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Pharmacology of 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2, and DOC at DAT, SERT, and NET: effects on binding and function
Source publication
Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C-I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4-chloroamphetamine (DOC) are used recreationally and may have d...
Context in source publication
Context 1
... the transporter assays, the phenethylamines had no measur- able or very low affinity for hDAT and hNET in the binding assays, and very low potency (at least micromolar) in the [ 3 H]dopamine and [ 3 H]norepinephrine uptake assays (Table 3). Only 2C-I had measurable affinity (high nanomolar) for hSERT and very low potency in the [ 3 H]serotonin uptake assay. ...
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At first glance, it appears there is little difference between the molecular structures of methylenedioxymethamphetamine (MDMA), which has an N-methyl attached to its amino group, and methylenedioxyamphetamine (MDA), a primary amine that is recognized to have hallucinogenic activity. It is known from studies with other hallucinogenic amphetamines t...
Citations
... HTR and locomotor activity play important roles in understanding the pharmacology of indoleamines and phenylalkylamines hallucinogens in animals Eshleman et al. 2014;Li et al. 2023). Phenylalkylamine hallucinogens, such as DOM and DOI, produced an inverted U-shaped dose-response function in both HTR and locomotor activity tests (Halberstadt et al. 2009Li et al. 2023). ...
... In addition to the 5-HT 2A receptor, DOM also exhibits high selectivity for the 5-HT 2C receptor (Egan et al. 1998;Ray 2010;Eshleman et al. 2014). Similar to the 5-HT 2A receptor, the 5-HT 2C receptor is also a Gα q/11 -proteincoupled receptor (Nichols and Nichols 2008). ...
... Analysis was performed using Student's t-test (e) Gα i/o pathway after co-administration of 8-OH-DPAT with DOM may go beyond PTX inhibition. In contrast to the high selectivity for 5-HT 2A/2C receptors, DOM exhibits a low affinity for 5-HT 1A sites (with over a 1000-fold selectivity for 5-HT 2 receptors compared to 5-HT 1 receptors) (Titeler et al. 1988;Ray 2010;Eshleman et al. 2014). The 5-HT 1A receptor, shows a distinct distribution in the brain. ...
Rationale
The phenylalkylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) exhibits an inverted U-shaped dose-response curve for both head twitch response (HTR) and locomotor activity in mice. Accumulated studies suggest that HTR and locomotor hyperactivity induced by DOM are mainly caused by the activation of serotonin 5-hydroxytryptamine 2 A receptor (5-HT2A receptor). However, the mechanisms underlying the biphasic dose response of HTR and locomotor activity induced by DOM, particularly at high doses, remain unclear.
Objectives
The primary objective of this study is to investigate the modulation of 5-HT2A/2C/1A receptors in HTR and locomotor activity, while also exploring the potential receptor mechanisms underlying the biphasic dose response of DOM.
Methods
In this study, we employed pharmacological methods to identify the specific 5-HT receptor subtypes responsible for mediating the biphasic dose-response effects of DOM on HTR and locomotor activity in C57BL/6J mice.
Results
The 5-HT2A receptor selective antagonist (R)-[2,3-di(methoxy)phenyl]-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (M100907) (500 µg/kg, i.p.) fully blocked the HTR at every dose of DOM (0.615–10 mg/kg, i.p.) in C57BL/6J mice. M100907 (50 µg/kg, i.p.) decreased the locomotor hyperactivity induced by a low dose of DOM (0.625, 1.25 mg/kg, i.p.), but had no effect on the locomotor hypoactivity induced by a high dose of DOM (10 mg/kg) in C57BL/6J mice. The 5-HT2C antagonist 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) (0.3, 1 mg/kg, i.p.) reduced the HTR induced by a dose of 2.5 mg/kg DOM, but did not affect the response to other doses. SB242084 (1 mg/kg, i.p.) significantly increased the locomotor activity induced by DOM (0.615–10 mg/kg, i.p.) in mice. The 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY100635) (1 mg/kg, i.p.) increased both HTR and locomotor activity induced by DOM in mice. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (1 mg/kg, i.p.) significantly reduced both the HTR and locomotor activity induced by DOM in mice. Additionally, pretreatment with the Gαi/o inhibitor PTX (0.25 µg/mouse, i.c.v.) enhanced the HTR induced by DOM and attenuated the effect of DOM on locomotor activity in mice.
