‐MeO‐PCMo) and analogues

Colestock, Tristan; Wallach, Jason; Mansi, Matt; Filemban, Nadine; Morris, Hamilton; Elliott, Simon; Westphal, Folker; Brandt, Simon D.; Adejare, Adeboye

doi:10.1002/dta.2213

Cited by 13 publications

(7 citation statements)

References 40 publications

(105 reference statements)

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“…For example, in the case of GABA (γ-aminobutyric acid) receptor, it has been recently reported how the introduction of morpholine to a 1,5-benzodiazepine derivative (such as clobazam) can increase the anxiolytic activity, by modulating the overall pharmacokinetic profile of compound 7 (Figure ). On the contrary, in the case of NMDA ( N -methyl- d -aspartate) receptor, a calcium channel target for achieving analgesic and antipyretic effects, the phencyclidine analogue 8 with agonist activity (Figure ) possesses a morpholine instead of a methylamino group (as in ketamine), resulting in the morpholine moiety directly interacting with the receptor as a pharmacophoric element …”

Section: Biological Activity Of Morpholine Derivatives In Mood Disord...mentioning

confidence: 99%

“…67 On the contrary, in the case of NMDA (N-methyl-Daspartate) receptor, a calcium channel target for achieving analgesic and antipyretic effects, the phencyclidine analogue 8 with agonist activity (Figure 8) possesses a morpholine instead of a methylamino group (as in ketamine), resulting in the morpholine moiety directly interacting with the receptor as a pharmacophoric element. 68 ■ BIOLOGICAL ACTIVITY OF MORPHOLINE DERIVATIVES IN NEURODEGENERATIVE DISEASES Parkinson's disease (PD) is a long-term progressive degenerative disorder that affects more than 10 million people worldwide, with a variety of clinical symptoms related to the motor system, such as shaking, rigidity, slowness of movement, and difficulty with walking. 69 Although many pharmacological agents have been specifically developed over the past decades, there is still no cure for Parkinson's disease, but only some treatments that can alleviate motor symptoms, even though with undesirable adverse effects.…”

Section: ■ Biological Activity Of Morpholine Derivatives In Mood Diso...mentioning

confidence: 99%

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Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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Developing drugs for the central nervous system (CNS) requires fine chemical modifications, as a strict balance between size and lipophilicity is necessary to improve the permeability through the blood-brain barrier (BBB). In this context, morpholine and its analogues represent valuable heterocycles, due to their conformational and physicochemical properties. In fact, the presence of a weak basic nitrogen atom and of an oxygen atom at the opposite position provides a peculiar pK a value and a flexible conformation to the ring, thus allowing it to take part in several lipophilic−hydrophilic interactions, and to improve blood solubility and brain permeability of the overall structure. In CNS-active compounds, morpholines are used (1) to enhance the potency through molecular interactions, (2) to act as a scaffold directing the appendages in the correct position, and (3) to modulate pharmacokinetic/ pharmacodynamic (PK/PD) properties. In this perspective, selected morpholinecontaining CNS drug candidates are discussed to reveal the active pharmacophores accountable for the (1) modulation of receptors involved in mood disorders and pain, (2) bioactivity toward enzymes and receptors responsible for neurodegenerative diseases, and (3) inhibition of enzymes involved in the pathology of CNS tumors. The medicinal chemistry/pharmacological activity of morpholine derivatives is discussed, in the effort to highlight the importance of morpholine ring interactions in the active site of different targets, particularly reporting binding features retrieved from PDB data, when available.

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Section: Biological Activity Of Morpholine Derivatives In Mood Disord...mentioning

confidence: 99%

Section: ■ Biological Activity Of Morpholine Derivatives In Mood Diso...mentioning

confidence: 99%

Occurrence of Morpholine in Central Nervous System Drug Discovery

Lenci

Calugi

Trabocchi

2021

ACS Chem. Neurosci.

