New Serotonergics with High Intracellular Bioavailability as Potentially Neuroplastic and Geroprotective Agents
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2026
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| _version_ | 1866902332202024960 |
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| author | Zaitsev, Yaroslav |
| author_facet | Zaitsev, Yaroslav |
| contents | <p><strong>Abstract</strong></p> <p><span><span><span><span><span><span><span><span>Erinacine A (</span></span></span></span></span></span></span></span><span><span><span><span><span><em><span><span>Hericium erinaceus)</span></span></em></span></span></span></span></span><span><span><span><span><span><span> </span></span></span></span></span></span><span><span><span><span><span><span><span><span>and psilocybin exhibit partially overlapping pharmacological profiles(pKi 5-HT ≈ 6.3 and 7.2 in silico respectively), but differ significantly in lipophilicity and the type of neuroplasticity induced. Carvacrol(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1007/s12640-021-00341-1"><span><span><span><span><span><span><u><span><span>Sisti et al., 2021</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), α-bisabolol(</span></span></span></span></span></span></span></span><a href="https://pubmed.ncbi.nlm.nih.gov/41412265/"><span><span><span><span><span><span><u><span><span>Kim et al., 2025</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), and β-asarone(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/molecules19055634"><span><span><span><span><span><span><u><span><span>Dong et al., 2014</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), which share serotonergic properties(Figure</span></span></span></span></span></span></span></span><span><span><span><span><span><span><strong><span>)</span></strong></span></span></span></span></span></span><span><span><span><span><span><span><span><span>, also show potential as neurotrophic agents.</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Furthermore, activation of 5-HT receptors leads to the upregulation of CREB and NF-κB/MAPK signaling pathways, thereby inducing neurogenesis, also serotonergic structures are aimed at targeted induction of BDNF in learning and memory areas CA1 and CA3 of the hippocampus (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.4103/1673-5374.191222"><span><span><span><span><span><span><u><span><span>Jiang et al., 2016</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>). This mechanism has been demonstrated by several lipophilic agents, including antidepressants like captodiamine(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1177/0269881113497614"><span><span><span><span><span><span><u><span><span>Ring & Regan, 2013</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) and neuroprotective terpenes such as carvacrol, α-bisabolol (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/nu14214648"><span><span><span><span><span><span><u><span><span>Arunachalam et al., 2022</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), and β-asarone. The neurogenic potential of these compounds correlates with their affinity for 5-HT receptors (Figure). Similarly, schisandrins(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/nu11071671"><span><span><span><span><span><span><u><span><span>Li et al., 2019</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) (in silico pKi ≈ 6.58) from Schisandra chinensis and ginsenosides(</span></span></span></span></span></span></span></span><a href="https://onlinelibrary.wiley.com/doi/10.1111/cns.70150"><span><span><span><span><span><span><u><span><span>Han et al., 2024</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) (in silico pKi ≈ 6.4) from Panax ginseng have been extensively documented as potent neuroprotective and neurotrophic agents.</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Fast neuroplasticity (e.g., psilocybin(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1038/s41598-022-16325-w"><span><span><span><span><span><span><u><span><span>Golden et al., 2022</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), ketamine(</span></span></span></span></span></span></span></span><a href="https://www.nature.com/articles/s41398-023-02451-0"><span><span><span><span><span><span><u><span><span>Kopelman et al., 2023</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>)) promotes synaptogenesis but can duplicate pathological connections and increase neural noise. In contrast, slow neuroplasticity—true neurogenesis and myelinogenesis—appears to be more beneficial for organic brain damage, depression, Alzheimer's disease, and related conditions. The lipophilic and amphiphilic synthetic terpenes and tryptophols presented in this study are designed for deep (intracellular) neurotrophic activity, targeting 5-HT1A receptors and potential allosteric sites. This is achieved through both deep regional penetration averaged mimetics and the selectivity of some candidates with high 5-HT1A affinity, as confirmed by in silico analysis (</span></span></span></span></span></span></span></span><a href="https://serotoninai.streamlit.app/"><span><span><span><span><span><span><u><span><span>https://serotoninai.streamlit.app</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>).</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Study structures exhibit varying levels of affinity (from moderate to high- pKi ≈ 7.8), different gradations of selectivity, high lipophilicity, and excellent bioavailability. Their deep penetration hypothetically ensures sustained "slow neuroplasticity" and more comprehensive 5-HT modulation. Furthermore, this study presents potential pharmacological analogs of hericenones: ultra-lipophilic lipophilic serotonin mimetics with potential activity within myelin sheaths and axons. Finally, psilocybin has also been shown to extend replicative lifespan by up to 50% through telomerase modulation and reduction of oxidative stress (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1038/s41514-025-00244-x"><span><span><span><span><span><span><u><span><span>Kato et al., 2025</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>).</span></span></span></span></span></span></span></span></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_18237924 |
| institution | Zenodo |
| language | eng |
