The leaves of Mitragyna speciosa (kratom), a plant native to Southeast Asia, are increasingly used as a pain reliever and for attenuation of opioid withdrawal symptoms. Using the tools of natural ...products chemistry, chemical synthesis, and pharmacology, we provide a detailed in vitro and in vivo pharmacological characterization of the alkaloids in kratom. We report that metabolism of kratom’s major alkaloid, mitragynine, in mice leads to formation of (a) a potent mu opioid receptor agonist antinociceptive agent, 7-hydroxymitragynine, through a CYP3A-mediated pathway, which exhibits reinforcing properties, inhibition of gastrointestinal (GI) transit and reduced hyperlocomotion, (b) a multifunctional mu agonist/delta-kappa antagonist, mitragynine pseudoindoxyl, through a CYP3A-mediated skeletal rearrangement, displaying reduced hyperlocomotion, inhibition of GI transit and reinforcing properties, and (c) a potentially toxic metabolite, 3-dehydromitragynine, through a non-CYP oxidation pathway. Our results indicate that the oxidative metabolism of the mitragynine template beyond 7-hydroxymitragynine may have implications in its overall pharmacology in vivo.
Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-opioid receptor (MOR) agonist, kurkinorin (
), derived from salvinorin A. In an effort ...to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated
for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound,
, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively,
is over 100× more potent than morphine and over 5× more potent than fentanyl
and elicits antinociception with limited tolerance development
. This is especially significant given that
lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.
The arylethylamines substituted in the aryl ring, side-chain carbons and on the terminal amine, comprise a large number of human mood and behaviour altering chemicals. Some of these psychotropic ...drugs have been used since pre-history, but in many states are proscribed and are consequently subject to clandestine synthesis and illegal traffic world-wide in the forms particularly of amphetamines and to a lesser extent tryptamines. The chemistry employed in the synthesis of these compounds is dictated often by the available precursors and relies usually on relatively simple, unsophisticated conversion reactions to a suitable product. The internet web sites and documentation of the recreational drug culture have been studied alongside the professional scientific and regulatory literature. The review demonstrates the great complexity of the chemistry and neuro-pharmacology of these chemicals and the challenge faced by legislative bodies to control their traffic and use for the sake of social welfare.
The degree of alkylation of the side chain nitrogen in tryptamines is one important factor that affects psychoactivity. The method of Speeter and Anthony is considered to be one of the most important ...synthetic preparative methods. The final step in this reaction is based on the reduction of a (substituted) indole-3-yl-glyoxalylamide to the desired tryptamine with metal hydride. Twelve symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamides and their corresponding tryptamine derivatives have been synthesised and characterised by gas chromatography EI-ion trap mass spectrometry, electrospray-triple quadrupole-tandem mass spectrometry and NMR spectroscopy. Mass spectral and NMR similarities and differences between the investigated compounds are discussed. A solvent dependency is observed that has to be taken into consideration for the unambiguous assignment of (1)H- and (13)C-NMR chemical shifts. The (1)H-NMR study demonstrated that one can evaluate the rotamer populations of the asymmetrical glyoxalylamides. In a forensic or clinical scenario where single or multiple reaction monitoring approaches are contemplated, the appropriate ion transitions of choice may then focus on the two main fragmentations, namely beta-cleavage (M+H(+)-->CH(2)N(+)R(2)R(3)) and/or alpha-cleavage (M+H(+)-->3-vinylindole(+)), respectively. The synthesis, NMR and MS analytical data presented provide the forensic analyst and clinical biochemist with a detailed and self-consistent body of information and mechanisms for the spectral identification of the more likely psychoactive tryptamines that may be met.
The tryptamine nucleus is a building block for many biologically-active derivatives (e.g., neurotransmitter serotonin or antimigraine drugs of the triptan series). A variety of
N,
N-dialkylation of ...the nitrogen side chain can result in derivatives with psychoactive and hallucinogenic properties that are accessible by a large number of synthetic procedures.
The renewed interest in human clinical studies coincides with increased public interest and exchange of information on the Internet, including discussion in scientific, popular and clandestine literature. Over the past few years, an increasing number of case reports have attracted the attention of clinical, pharmaceutical, forensic and public-health communities, underlining the current lack of pharmaco-toxicological and analytical data.
This review assesses the current state of knowledge about the analytical profiling of drugs and by-products obtained from synthetic procedures discussed on Internet websites and scientific literature. Due to space considerations, we focus on detection using mass spectrometry (MS). We discuss commonalities and differences when considering fragmentation under a variety of ionization conditions and mass analysis using single-stage and multi-stage modes of MS.