Conclusions
Receptor subtypes 5-HT2C and 5-HT1A are implicated in the inverted U-shaped dose-response curves of HTR and locomotor activity induced by DOM in mice. The biphasic dose-response function of HTR and locomotor activity induced by DOM has different mechanisms in mice.
... While looking into the reason for this apparent discrepancy was not within the scope of this manuscript, the known promiscuous receptor activation potential of several of these compounds (e.g. binding and activating a multitude of 5-HT 2 Rs (Porter et al. 1999;Ray 2010;Halberstadt and Geyer 2011;Eshleman et al. 2014Eshleman et al. , 2018), combined with a more downstream event being scored by the Aequoscreen® assay (as opposed to a receptor-proximal event scored by the βarr2 assay), may be an obvious explanation. ...
New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. Their molecular targets are often inadequately elucidated, which contributes to the delayed characterization of their pharmacological effects. Inspired by earlier findings, this study set out to investigate the µ opioid receptor (MOR) activation potential of a large set of psychedelics, substances which typically activate the serotonin (5-HT2A) receptor as their target receptor. We observed that some substances carrying the N-benzyl phenethylamine (NBOMe) structure activated MOR, as confirmed by both the NanoBiT® βarr2 recruitment assay and the G protein-based AequoScreen® Ca²⁺ release assay. The use of two orthogonal systems proved beneficial as some aspecific, receptor independent effects were found for various analogs when using the Ca²⁺ release assay. The specific ‘off-target’ effects at MOR could be blocked by the opioid antagonist naloxone, suggesting that these NBOMes occupy the same common opioid binding pocket as conventional opioids. This was corroborated by molecular docking, which revealed the plausibility of multiple interactions of 25I-NBOMe with MOR, similar to those observed for opioids. Additionally, structure–activity relationship findings seen in vitro were rationalized in silico for two 25I-NBOMe isomers. Overall, as MOR activity of these psychedelics was only noticed at high concentrations, we consider it unlikely that for the tested compounds there will be a relevant opioid toxicity in vivo at physiologically relevant concentrations. However, small modifications to the original NBOMe structure may result in a panel of more efficacious and potent MOR agonists, potentially exhibiting a dual MOR/5-HT2A activation potential.
... DMT activates 5-HT 2A with nM potency (Blough et al., 2014;Eshleman et al., 2014;Rickli et al., 2016). 5-HT 2A is an excitatory G q/11 G protein-coupled receptor (GPCR) that is expressed at high levels in cortex layer V pyramidal, glutamatergic neurons Marek, 1997, 1999). ...
... The co-administration of pindolol, an agonist of 5-HT 1A , potentiates the effects of DMT in humans (Strassman et al., 1996). DMT is also known to bind to 5-HT 2C (Keiser et al., 2009;Ray, 2010;Eshleman et al., 2014), an excitatory GPCR that is expressed in deep, cortical GABAergic interneurons (Nocjar et al., 2015). 5-HT 2C agonists have also been shown to block DMT-dependent behavioral cues in rats (Carbonaro et al., 2015). ...
... DMT is known to activate phospholipase A2 through 5-HT 2A with 105% efficacy when compared to 5-HT. In turn, phospholipase A2 recruits mitogen-activated protein kinases (extracellular signal-related kinase 1/2 and p38) (Eshleman et al., 2014). Furthermore, DMT and other psychedelics, but not 5-HT, are known to increase the number of branches and mature spines in the dendritic trees of cortex layer V pyramidal neurons in mice. ...