| publishDate | 2026 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | New Serotonergics with High Intracellular Bioavailability as Potentially Neuroplastic and Geroprotective Agents Zaitsev, Yaroslav Erinacine A hericenones Hericium erinaceus neurotrophic agents rational drug design non-psychedelic neuroplasticity slow neuroplasticity lipophilic 5-HT1A mimetics NGF/BDNF induction telomerase modulation geroprotectors MAPK/NF-κB signaling in silico screening SAR library <p><strong>Abstract</strong></p> <p><span><span><span><span><span><span><span><span>Erinacine A (</span></span></span></span></span></span></span></span><span><span><span><span><span><em><span><span>Hericium erinaceus)</span></span></em></span></span></span></span></span><span><span><span><span><span><span> </span></span></span></span></span></span><span><span><span><span><span><span><span><span>and psilocybin exhibit partially overlapping pharmacological profiles(pKi 5-HT ≈ 6.3 and 7.2 in silico respectively), but differ significantly in lipophilicity and the type of neuroplasticity induced. Carvacrol(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1007/s12640-021-00341-1"><span><span><span><span><span><span><u><span><span>Sisti et al., 2021</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), α-bisabolol(</span></span></span></span></span></span></span></span><a href="https://pubmed.ncbi.nlm.nih.gov/41412265/"><span><span><span><span><span><span><u><span><span>Kim et al., 2025</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), and β-asarone(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/molecules19055634"><span><span><span><span><span><span><u><span><span>Dong et al., 2014</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), which share serotonergic properties(Figure</span></span></span></span></span></span></span></span><span><span><span><span><span><span><strong><span>)</span></strong></span></span></span></span></span></span><span><span><span><span><span><span><span><span>, also show potential as neurotrophic agents.</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Furthermore, activation of 5-HT receptors leads to the upregulation of CREB and NF-κB/MAPK signaling pathways, thereby inducing neurogenesis, also serotonergic structures are aimed at targeted induction of BDNF in learning and memory areas CA1 and CA3 of the hippocampus (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.4103/1673-5374.191222"><span><span><span><span><span><span><u><span><span>Jiang et al., 2016</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>). This mechanism has been demonstrated by several lipophilic agents, including antidepressants like captodiamine(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1177/0269881113497614"><span><span><span><span><span><span><u><span><span>Ring & Regan, 2013</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) and neuroprotective terpenes such as carvacrol, α-bisabolol (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/nu14214648"><span><span><span><span><span><span><u><span><span>Arunachalam et al., 2022</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), and β-asarone. The neurogenic potential of these compounds correlates with their affinity for 5-HT receptors (Figure). Similarly, schisandrins(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.3390/nu11071671"><span><span><span><span><span><span><u><span><span>Li et al., 2019</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) (in silico pKi ≈ 6.58) from Schisandra chinensis and ginsenosides(</span></span></span></span></span></span></span></span><a href="https://onlinelibrary.wiley.com/doi/10.1111/cns.70150"><span><span><span><span><span><span><u><span><span>Han et al., 2024</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>) (in silico pKi ≈ 6.4) from Panax ginseng have been extensively documented as potent neuroprotective and neurotrophic agents.</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Fast neuroplasticity (e.g., psilocybin(</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1038/s41598-022-16325-w"><span><span><span><span><span><span><u><span><span>Golden et al., 2022</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>), ketamine(</span></span></span></span></span></span></span></span><a href="https://www.nature.com/articles/s41398-023-02451-0"><span><span><span><span><span><span><u><span><span>Kopelman et al., 2023</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>)) promotes synaptogenesis but can duplicate pathological connections and increase neural noise. In contrast, slow neuroplasticity—true neurogenesis and myelinogenesis—appears to be more beneficial for organic brain damage, depression, Alzheimer's disease, and related conditions. The lipophilic and amphiphilic synthetic terpenes and tryptophols presented in this study are designed for deep (intracellular) neurotrophic activity, targeting 5-HT1A receptors and potential allosteric sites. This is achieved through both deep regional penetration averaged mimetics and the selectivity of some candidates with high 5-HT1A affinity, as confirmed by in silico analysis (</span></span></span></span></span></span></span></span><a href="https://serotoninai.streamlit.app/"><span><span><span><span><span><span><u><span><span>https://serotoninai.streamlit.app</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>).</span></span></span></span></span></span></span></span></p> <p><span><span><span><span><span><span><span><span>Study structures exhibit varying levels of affinity (from moderate to high- pKi ≈ 7.8), different gradations of selectivity, high lipophilicity, and excellent bioavailability. Their deep penetration hypothetically ensures sustained "slow neuroplasticity" and more comprehensive 5-HT modulation. Furthermore, this study presents potential pharmacological analogs of hericenones: ultra-lipophilic lipophilic serotonin mimetics with potential activity within myelin sheaths and axons. Finally, psilocybin has also been shown to extend replicative lifespan by up to 50% through telomerase modulation and reduction of oxidative stress (</span></span></span></span></span></span></span></span><a href="https://doi.org/10.1038/s41514-025-00244-x"><span><span><span><span><span><span><u><span><span>Kato et al., 2025</span></span></u></span></span></span></span></span></span></a><span><span><span><span><span><span><span><span>).</span></span></span></span></span></span></span></span></p> |
| title | New Serotonergics with High Intracellular Bioavailability as Potentially Neuroplastic and Geroprotective Agents |
| topic | Erinacine A hericenones Hericium erinaceus neurotrophic agents rational drug design non-psychedelic neuroplasticity slow neuroplasticity lipophilic 5-HT1A mimetics NGF/BDNF induction telomerase modulation geroprotectors MAPK/NF-κB signaling in silico screening SAR library |
| url | https://doi.org/10.5281/zenodo.18237924 |