Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore.
Thomas W. Flanagan, Gerald Billac, Alexus N. Landry, Melaine N. Sebastian, Stephania A Cormier, Charles D. Nichols
ACS Pharmacology & Translational Science April 9, 2021 DOI: 10.1021/acsptsci.0c00063 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | ergoline |
| Topics | Serotonin |
| Keywords | Inflammation reduction Inflammation suppression Anti-inflammatory effects Inflammation relief Inflammation treatment Psychedelic research Psychedelic compounds Hallucinogen studies Entheogen research Psychotropic substance investigation Drug discovery Pharmaceutical research Drug development Compound screening Therapeutic discovery Novel drug identification Serotonin 2a receptor 5-hydroxytryptamine 2a receptor Receptor activation Receptor pathways Molecular targets Non-psychoactive drugs Non-hallucinogenic drugs Non-mind-altering treatments Non-euphoric therapies Non-psychotropic drugs Non-psychoactive therapeutics |
| Citations | 50 |
| Key findings | The drug 2,5-dimethoxyphenethylamine (2C-H) is the pharmacophore for anti-inflammatory activity at the 5-HT2A receptor, and anti-inflammatory effects are mediated by functionally selective mechanisms distinct from canonical calcium signaling and behavioral activity. |
Abstract
Psychedelic drugs can exert potent anti-inflammatory effects. However, anti-inflammatory effects do not appear to correlate with behavioral activity, suggesting different underlying mechanisms. We hypothesized that the distinct structural features of psychedelics underlie functionally selective mechanisms at the target 5-HT2A receptor to elicit maximal anti-inflammatory effects. In order to test this hypothesis, we developed a new rat-based screening platform for allergic asthma. Next, we investigated 21 agonists at the 5-HT2A receptor from the three primary chemotypes (phenylalkylamine, ergoline, and tryptamine) for their ability to prevent airways hyperresponsiveness as a measure of pulmonary inflammation. Furthermore, we assessed each drug for in vitro activation of the canonical signaling pathway, calcium mobilization, from the 5-HT2A receptor. We find that the drug 2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity and identify structural modifications that are either permissive or detrimental to anti-inflammatory activity. Additionally, there is no correlation between the ability of a particular psychedelic to activate intracellular calcium mobilization and to prevent the symptoms of asthma or with behavioral potencies. Our results support the notions that specific structural features mediate functional selectivity underlying anti-inflammatory activity and that relevant receptor activated pathways necessary for anti-inflammatory activity are different from canonical signaling pathways. Our results inform on the nature of interactions between ligands at the 5-HT2A receptor as they relate to anti-inflammatory activity and are crucial for the development of new 5-HT2A receptor agonists for anti-inflammatory therapeutics in the clinic that may be devoid of behavioral activity.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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- Psychedelic-inspired approaches for treating neurodegenerative disorders. Journal of Neurochemistry July 1, 2022
- Neuroinflammation and neuroprogression in depression: Effects of alternative drug treatments Brain, Behavior, & Immunity - Health November 7, 2022
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Cites 7
- Psychedelics as anti-inflammatory agents International Review of Psychiatry July 4, 2018
- Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS One 2014
- Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Current Drug Metabolism October 1, 2010
- Psychedelic Drugs in Biomedicine TIPS - Trends in Pharmacological Sciences September 22, 2017
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
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