Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs
Michael J. Cunningham, Hailey A. Bock, Inis C. Serrano, Benjamin Bechand, D. J. Vidyadhara, Emma M. Bonniwell, David Lankri, Priscilla Duggan, Antonina L. Nazarova, Andrew B. Cao, Maggie M. Calkins, Prashant Khirsariya, Christopher Hwu, Vsevolod Katritch, Sreeganga S. Chandra, John D. Mccorvy, Dalibor Sames
ACS Chemical Neuroscience December 15, 2022 DOI: 10.1021/acschemneuro.2c00597 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Intervention | Ariadne |
| Topics | LSD Serotonin |
| Keywords | Hallucinogen Pharmacology Partial agonist 5-HT Receptor |
| Citations | 65 |
| Key points | Ariadne is a non-hallucinogenic 5-HT2A agonist with lower signaling efficacy than DOM, and it rescued motor deficits in a mouse model of Parkinson's disease. |
Abstract
Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and β-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.
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
Cited by 53
- Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications December 15, 2023
- Therapeutic mechanisms of psychedelics and entactogens. Neuropsychopharmacology July 24, 2023
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Psychedelics as Transformative Therapeutics. American Journal of Psychiatry May 1, 2023
- Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics. Molecular Psychiatry September 1, 2023
and 48 more in the library
Cites 16
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Hallucinogens and Serotonin 5-HT2A Receptor-Mediated Signaling Pathways Current Topics in Behavioral Neurosciences 2017
- Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. Neuropharmacology May 1, 2020
- 2,5-Dimethoxy-4-methyl-amphetamine (STP): A New Hallucinogenic Drug Science November 3, 1967
- Effect of Ring Fluorination on the Pharmacology of Hallucinogenic Tryptamines Journal of Medicinal Chemistry October 19, 2000
and 11 more in the library