... Unlike the LSD discriminative cue, pharmacological characterisation of the DOI or DOM responses show no contribution from 5-HT 1A receptors, dopamine receptors, or α 2 -adrenoceptors (Glennon and Hauck, 1985;Schreiber et al., 1994;Fiorella et al., 1997;Benneyworth et al., 2005;Marona-Lewicka et al., 2009). In addition to cross-substitution between DOI, DOB and DOM, a large raft of serotonergic psychedelics have been reported to generalise to these 5-HT 2A partial agonists (see Glennon et al., 1983;Eshleman et al., 2014;Halberstadt et al., 2020). Glennon et al. (1983) and Halberstadt et al. (2020) have described strong correlations between the potency of 5-HT 2A agonists to produce hallucinations in humans and their potency to generalise to DOM in drug-discrimination. ...
... Fenfluramine is a 5-HT releasing agent that is structurally and pharmacologically related to MDMA that induces head-twitches (Green and Heal, 1985;Heal et al., 1992) and at supratherapeutic doses is hallucinogenic in humans (Levin, 1973;Griffith et al., 1975). More recently, novel substituted phenethylamines have appeared as "designer drugs" which possess both 5-HT 2A agonist and monoamine releasing properties, e.g., 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,5dimethoxy-4-methylphenethylamine (2C-D), 2,5-dimethoxy-4ethylphenethylamine (2C-E), 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5dimethoxy-4-chloroamphetamine (DOC) (Eshleman et al., 2014). This finding confirms the feasibility of combining these two pharmacological actions in a single molecule. ...
... Evaluating the cue elicited by a novel drug-candidate with mixed 5-HT 2A agonist/monoamine releasing effects is even more problematic because compounds with this pharmacological profile do not consistently generalise either to 5-HT 2A agonists or MDMA. Based on the results reported by Eshleman et al. (2014), most would, however, achieve >60% generalisation to the cues produced by MDMA or a 5-HT 2A agonist and, therefore, exceed the threshold which the FDA sets for compounds sharing some pharmacological similarity to the training substance of abuse (CDER/FDA, 2017). ...
Research on classical psychedelics (psilocybin, LSD and DMT) and entactogen, MDMA, has produced a renaissance in the search for more effective drugs to treat psychiatric, neurological and various peripheral disorders. Psychedelics and entactogens act though interaction with 5-HT 2A and other serotonergic receptors and/or monoamine reuptake transporters. 5-HT, which serves as a neurotransmitter and hormone, is ubiquitously distributed in the brain and peripheral organs, tissues and cells where it has vasoconstrictor, pro-inflammatory and pro-nociceptive actions. Serotonergic psychedelics and entactogens have known safety and toxicity risks. For these drugs, the risks been extensively researched and empirically assessed through human experience. However, novel drug-candidates require thorough non-clinical testing not only to predict clinical efficacy, but also to address the risks they pose during clinical development and later after approval as prescription medicines. We have defined the challenges researchers will encounter when developing novel serotonergic psychedelics and entactogens. We describe screening techniques to predict clinical efficacy and address the safety/toxicity risks emerging from our knowledge of the existing drugs: 1) An early-stage, non-clinical screening cascade to pharmacologically characterise novel drug-candidates. 2) Models to detect hallucinogenic activity. 3) Models to differentiate hallucinogens from entactogens. 4) Non-clinical preclinical lead optimisation technology (PLOT) screening to select drug-candidates. 5) Modified animal models to evaluate the abuse and dependence risks of novel psychedelics in Safety Pharma-cology testing. Our intention has been to design non-clinical screening strategies that will reset the balance between benefits and harms to deliver more effective and safer novel psychedelics for clinical use.
... 2C-T-7 produces hallucinogen-like effects in rats and monkeys trained to discriminate DOM (Khorana et al. 2004;Li et al. 2010Li et al. , 2008. When tested in rats trained to discriminate LSD or DMT, however, 2C-T-7 and 2C-T-2 produced partial generalization but did not fully substitute for the training drug (Eshleman et al. 2014;Fantegrossi et al. 2005). Rats can also be trained to discriminate 2C-T-7 from saline using two-lever drug discrimination procedures and substitution is blocked by the selective 5-HT 2A antagonist M100907, indicating the stimulus cue is mediated by the 5-HT 2A receptor (Fantegrossi et al. 2005). ...
