Structure–activity relationships of serotonin 5‐HT<sub>2A</sub> agonists

Nichols, David E.

doi:10.1002/wmts.42

Cited by 66 publications

(97 citation statements)

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“…Classical hallucinogens can be divided into two main structural classes: indoleamines and phenylalkylamines (Nichols, 2012). Indoleamines include the tetracyclic ergoline (+)-lysergic acid diethylamide (LSD) and the chemically simpler indolealkylamines, which includes N,N -dimethyltryptamine (DMT), N,N -dipropyltryptamine (DPT), 5-methoxy-DMT (5-MeO-DMT), and psilocybin (4-phosphoryloxy-DMT) and its active O -dephosphorylated metabolite psilocin (4-hydroxy-DMT).…”

Section: Pharmacology Of Hallucinogensmentioning

confidence: 99%

“…However, compared with σ 1 and SERT, tryptamines are more potent at 5-HT 1A and 5-HT 2A receptors by several orders of magnitude, so the former sites probably do not contribute to the hallucinogenic response. LSD and other ergoline hallucinogens display high affinity for 5-HT receptors, as well as dopaminergic and adrenergic receptors (reviewed by: Halberstadt and Geyer, 2011; Nichols, 2012). …”

Section: Pharmacology Of Hallucinogensmentioning

confidence: 99%

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Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Halberstadt

2015

Behavioural Brain Research

239

203

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Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy.

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Section: Pharmacology Of Hallucinogensmentioning

confidence: 99%

Section: Pharmacology Of Hallucinogensmentioning

confidence: 99%

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Halberstadt

2015

Behavioural Brain Research

239

203

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“…A range of lysergamide derivatives have been prepared to explore their molecular pharmacology but the extent to which these show psychoactive properties in humans is not always clear . In recent years, several lysergamide derivatives have been distributed as new psychoactive substances (NPS) or ‘research chemicals’ in the UK and Europe .…”

Section: Introductionmentioning

confidence: 99%

Return of the lysergamides. Part I: Analytical and behavioural characterization of 1‐propionyl‐d‐lysergic acid diethylamide (1P‐LSD)

Brandt

Kavanagh

Westphal³

et al. 2015

Drug Testing and Analysis

170

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1-Propionyl-d-lysergic acid diethylamide hemitartrate (1P-LSD) has become available as a ‘research chemical’ in form of blotters and powdered material. This non-controlled derivative of d-lysergic acid diethylamide (LSD) has previously not been described in the published literature despite being closely related to 1-acetyl-LSD (ALD-52), which was developed in the 1950s. This study describes the characterization of 1P-LSD in comparison with LSD using various chromatographic, mass spectrometric methods and nuclear magnetic resonance spectroscopy. An important feature common to LSD and other serotonergic hallucinogens is that they produce 5-HT2A-receptor activation and induce the head-twitch response (HTR) in rats and mice. In order to assess whether 1P-LSD displays LSD-like properties and activates the 5-HT2A receptor, male C57BL/6J mice were injected with vehicle (saline) or 1P-LSD (0.025–0.8 mg/kg, IP) and HTR assessed for 30 min using magnetometer coil recordings. It was found that 1P-LSD produced a dose-dependent increase in HTR counts, and that it had ~38% (ED50 = 349.6 nmol/kg) of the potency of LSD (ED50 = 132.8 nmol/kg). Furthermore, the HTR was abolished when 1P-LSD administration followed pre-treatment with the selective 5-HT2A receptor antagonist M100907 (0.1 mg/kg, SC), which confirms that the behavioral response is mediated by activation of the 5-HT2A receptor. These results indicate that 1P-LSD produces LSD-like effects in mice, consistent with its classification as a serotonergic hallucinogen. Nevertheless, the extent to which 1P-LSD might show psychoactive effects in humans similar to LSD remains to be investigated.

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“…The fact that a range of closely related N , N ‐dialkylated tryptamines (e.g. sumatriptan) show important therapeutic applications demonstrates that there is a need to disentangle the different pharmacological features associated with the tryptamine template . Anecdotal reports suggest that 5‐MeO‐DALT ( 7 ) might provide relief from cluster headaches .…”

Section: Resultsmentioning

confidence: 99%

Analytical characterization of N,N‐diallyltryptamine (DALT) and 16 ring‐substituted derivatives

Brandt

Kavanagh

Dowling

et al. 2016

Drug Testing and Analysis

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Many N,N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and ‘research chemical’ whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors’ laboratories included the preparation and biological evaluation of previously unreported N,N-diallyltryptamines (DALTs). This report describes the analytical characterization of seventeen DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors’ laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, ultraviolet diode array detection and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances.

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Structure–activity relationships of serotonin 5‐HT_2A agonists

Cited by 66 publications

References 100 publications

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Return of the lysergamides. Part I: Analytical and behavioural characterization of 1‐propionyl‐d‐lysergic acid diethylamide (1P‐LSD)

Analytical characterization of N,N‐diallyltryptamine (DALT) and 16 ring‐substituted derivatives

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Structure–activity relationships of serotonin 5‐HT2A agonists

Cited by 66 publications

References 100 publications

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

Return of the lysergamides. Part I: Analytical and behavioural characterization of 1‐propionyl‐d‐lysergic acid diethylamide (1P‐LSD)

Analytical characterization of N,N‐diallyltryptamine (DALT) and 16 ring‐substituted derivatives

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Structure–activity relationships of serotonin 5‐HT_2A agonists