“Selective” serotonin 5-HT2A receptor antagonists

Casey, Austen B.; Cui, Meng; Booth, Raymond G.; Canal, Clinton E.

doi:10.1016/j.bcp.2022.115028

Cited by 49 publications

(35 citation statements)

References 161 publications

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“…This model of a single DOI administration also led to tolerance to HTR induced by the same psychedelic 5-HT 2A R agonist. We also report that pretreatment with a single dose of the relatively selective 5-HT 2A R antagonist M100907 (1 mg/kg) (also known as volinanserin 43 ) precluded tolerance to HTR elicited by DOI. The lower dose of M100907 (0.1 mg/kg) was only partially effective at blocking the hours-long effect of DOI on HTR and the development of tolerance the day after.…”

Section: ■ Results and Discussionmentioning

confidence: 78%

“…On day 1, mice received vehicle or 1 mg/kg of the relatively selective 5-HT 2A R antagonist M100907 43 prior to the administration of DOI (1 mg/kg). After this, on day 2, all animals received the same dose of DOI (1 mg/kg) (Figure 2A).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Our results in the present study hint toward a magnitude-matching effect on the ability of M100907 to antagonize the acute HTR to DOI and the posterior development of tolerance. However, considering the polypharmacology of this ligand, we cannot fully exclude the possibility that the effects of this serotonergic antagonist preventing tolerance to HTR induced by DOI are mediated via additional GPCR targets.…”

Section: Resultsmentioning

confidence: 99%

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Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Revenga

Jaster

McGinn

et al. 2022

ACS Chem. Neurosci.

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Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT 2A R) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT 2A R antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT 2A R agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT 2A R density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT 2A R, is not observable upon repeated administration of nonpsychedelic 5-HT 2A R agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

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Section: ■ Results and Discussionmentioning

confidence: 78%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Revenga

Jaster

McGinn

et al. 2022

ACS Chem. Neurosci.

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“…To the best of our knowledge, there are no potent 5-HT 2A receptor agonists that either lack affinity for 5-HT 2C receptors or exhibit 5-HT 2C receptor antagonism. Moreover, a truly selective 5-HT 2A receptor antagonist has not yet been identified 140 . This dearth of selective pharmacological tools impedes our ability to achieve a full mechanistic understanding of psychedelic drug action.…”

Section: Open Questionsmentioning

confidence: 99%

Vertebral arteries do not experience tensile force during manual cervical spine manipulation applied to human cadavers

Gorrell

Sawatsky

Edwards

2022

Journal of Manual & Manipulative Therapy

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Background: The vertebral artery (VA) may be stretched and subsequently damaged during manual cervical spine manipulation. The objective of this study was to measure VA length changes that occur during cervical spine manipulation and to compare these to the VA failure length. Methods: Piezoelectric ultrasound crystals were implanted along the length of the VA (C1 to C7) and were used to measure length changes during cervical spine manipulation of seven un-embalmed, post-rigor human cadavers. Arteries were then excised, and elongation from arbitrary in-situ head/neck positions to first force (0.1 N) was measured. Following this, VA were stretched (8.33 mm/s) to mechanical failure. Failure was defined as the instance when VA elongation resulted in a decrease in force. Results: From arbitrary in-situ head/neck positions, the greatest average VA length change during spinal manipulation was [mean (range)] 5.1% (1.1 to 15.1%). From arbitrary in-situ head/neck positions, arteries were elongated on average 33.5% (4.6 to 84.6%) prior to first force occurrence and 51.3% (16.3 to 105.1%) to failure. Average failure forces were 3.4 N (1.4 to 9.7 N). Conclusions: Measured in arbitrary in-situ head/neck positions, VA were slack. It appears that this slack must be taken up prior to VA experiencing tensile force. During cervical spine manipulations (using cervical spine extension and rotation), arterial length changes remained below that slack length, suggesting that VA elongated but were not stretched during the manipulation. However, in order to answer the question if cervical spine manipulation is safe from a mechanical perspective, the testing performed here needs to be repeated using a defined in-situ head/neck position and take into consideration other structures (e.g. carotid arteries).

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“…MAO-A inhibitors are one of the most widely used groups of antidepressant agents regulating the metabolism of 5-HT, and the discovery of novel MAO-A inhibitors has important implications for the treatment of depression . The serotonin 2A receptor (5-HT 2A R) is a G protein-coupled receptor known for its pivotal roles in cognition, behavior, and physiological functions, making it a promising candidate for the treatment of psychiatric disorders (especially depression). − Indeed, preferentially blocking 5-HT 2A R in the presynaptic membrane by modulating the release of 5-HT in the treatment of negative symptoms has always been suggested to be important for the clinical outcome and performance of the prototype atypical antipsychotic drug. − 5-HT 2A R antagonists can effectively treat dimensions of psychosis and effectively avoid the occurrence of the serotonin syndrome, without untoward side effects associated with the off-target binding of more promiscuous antipsychotic agents . Therefore, designing dual-target inhibitors that can target MAO-A to relieve 5-HT degradation and target 5-HT 2A R to inhibit 5-HT reuptake can synergistically promote interstitial 5-HT level, which is conducive to more efficient antidepressant active.…”

Section: Introductionmentioning

confidence: 99%

Development of MAO-A and 5-HT_2AR Dual Inhibitors with Improved Antidepressant Activity

Sun

Zhong

et al. 2022

J. Med. Chem.

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Designing dual-target inhibitors targeting 5-HT2AR and MAO-A could synergistically promote interstitial 5-HT levels, so as to exhibit a more efficient antidepressant effect. On the premise of maintaining the original pharmacophore binding, arylpiperazine scaffolds and 5-oxygen-substituted oxoisoaporphines were hybridized to afford 15 dual-target inhibitors through suitable linkers. Among all inhibitors, I 14 exhibited the best inhibitory activities against 5-HT2AR and MAO-A. In vitro cell proliferation assays showed that most compounds were nontoxic to neuronal cells and normal hepatocytes. I 14 also significantly ameliorated the depression-like behavior of zebrafish and mice. Further study revealed that I 14 was able to occupy the active cavity of 5-HT2AR and MAO-A with multiple hydrogen bonding forces and π–π stacking interaction. I 14 was also able to repair the damage of mice hippocampal neuronal cells and reduce the expression of 5-HT2AR in mice brain tissue. In conclusion, I 14 could be a potential antidepressant candidate for further study.

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“Selective” serotonin 5-HT2A receptor antagonists

Cited by 49 publications

References 161 publications

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Vertebral arteries do not experience tensile force during manual cervical spine manipulation applied to human cadavers

Development of MAO-A and 5-HT_2AR Dual Inhibitors with Improved Antidepressant Activity

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“Selective” serotonin 5-HT2A receptor antagonists

Cited by 49 publications

References 161 publications

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice

Vertebral arteries do not experience tensile force during manual cervical spine manipulation applied to human cadavers

Development of MAO-A and 5-HT2AR Dual Inhibitors with Improved Antidepressant Activity

Contact Info

Product

Resources

About

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Development of MAO-A and 5-HT_2AR Dual Inhibitors with Improved Antidepressant Activity