... With the exception of ALEPH-1 and 2C-T-21, the phenylalkylamines evaluated above were previously found to bind to and activate 5-HT 2 receptor subtypes (Fantegrossi et al., 2005;Eshleman et al., 2014;Rickli et al., 2015;Luethi et al., 2018). Binding and functional assays were therefore performed with ALEPH-1 and 2C-T-21 to assess their interaction with human 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors. ...
Rationale
4-Thio-substituted phenylalkylamines such as 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2) and 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) produce psychedelic effects in humans and have been distributed as recreational drugs.
Objectives
The present studies were conducted to examine the structure–activity relationships (SAR) of a series of 4-thio-substituted phenylalkylamines using the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by psychedelic drugs in mice. The HTR is commonly used as a behavioral proxy in rodents for human psychedelic effects and can be used to discriminate hallucinogenic and non-hallucinogenic 5-HT2A agonists.
Methods
HTR dose–response studies with twelve different 4-thio-substituted phenylalkylamines were conducted in male C57BL/6 J mice. To detect the HTR, head movement was recorded electronically using a magnetometer coil and then head twitches were identified in the recordings using a validated method based on artificial intelligence.
Results
2C-T, the parent compound of this series, had relatively low potency in the HTR paradigm, but adding an α-methyl group increased potency fivefold. Potency was also increased when the 4-methylthio group was extended by one to three methylene units. Fluorination of the 4-position alkylthio chain, however, was detrimental for activity, as was the presence of a 4-allylthio substituent versus a propylthio group. 2C-T analogs containing a 4-benzylthio group showed little or no effect in the HTR paradigm, which is consistent with evidence that bulky 4-substituents can dampen agonist efficacy at the 5-HT2A receptor. Binding and functional studies confirmed that the compounds have nanomolar affinity for 5-HT2 receptor subtypes and act as partial agonists at 5-HT2A.
Conclusions
In general, there were close parallels between the HTR data and the known SAR governing activity of phenylalkylamines at the 5-HT2A receptor. These findings further support the classification of 2C-T compounds as psychedelic drugs.
... Neurons expressing 5-HT 2A receptors are located mainly on layer V of pyramidal neurons from the neocortex, but also in limbic and basal ganglia structures such as the mammillary bodies of the hypothalamus, hippocampus, nucleus accumbens (NAc), amygdala, caudate, and putamen [134,135]. On a molecular level, the activation of these receptors induces intracellular signaling cascades which include phosphoinositide-specific phospholipase C (PLC)-induced increase in inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), extracellular signal-regulated kinases (ERK), tyrosine kinase pathways, and a β-arrestin2-mediated pathway that results from serotonin binding [135][136][137][138]. DMT binding to these receptors activates the phospholipase A2 signal transduction pathway, leading to more arachidonic acid release and less inositol phosphate formation [104,139].While 5-HT 2A modulation by DMT is considered to be the main mechanism of action from ayahuasca, β-carbolines can also act as serotonin 5-HT 2A receptor agonists, although generally with less affinity (K i 230 nM for harmine, 7780 nM for harmaline, and >10,000 nM for THH) [140,141]. ...
Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca’s therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca’s components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.
... Substituted phenethylamines of the 2C-X family show full agonist affinity at the 5-HT2A and 5-HT2C receptor sites. Effects of these compounds seem biphasic, with stimulation and increased sensory experience at low doses, hallucinations with moderate doses, and high doses resulting in hallucinogenic sensorium (Eshleman et al., 2014). ...
A rapid review synthesizing published research on the possible therapeutic applications of psychedelics.
... Interestingly, this is similar to in vitro EC 50 values associated with activation of the 5-HT2A receptor (201-269 nM). 30 This potentially supports the idea that the psychedelic effects of DMT are mainly mediated through agonism at the 5-HT2A receptor. ...
