Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor

Dong, Chunyang; Ly, Calvin; Dunlap, Lee E.; Vargas, Maxemiliano V.; Sun, Junqing; Hwang, In Wook; Azinfar, Arya; Oh, Won Chan; Wetsel, William C.; Olson, David E.; Tian, Lin

doi:10.2139/ssrn.3745934

Cited by 2 publications

(1 citation statement)

References 63 publications

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“…TBG is only one of several non-hallucinogenic psychoplastogens recently disclosed. 22,23 It will be interesting to see if other non-hallucinogenic psychoplastogens like AAZ-A-154 (AAZ) produce similar anti-addictive effects, or if the therapeutic properties of TBG are unique to its ibogaine-like scaffold. We suspect that other psychoplastogens will also prove useful for treating addiction.…”

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confidence: 99%

Engineering Safer Psychedelics for Treating Addiction

Peters

Olson

2021

J Exp Neurosci

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Addiction is best described as a disorder of maladaptive neuroplasticity involving the simultaneous strengthening of reward circuitry that drives compulsive drug seeking and weakening of circuits involved in executive control over harmful behaviors. Psychedelics have shown great promise for treating addiction, with many people attributing their therapeutic effects to insights gained while under the influence of the drug. However, psychedelics are also potent psychoplastogens—molecules capable of rapidly re-wiring the adult brain. The advent of non-hallucinogenic psychoplastogens with anti-addictive properties raises the intriguing possibility that hallucinations might not be necessary for all therapeutic effects of psychedelic-based medicines, so long as the underlying pathological neural circuitry can be remedied. One of these non-hallucinogenic psychoplastogens, tabernanthalog (TBG), appears to have long-lasting therapeutic effects in preclinical models relevant to alcohol and opioid addiction. Here, we discuss the implications of these results for the development of addiction treatments, as well as the next steps for advancing TBG and related non-hallucinogenic psychoplastogens as addiction therapeutics.

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confidence: 99%

Engineering Safer Psychedelics for Treating Addiction

Peters

Olson

2021

J Exp Neurosci

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PIEZO1 discriminates mechanical stimuli

Özkan

Wijerathne

Gettas

et al. 2022

Preprint

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Mechanosensitive Piezo channels are anticipated to open their pore by flattening of large transmembrane domains called blades. Yet, direct experimental evidence for the coupling between blade motions and pore opening remains sparse. Here, we report unambiguous correlations between flow-induced Piezo1 opening and fluorimetric signals from conformation-sensitive probes genetically-inserted at two blade locations, one extracellular distal and the other intracellular proximal. Inhibition of gating motions near the pore with disulfide crosslinks reduced the amplitude of fluorescence signals from the most distal probe, consistent with long-range pore-blade conformational coupling. Interestingly, both probes remained fluorimetrically silent when Piezo1 opening was evoked with hypotonic shocks, cellular indentations, or application of the chemical activator Yoda1. This work provides direct experimental evidence that the Piezo1 blades act as mechanosensory domains and suggests that different mechanical stimuli activate Piezo1 through distinct mechanotransduction pathways.

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Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor

Cited by 2 publications

References 63 publications

Engineering Safer Psychedelics for Treating Addiction

Engineering Safer Psychedelics for Treating Addiction

PIEZO1 discriminates mechanical stimuli

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