Key features of mass-spectral fragmentation include formation of iminium-ion C
nH
2n+2N
+, normally assumed to be represented by appropriately substituted CH
2
N
+(R
1R
2) species. Isomeric derivatives can often be differentiated by secondary and tertiary fragmentations that form C
nH
2n+2N
+ species after loss of neutrals. Soft-ionization techniques (e.g., electrospray) are often characterized by intense 3-vinylindole
+-type species that reflect the extent of substitution on the indole ring. The fact that some tryptamines were found sensitive to halogenated solvents reminds the analyst to be aware of the potential for misinterpreting data when investigating the presence of route-specific impurities.
Many tryptamine derivatives are known to induce altered states of consciousness and are increasingly of interest in forensic and neurobiological studies. The analytical chemistry of certain synthetic ...routes to the tryptamines is discussed and likely side products and impurities identified, where literature reports are available. Recent examples from the authors’ laboratory are presented to highlight future prospects and implications for analytical procedures. The aim of this review is to provide the analytical chemist with the foundation chemistry and some analytical targets to be able to undertake direct characterisation of products and intermediates. These might become available from interdiction of clandestine operations in a forensic environment or during the synthesis of the tryptamines for investigative neurobiological and clinical procedures.
5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), a new psychoactive tryptamine derivative, has been synthesised by the Speeter and Anthony procedure. This synthetic route was characterised by ...ESI-MS-MS, ESI-TOF-MS and NMR. Side products have been identified as 3-(2-N,N-diisopropylamino-ethyl)-1H-indol-5-ol (5), 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanol (6), 2-(5-methoxy-1H-indol-3-yl)-ethanol (7) and 2-N,N-diisopropylamino-1-(5-methoxy-1H-indol-3-yl)-ethanone (8).
Twelve symmetrically and 13 asymmetrically N,N-disubstituted glyoxalylamide precursors and their corresponding tryptamine derivatives have been characterised by gas chromatography low-pressure ...chemical ionisation ion trap tandem mass spectrometry (CI-IT-MS-MS) with internal (in situ) ionisation using methanol as the chemical ionisation reagent. Mass spectral differences and similarities between the investigated compounds are discussed and put into context with previous investigations. In tryptamines the formation of CH2=N+R2R3 iminium ions after beta-cleavage appears to be the dominating process. Dissociation of the protonated molecule into 3-vinylindole+ for example, appears to be a minor pathway when compared with electrospray triple quadrupole tandem mass spectrometry (ESI-TQ-MS-MS) where this ion transition was found to be of distinctive importance. CI-IT-MS-MS is also found to enable the differentiation between most isomeric derivatives studied.
The psychoactive properties of
N,
N-dimethyltryptamine (DMT) are known to induce altered states of consciousness in humans. These properties attract great interest from clinical, neuroscientific, ...clandestine and forensic communities. The
Breath of Hope Synthesis was reported on an internet website as a convenient two-step methodology for the preparation of DMT. The analytical characterisation of the first stage was the subject of previous publications by the authors and involved the thermal decarboxylation of tryptophan and the formation of tryptamine. The present study reports on the characterisation of the second step of this procedure which was based on the methylation of tryptamine. This employed methyl iodide and benzyltriethylammonium chloride/sodium hydroxide as a phase transfer catalyst. The reaction product was characterised by liquid chromatography/electrospray ionisation tandem mass spectrometry and orthogonal acceleration time-of-flight mass spectrometry. Quantitative evaluation was carried out in positive multiple reaction monitoring mode (MRM), which included synthesis of the identified reaction products. MRM screening of the product did not lead to the detection of DMT. Instead, 11.1% tryptamine starting material, 21.0%
N,
N,
N-trimethyltryptammonium iodide (TMT) and 47.4% 1-
N-methyl-TMT were detected. A 0.5% trace of the monomethylated
N-methyltryptamine was also detected. This study demonstrated the impact on product purity of doubtful synthetic methodologies discussed on the internet.
A number of
N,
N-dialkylated tryptamines show psychoactive properties in man which resulted in a renewed interest in psychopharmacological research. Attempts to manufacture these derivatives are ...increasing within a clandestine environment, where literature procedures are adapted and information is exchanged on the Internet. One such example is based on the thermolytic decarboxylation of tryptophan to tryptamine as the precursor to psychoactive derivatives. This procedure was proposed to make use of household solvents such as
turpentine substitute and
white spirit to facilitate decarboxylation. Discussions on websites also suggested the catalytic use of natural oils in order to accelerate these reactions. In this research, the analytical characterization of this preparation procedure was carried out using gas chromatography–ion trap single and tandem stage mass spectrometry in electron and chemical ionization mode that led to the identification of previously unreported 1-mono and 1,1-disubstituted tetrahydro-β-carboline (THBCs) by-products. The tryptamine product and several THBC by-products were determined quantitatively and a “fingerprint” analysis of the crude products allowed for the differentiation between the essential oil catalysts involved as indicated by the presence of tetrahydro-β-carbolines and their imine intermediates.
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