Pharmacological Mechanism of the Non-hallucinogenic 5-HT_2A Agonist Ariadne and Analogs

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.

α-Ethyltryptamine: A Ratiocinatory Review of a Forgotten Antidepressant

“…BL-3912 displayed affinity for h5-HT 2A receptors ( K i = 120, 53, and 220 nM for the racemate, R (−), and S (+) isomer, respectively), the racemate and R (−) isomer demonstrated partial 5-HT 2A agonist action, and the racemate showed a “ markedly attenuated ” head-twitch response in mice relative to control. The authors argued that on the basis of their studies (not all of which are discussed here), and the lack of hallucinogenic action in humans, that this “ provides the strongest support for the therapeutic potential of non-hallucinogenic 5-HT 2A receptor agonists ” . They also suggested that weak 5-HT 2A signaling efficacy might account for the lack of hallucinogenic action.…”

“…So, here, as with DOM, homologation of α-MeT to AET resulted in decreased DOMlike potency but in the emergence of MDMA-like action. Recently, Cunningham et al 104 reinvestigated BL-3912 (15). BL-3912 displayed affinity for h5-HT 2A receptors (K i = 120, 53, and 220 nM for the racemate, R(−), and S(+) isomer, respectively), the racemate and R(−) isomer demonstrated partial 5-HT 2A agonist action, and the racemate showed a "markedly attenuated" head-twitch response in mice relative to control.…”

Effects of serotonergic psychedelics on mitochondria: Transdiagnostic implications for mitochondria-related pathologies

“…It is of importance to note that not only serotonergic psychedelics but also non-hallucinogenic 5-HT 2A agonists showed effects on mitochondria. Non-hallucinogenic 5-HT agonists may have similar therapeutic effects as serotonergic psychedelics (Cunningham et al, 2023) and comparable effectiveness should be investigated (Kaplan et al, 2022).…”

Structure–Activity Assessment and In-Depth Analysis of Biased Agonism in a Set of Phenylalkylamine 5-HT2A Receptor Agonists

“…16 One of the proposed hypotheses concerning differences in signaling properties between psychedelic and nonpsychedelic 5-HT 2A agonists is the signaling efficacy hypothesis, as the nonpsychedelic substance Ariadne, a structural analogue of the psychedelic DOM, showed reduced activity in different in vitro signaling channels. 17 Another possible explanation is the phenomenon "biased agonism," which is defined as a ligand activating one (or a subset of) signaling pathway(s) of the receptor, in preference to others. 18−22 Biased agonism is thought to arise from the stabilization of distinct active receptor conformations by different ligands/agonists, 23 and the 5-HT 2A receptor was actually one of the first GPCRs for which this phenomenon was proposed.…”

“…In terms of receptor localization, a recent study suggests the intracellular 5-HT 2A to be responsible for the neuroplasticity-promoting effects of psychedelic substances . One of the proposed hypotheses concerning differences in signaling properties between psychedelic and nonpsychedelic 5-HT 2A agonists is the signaling efficacy hypothesis, as the nonpsychedelic substance Ariadne, a structural analogue of the psychedelic DOM, showed reduced activity in different in vitro signaling channels . Another possible explanation is the phenomenon “biased agonism,” which is defined as a ligand activating one (or a subset of) signaling pathway(s) of the receptor, in preference to others. − Biased agonism is thought to arise from the stabilization of distinct active receptor conformations by different ligands/agonists, and the 5-HT 2A receptor was actually one of the first GPCRs for which this phenomenon was proposed. , Historically, in vitro investigations of biased agonism at 5-HT 2A have compared PLC-mediated IP accumulation and PLA 2 -mediated AA release. ,− More recently, βarr recruitment has been assessed comparatively to Gα q protein activation/recruitment. − In this context, a recent study suggested that the βarr activity of 5-HT 2A ligands is important for the antidepressant effects of psychedelics, while βarr recruitment alone appeared to be insufficient for the psychoactive actions, indicating that these latter effects require both G protein and βarr transduction.…”