N,N‐dimethyltryptamine (DMT) is a psychedelic compound that is believed to have potential as a therapeutic option in several psychiatric disorders. The number of clinical investigations with DMT is increasing. However, very little is known about the pharmacokinetic properties of DMT as well as any relationship between its exposure and effects. This study aimed to characterize population pharmacokinetics of DMT as well as the relationship between DMT plasma concentrations and its psychedelic effects as measured through subjective intensity ratings. Data was obtained from 13 healthy subjects after intravenous administration of DMT. The data was analyzed using nonlinear mixed‐effects modelling in NONMEM. DMT plasma concentrations were described by a two‐compartment model with first‐order elimination leading to formation of the major metabolite indole 3‐acetic acid. The relationship between plasma concentrations and psychedelic intensity was described by an effect site compartment model with a sigmoid Emax response. DMT clearance was estimated at 26 L/min, a high value indicating elimination of DMT to be independent of blood flow. Higher concentrations of DMT were associated with a more intense experience with an EC50,e estimated at 95 nM. The maximum achievable intensity rating was 10 and the simulated median maximum rating was 0, 2, 4, 8 and 9 after doses of 1, 4, 7, 14 and 20 mg respectively. The model can be useful in predicting suitable doses for clinical investigations of DMT based on the desired intensity of the subjective experience.
... While looking into the reason for this apparent discrepancy was not within the scope of this manuscript, the known promiscuous receptor activation potential of several of these compounds (e.g. binding and activating a multitude of 5-HT 2 Rs (Porter et al. 1999;Ray 2010;Halberstadt and Geyer 2011;Eshleman et al. 2014Eshleman et al. , 2018), combined with a more downstream event being scored by the Aequoscreen® assay (as opposed to a receptor-proximal event scored by the βarr2 assay), may be an obvious explanation. ...
Aim
New psychoactive substances (NPS) are introduced on the illicit drug market at a rapid pace. They are usually poorly pharmacologically characterized, leaving users unaware of the potential harms they could be exposed to. Apart from the unknown effects and potencies of these new substances, their exact molecular targets are often inadequately elucidated. Guided by recent literature, we investigated the μ opioid receptor (MOR) activation potential of a large set of psychedelics, which typically activate their target receptor, the serotonin (5-HT2A) receptor.
Method
Screening for MOR activity of a panel of psychedelics was done using a cell-based NanoBiT® bioassay. The NanoBiT® assay monitors the recruitment of the intracellular signaling protein β-arrestin2 to the ligand activated MOR receptor. The principle exploits functional complementation of a split nanoluciferase enzyme of which the inactive subunits are either fused to the receptor and βarr2. Receptor activation causes the 2 subunits to come in close proximity, resulting in restoration of the nanoluciferase activity. Upon addition of the substrate, a luminescent signal can be detected using a luminometer. Based on the results of this initial screening, MOR activity of a selected panel of NBOMes and NBOMe analogs was evaluated using the both the NanoBiT® and AequoScreen® assay, the latter measuring the rapid intracellular calcium flux caused by receptor activation, a more downstream effect caused by G protein signaling.
Results
Using the NanoBiT® assay, 5 NBOMes showed MOR activation potential. Based on these findings, a panel of NBOMe analogs was selected and evaluated using 2 distinct assays. Comparing both assays, the same overall trends regarding MOR activity could be determined. The iodo analog 25I-NBOMe was more potent than the bromo substituted 25B-NBOMe, which was more potent than the chloro analog 25C-NBOMe, signifying that MOR activity increased with an increased size of the halogen atom. Similarly, MOR activity increased with increasing size of the alkyl side chain, with the ethylated 25E-NBOMe being more active than the methylated 25D-NBOMe. However, a propyl or isopropyl side chain might be too long or bulky, as the 25P-NBOMe and 25iP-NBOMe showed a substantial decrease in activity. NBOMe compounds were more active at MOR than their NBOH counterparts, whereas earlier data showed that they had a similar activity at their designated target receptor 5-HT2A. Moving the methoxy group from position 2 to position 3 or 4 resulted in an important decrease in MOR activity. Furthermore, the effects at MOR of the analyzed compounds could be blocked by the opioid antagonist naloxone, suggesting that these NBOMes occupy the same common opioid binding pocket as conventional opioids. Using the AequoScreen® assay, aspecific, receptor independent effects were found for the alkylated 25iP-NBOMe, 25E-NBOMe and 25D-NBOMe, indicating that these may directly interact with other targets in the downstream signaling pathway.
