Synthesis of [<sup>13</sup>C<sub>6</sub>]‐labelled phenethylamine derivatives for drug quantification in biological samples

Karlsen, Morten; Liu, Huiling; Berg, Thomas; Johansen, Jon Eigill; Hoff, Bård Helge

doi:10.1002/jlcr.3193

Cited by 8 publications

(4 citation statements)

References 33 publications

(34 reference statements)

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“…The Henry reaction is a well-established means of generating nitroalkenes. We found that sonication of the appropriate substituted benzaldehyde and nitroalkane partners in the presence of a butylamine catalyst in acetic acid produced the corresponding nitrostyrenes that were readily purified by either trituration with cold methanol or chromatography over a small silica pad using a toluene-based eluent . The reduction of these nitrostyrenes was performed using lithium aluminum hydride in most cases.…”

Section: Resultsmentioning

confidence: 99%

“…We found that sonication of the appropriate substituted benzaldehyde and nitroalkane partners in the presence of a butylamine catalyst in acetic acid produced the corresponding nitrostyrenes that were readily purified by either trituration with cold methanol or chromatography over a small silica pad using a toluene-based eluent. 16 The reduction of these nitrostyrenes was performed using lithium aluminum hydride in most cases. In cases where the 4-substituent was trifluoromethyl, iodo, bromo, or chloro, alane (aluminum hydride) formed in situ was instead used to prevent dehalogenation.…”

Section: Synthesis Of Ariadne and Its Analogs Majority Ofmentioning

confidence: 99%

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

Cunningham

Bock

Serrano

et al. 2022

ACS Chem. Neurosci.

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Synthesis Of Ariadne and Its Analogs Majority Ofmentioning

confidence: 99%

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

Cunningham

Bock

Serrano

et al. 2022

ACS Chem. Neurosci.

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“…The conversion is having 95 % yield and required continuous removal of methanol by toluene azeotrope. [41] Scheme 32. N-formylation of phenylalanine ethyl ester.…”

Section: Synthesis Of 13 C 6 Labelled 2-hydroxybenzaldehydementioning

confidence: 99%

“…In this process, ortho‐specific formylation has been done with the use of magnesium methoxide and formaldehyde (Scheme 35). The conversion is having 95 % yield and required continuous removal of methanol by toluene azeotrope [41] …”

Section: Formylation Of Phenolic Compoundsmentioning

confidence: 99%

Recent Advances On Direct Formylation Reactions

Kherudkar,

Bhattacharjee,

Nawkhare

et al. 2023

The Chemical Record

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Aldehydes serve as the key functional group in organic synthesis and are valuable intermediates. The various advanced methods of direct formylation reactions have been reviewed in this article. Overcoming the drawbacks of the traditional methods of formylation, newer methods involving homo and heterogenous catalysts, one pot reactions, solvent free techniques are elaborated, which can be performed under mild conditions and using inexpensive resources.

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Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin

2020

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Synthesis of [¹³C₆]‐labelled phenethylamine derivatives for drug quantification in biological samples

Cited by 8 publications

References 33 publications

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

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

Recent Advances On Direct Formylation Reactions

Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin

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Synthesis of [13C6]‐labelled phenethylamine derivatives for drug quantification in biological samples

Cited by 8 publications

References 33 publications

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

Pharmacological Mechanism of the Non-hallucinogenic 5-HT2A Agonist Ariadne and Analogs

Recent Advances On Direct Formylation Reactions

Facile synthesis of bromo- and mixed bromo/chloro dibenzo-p-dioxins and [14C]-labeled 1,3,7,8-tetrabromodibenzo-p-dioxin

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Product

Resources

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Synthesis of [¹³C₆]‐labelled phenethylamine derivatives for drug quantification in biological samples

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

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