bioRxiv (Cold Spring Harbor Laboratory)
July 31, 2023
Jason Wallach, Andrew B. Cao, Maggie M. Calkins et al.
11 citations
preprint
Serotonergic psychedelics show therapeutic promise, but the specific signaling pathways responsible for their effects have been unclear. Researchers developed a series of 5-HT2A receptor ligands with varying Gq efficacies, including β-arrestin-biased ligands. They found that 5-HT2A-Gq efficacy, not β-arrestin2 efficacy, predicts psychedelic potential, measured by head-twitch response in male mice. Disrupting Gq-PLC signaling reduced this response, and a threshold of Gq activation is needed for psychedelic-like effects, explaining why some partial agonists like lisuride are non-psychedelic. β-arrestin-biased agonists caused receptor downregulation and tachyphylaxis, and showed an anti-psychotic-like profile. This fine-tuning of 5-HT2A signaling can generate ligands distinct from classical psychedelics.
Frontiers in Pharmacology
January 1, 2013
Wendy K. Adams, Adam L. Halberstadt, Maarten van den Buuse
11 citations
Blocking NMDA receptors with phencyclidine (PCP) can produce schizophrenia-like symptoms in humans, but PCP also affects other systems. Rats with serotonin-depleting lesions in the dorsal hippocampus showed increased hyperactivity from PCP but not from the more selective NMDA blocker MK-801. Lesions in the ventral hippocampus had no effect. PCP and MK-801 both made the rats' movement paths smoother and less predictable, but the dorsal hippocampus lesions did not alter these qualitative effects for PCP, though they slightly reduced MK-801's effect on unpredictability. The results reveal a functional difference between PCP and MK-801 related to serotonin in the dorsal hippocampus, relevant to schizophrenia research.
Psychopharmacology
December 7, 2022
Adam L. Halberstadt, Dino Luethi, Marius C. Hoener et al.
7 citations
A series of 4-thio-substituted phenylalkylamines, including the psychedelic drugs 2C-T-2 and 2C-T-7, were tested in mice using the head twitch response (HTR), a behavioral proxy for human psychedelic effects. Adding an α-methyl group to the parent compound 2C-T increased potency fivefold, and extending the 4-methylthio group by one to three methylene units also increased potency. Fluorination of the 4-position alkylthio chain or a 4-allylthio substituent reduced activity, and bulky 4-benzylthio groups showed little or no effect. Binding studies confirmed nanomolar affinity for 5-HT2 receptor subtypes and partial agonism at 5-HT2A, supporting classification of these compounds as psychedelic drugs.
Drug Testing and Analysis
August 24, 2020
Simon D. Brandt, Pierce V. Kavanagh, Folker Westphal et al.
5 citations
N-ethyl-N-cyclopropyl lysergamide (ECPLA) produces LSD-like behavioral effects in mice and may act as a hallucinogen in humans. ECPLA is an isomer of the recreational drug LSZ. Several analytical methods—mass spectrometry, gas and liquid chromatography, nuclear magnetic resonance spectroscopy, and GC condensed-phase infrared spectroscopy—can differentiate ECPLA from LSZ. Key mass spectral differences include ion abundances at m/z 196, 207/208, 98, and 41. Electrospray ionization spectra show lysergamide-related ions, and LSZ (but not ECPLA) produces product ions at m/z 267 and 98 under the conditions used. These data support forensic and clinical detection of ECPLA.
UNC Libraries
October 29, 2020
Simon D. Brandt, Maria F. Sassano, David E. Nichols et al.
4 citations
A series of N-benzylated-5-methoxytryptamine analogues and N-benzylated analogues of 2,5-dimethoxy-4-iodophenethylamine (2C-I) were synthesized and tested. Most compounds showed highest affinity for the 5-HT2 family of serotonin receptors. Substitution at the para position of the benzyl group reduced affinity, while ortho or meta substitution enhanced it. Large lipophilic groups improved affinity but often reduced functional activity. Functional potency was measured at human 5-HT2A, 5-HT2B, and 5-HT2C receptors and rat 5-HT2A and 5-HT2C receptors using intracellular calcium mobilization. Several tryptamine congeners were very potent functionally (EC50 values from 7.6 to 63 nM) but were mostly partial agonists. In mouse head twitch tests, many compounds induced the behavior, which correlated significantly with functional potency at the rat 5-HT2A receptor.
Schizophrenia Bulletin
April 17, 2025
Nathan H. Heller, Frederick S. Barrett, Tobias Buchborn et al.
3 citations
Visual hallucinations in Lewy body diseases (Parkinson's disease and dementia with Lewy bodies) and those induced by serotonergic psychedelics (psilocybin, mescaline) share overlapping phenomenology and neural mechanisms, despite different underlying causes. Both conditions produce visual aberrations from minor distortions to complex hallucinations, including illusory motion and entity encounters. Neuroimaging shows a common pattern of overactive associative cortex and underactive sensory cortex. Serotonin 2A receptor modulation is involved in both: psychedelics act through 5-HT2A and 5-HT1A receptors, while in Lewy body diseases, 5-HT2A receptor upregulation correlates with increased hallucinations, and blocking it with pimavanserin reduces them. Shared cortical signatures include reduced visual evoked responses and shifts toward visual excitation.
Journal of the American Chemical Society
December 16, 2025
J.O.S. Beckett, Ryan Buzdygon, Steven Nguyen et al.
1 citation
A new chemical method uses light to trigger a cyclization reaction that attaches a functional group to the fourth carbon of the indole ring, enabling the efficient synthesis of ring-constrained tryptamine analogs. Amino acids were linked to tryptamine and exposed to UV light to produce lactams bridging specific positions on the indole structure. The resulting reduced lactams, called azocinoindoles, were tested for activity at the serotonin 5-HT2A receptor. In computer models and lab experiments, these compounds acted as full or partial activators of the receptor's Gq signaling pathway. In mice, they suppressed the head-twitch response, a behavior linked to hallucinogenic effects, suggesting these compounds are nonhallucinogenic 5-HT2A agonists.
ACS Chem Neurosci
March 4, 2026
Nina Kastner, Núria Nadal-Gratacós, Selina Hemmer et al.
correction
A correction notice clarifies that two errors in the original paper do not affect the accuracy of the results, interpretations, or conclusions. The first correction addresses a presentation issue in Table 1, confirming the data are correct. The second correction clarifies that thigmotaxis, a measure of anxiety-like behavior, was evaluated in rats given SDA or SDMA compounds. Compared to saline, only the 10 mg/kg dose of SDA significantly increased thigmotaxis, meaning the rats spent less time in the center of the arena.
ACS Chemical Neuroscience
December 2, 2025
Nina Kastner, Núria Nadal‐gratacós, Selina Hemmer et al.
Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
Journal of Medicinal Chemistry
September 25, 2025
Tyler G. Fenske, J. M. T. Mckee, Natalie G. Cavalco et al.
Selectivity for the 5-HT2A receptor over the closely related 5-HT2C receptor can be achieved by targeting residue L1232.53 in transmembrane 2 of the extended binding pocket through increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. This selectivity was confirmed across 5-HT2C RNA editing isoforms, TM2 reciprocal mutants, and mouse orthologs, producing the most highly selective 5-HT2A agonists to date. Using structure–activity relationships, molecular docking, and mouse head-twitch response assays, the work demonstrates that such agonists can be rationally designed to improve target engagement, advancing the study of the neurobiological mechanisms of psychedelic effects.