Conclusion
A limited potential to activate the MOR was found for 10 NBOMes and NBOMe analogs, which was confirmed using 2 distinct cell-based assays. Structure-activity relationships could be determined, and additional experiments revealed that the effects of these psychedelics at MOR could be antagonized by naloxone, signifying that these substances occupy the same binding pocket as common opioids. Some compounds showed an aspecific effect in the AequoScreen® assay, which was not observed using the NanoBiT® assay. As MOR activity of these psychedelics was only noticed at high concentrations, it is unlikely that these will contribute to pronounced opioid toxicity at physiologically relevant concentrations. However, small modifications to the original NBOMe structure may result in a panel of more efficacious and potent MOR agonists.
... There are reports of DMT's nM binding to several 5-HT receptors (5-HTRs), as well as to DA receptor 1, adrenergic receptor α 1B, 2B and 2C, and imidazoline receptor 1 (Keiser et al., 2009;Ray, 2010). Functional analysis have shown that DMT is an agonist at 5-HTRs 1A, 2A (5-HT 2A ), 2B and 2C (Eshleman et al., 2014;Rickli et al., 2016), rodent trace amine-associated receptor (TAAR) 1 (Bunzow et al., 2001;Simmler et al., 2016) and sigma 1 receptor (σ 1 ; Fontanilla et al., 2009;Johannessen et al., 2011;Mavlyutov et al., 2012). ...
... Importantly, 5-HT 2A couples to phospholipase A2 (PLA2), promoting arachidonic acid (AA) cleavage and subsequently activating the mitogen-activated protein kinase (MAPK) cascade (Berg et al., 1998;Kurrasch-Orbaugh et al., 2003a). DMT promotes AA cleavage with an EC50 of 260 ± 120 nM and an intrinsic activity of 105% compared to 5-HT in transfected HEK293 cells (Eshleman et al., 2014). Another experiment using transfected NIH/3T3 fibroblasts proved that while DMTs (psilocin and 5-MeO-DMT) have a clear preference for activating PLA2 over PLC cascade, non-dimethylated TAs (5-HT and TA) have no preference for any specific pathway. ...
... Moreover, the effects of a chemical at a given receptor not only depend on binding affinity but also on potency, intrinsic activity, occupancy and, in the case of GPCRs, biased agonism. DMT preferably activates 5-HT 2A in its PLA2-coupled state (Eshleman et al., 2014). Because only 3% occupancy is needed to reach E max (Kurrasch-Orbaugh et al., 2003b), the K i value, which represents the equilibrium of total ligand-receptor complexes versus competitor-receptor complexes, is of minor relevance. ...
N,N-dimethyltryptamine (DMT) is a potent psychedelic naturally produced by many plants and animals, including humans. Whether or not DMT is significant to mammalian physiology, especially within the central nervous system, is a debate that started in the early 1960s and continues to this day. This review integrates historical and recent literature to clarify this issue, giving special attention to the most controversial subjects of DMT’s biosynthesis, its storage in synaptic vesicles and the activation receptors like sigma-1. Less discussed topics, like DMT’s metabolic regulation or the biased activation of serotonin receptors, are highlighted. We conclude that most of the arguments dismissing endogenous DMT’s relevance are based on obsolete data or misleading assumptions. Data strongly suggest that DMT can be relevant as a neurotransmitter, neuromodulator, hormone and immunomodulator, as well as being important to pregnancy and development. Key experiments are addressed to definitely prove what specific roles DMT plays in mammalian physiology.
