Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogs

Glennon, Richard A.; Liebowitz, Stephen M.; Mack, Elizabeth C.

doi:10.1021/jm00206a022

Cited by 42 publications

(19 citation statements)

References 3 publications

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“…N-alkylation or N,N-dialkylation proved detrimental to the potency of most phenylalkylamines. [172,174,175] An exception was found in a series of N-benzyl substituted phenylalkylamines; [176] affinity studies comparing 2C-B (11) with its N-benzylated analogues (29-31) revealed an approximate twofold increase in binding affinity for [ 125 I]DOI labeled 5-HT 2A receptors. Moreover compounds 29-31 showed increased subtype selectivity (> 100 fold) for 5-HT 2A over 5-HT 2C receptors, however the question whether 29-31 act as agonists or antagonists has not been addressed.…”

Section: Wwwchemmedchemorgmentioning

confidence: 99%

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

2008

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Agonist activation of central 5-HT(2A) receptors results in diverse effects, such as hallucinations and changes of consciousness. Recent findings indicate that activation of the 5-HT(2A) receptor also leads to interesting physiological responses, possibly holding therapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5-HT(2A) ligands with agonist profiles are primarily derived from phenylalkylamines, indolealkylamines, and certain piperazines. Of these, phenylalkylamines, most notably substituted phenylisopropylamines, are considered the most selective agonists for 5-HT(2) receptors. This review summarizes the structure-activity relationships (SAR) of phenylalkylamines as agonist ligands for 5-HT(2A) receptors. Selectivity is a central theme, as is selectivity for the 5-HT(2A) receptor and for its specific signaling pathways. SAR data from receptor affinity studies, functional assays, behavioral drug discrimination as well as human studies are discussed.

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Section: Wwwchemmedchemorgmentioning

confidence: 99%

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

2008

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“…There is a significant literature correlating the binding affinity of DMT and related hallucinogens for the 5HT2A receptor and its subset of receptors with other hallucinogens and their subsequent behavioral effects (Glennon et al, 1978 ; Nichols, 2004 , 2016 ; Blough et al, 2014 ; Carbonaro and Gatch, 2016 ). However, DMT has been shown to interact with a variety of ionotropic and metabotropic receptors.…”

Section: Receptor Binding Of Dmt: 5-ht2a Taars and Sigma-1 Receptormentioning

confidence: 99%

N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function

2018

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This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.

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“…DMT produces psychoactive effects through multiple neural mechanisms. DMT and related psychoactive tryptamines bind to numerous identified macromolecular sites comprising various serotonin, dopamine, and adrenergic receptors, [25][26][27][28][29] serotonin uptake transporters, [30][31][32][33] trace amine-associated receptors (TAARs), 34 monoamine oxidase enzymes, 35,36 and sigma-1 receptors. 37 Among the serotonin receptors, the 5-HT 2A receptor plays a key role in mediating the psychedelic effects of DMT, and experimental evidence points to the participation of 5-HT 1A , 5-HT 2B , 5-HT 2C , and 5-HT 7 receptors as well.…”

Section: Pharmacologymentioning

confidence: 99%

Synthesis and characterization of high‐purity N,N‐dimethyltryptamine hemifumarate for human clinical trials

Cozzi

Daley²

2020

Drug Testing and Analysis

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Since 2006, there has been a resurgent interest in the pharmacology and therapeutics of psychedelic drugs. Psilocybin, the 4-phosphoryl ester of N,Ndimethyltryptamine (DMT), has been studied most often, but DMT itself is also appealing because of its brief but profound psychological effects and its presence as an endogenous substance in mammalian brain. Although there have been a few studies of ayahuasca, a DMT-containing water infusion, only one human study with pure DMT has been reported since the early 2000s. Newly planned clinical trials to assess the safety and efficacy of DMT in humans with major depressive disorders require high-purity water-soluble DMT for intravenous administration. Accordingly, we synthesized and characterized DMT hemifumarate for these upcoming studies. The synthetic approach of Speeter and Anthony was slightly modified to gain some efficiency in time. In particular, this is the first known report to use aluminum hydride, generated in situ from lithium aluminum hydride, to reduce the intermediate 2-(1Hindol-3-yl)-N,N-dimethyl-2-oxoacetamide to DMT. A quench protocol was developed to produce a good yield of exceptionally pure free base DMT upon workup, which was then converted to the hemifumarate salt. Analysis of the final product included differential scanning calorimetry, thermogravimetric analysis, gas chromatographymass spectrometry (GC-MS), 1 H and 13 C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, residual solvent analysis by GC headspace sampling, X-ray powder diffraction analysis, and residual lithium analysis by inductively coupled plasma-mass spectrometry. The DMT hemifumarate was minimally 99.9% pure, with no significant impurities or residual solvents, thus meeting regulatory standards for administration to humans.

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Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogs

Cited by 42 publications

References 3 publications

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function

Synthesis and characterization of high‐purity N,N‐dimethyltryptamine hemifumarate for human clinical trials

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Serotonin receptor binding affinities of several hallucinogenic phenylalkylamine and N,N-dimethyltryptamine analogs

Cited by 42 publications

References 3 publications

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT2A Receptors

N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function

Synthesis and characterization of high‐purity N,N‐dimethyltryptamine hemifumarate for human clinical trials

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Product

Resources

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Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors

Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5‐HT_2A Receptors