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“…Similarly diphenidine is abbreviated DPP. 7 Following on from previous work on the analytical and pharmacological characterization of dissociative substances, [10][11][12][13][14][15] it was considered necessary to extend the explorations to emerging NPS of this type. Some basic analytical data for fluorolintane are available in the public domain 16 and a synthetic route has recently been described.…”

Section: Introductionmentioning

confidence: 99%

Syntheses and analytical characterizations of the research chemical 1‐[1‐(2‐fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane) and five of its isomers

Dybek

Wallach

Kavanagh

et al. 2019

Drug Testing and Analysis

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A number of substances based on the 1,2‐diarylethylamine template have been investigated for various potential clinical applications whereas others have been encountered as research chemicals sold for non‐medical use. Some of these substances have transpired to function as NMDA receptor antagonists that elicit dissociative effects in people who use these substances recreationally. 1‐[1‐(2‐Fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane, 2‐F‐DPPy) has recently appeared as a research chemical, which users report has dissociative effects. One common difficulty encountered by stakeholders confronting the appearance of new psychoactive substances is the presence of positional isomers. In the case of fluorolintane, the presence of the fluorine substituent on either the phenyl and benzyl moieties of the 1,2‐diarylethylamine structure results in a total number of six possible racemic isomers, namely 2‐F‐, 3‐F‐, and 4‐F‐DPPy (phenyl ring substituents) and 2”‐F‐, 3”‐F‐, and 4”‐F‐DPPy (benzyl ring substituents). The present study reports the chemical syntheses and comprehensive analytical characterizations of the two sets of three positional isomers. These studies included various low‐ and high‐resolution mass spectrometry platforms, gas‐ and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy and GC‐condensed phase and attenuated total reflection infrared spectroscopy analyses. The differentiation between each set of three isomers was possible under a variety of experimental conditions including GC chemical ionization triple quadrupole tandem mass spectrometric analysis of the [M + H – HF]+ species. The latter MS method was particularly helpful as it revealed distinct formations of product ions for each of the six investigated substances.

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“…called “NBOMes” . Other examples include methoxy or methylenedioxy analogues of arylcyclohexylamines such as PCP (e.g., 3‐MeO‐PCP) and associated morpholine analogues (e.g., 3‐MeO‐PCMo and 3,4‐MD‐PCMo) or N ‐alkyl analogues . These substances have pharmacological activity in their own right and do not act as prodrugs (e.g., 3‐MeO‐PCP does not metabolize to form PCP); however, other derivatives and analogues of hallucinogenic substances (below) have been developed, discussed, and made available for online purchase that could be considered to be prodrugs.…”

Section: Prodrugs Of Psychoactive Substancesmentioning

confidence: 99%

Prodrugs of New Psychoactive Substances (NPS): A New Challenge

Elliott

Holdbrook

Brandt

2020

Journal of Forensic Sciences

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The concept of a substance acting as a prodrug for an intended drug is not new and has been known and utilized with particular benefits within medicine for efficacy and patient safety. Prodrugs of psychoactive substances are also not particularly new but this has also extended to considerations of prodrugs of new psychoactive substances (NPS). The continuing evolution of NPS has been a constant forensic challenge. In some countries, this constant evolution has led to the introduction of various alternative methods of drug control. Whether for this reason or in the pursuit of user experimentation, prodrugs of NPS have been discussed, developed, and exploited, posing some distinct forensic challenges. This is especially the case within toxicological analysis of biological fluids and for some substances, also forensic chemical analysis, through inherent instability of the prodrug or metabolism in the body. Particular examples of NPS prodrugs include 1-propanoyl-LSD, 1-butanoyl-LSD, 1-acetyl-LSD, and 2C-B-AN. This is in addition to associated substances and medicines that may be used for an intended pharmacological effect. Various prodrugs for stimulant and hallucinogenic substances in particular have appeared in the literature and have been discussed within drug user forums and made available for purchase online. Presently, drug monitoring data from national and international systems indicate that prodrugs are not widely available or problematic. Nevertheless, it is important that there is sufficient awareness of the prodrug concept and potential impact and associated forensic implications, not just for chemical analysis but also for toxicological considerations when a substance has been used.

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Syntheses, analytical and pharmacological characterizations of the ‘legal high’ 4‐[1‐(3‐methoxyphenyl)cyclohexyl]morpholine (3‐MeO‐PCMo) and analogues

Cited by 13 publications

References 40 publications

Occurrence of Morpholine in Central Nervous System Drug Discovery

Occurrence of Morpholine in Central Nervous System Drug Discovery

Syntheses and analytical characterizations of the research chemical 1‐[1‐(2‐fluorophenyl)‐2‐phenylethyl]pyrrolidine (fluorolintane) and five of its isomers

Prodrugs of New Psychoactive Substances (NPS): A New Challenge

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