作者: Gibbons, William J. ; Jones, J. Andrew ; Wells, Hunter G. ; Nguyen, Quynh ; Sandoval, Oscar ; Friedberg, Lucas M. ; Roberts, Brianna R. ; Rakoczy, Ryan J. ; McMurray, Matthew S. ; Sciortino, Jon H. ; Sen, Abhishek K. ; Runge, Grace N.

Background and Purpose:

Demand for new antidepressants has resulted in a re‐evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin‐containing “magic” mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects.

Experimental Approach:

We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood–brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound.

Key Results:

In vitro enzyme kinetics assays found that all compounds had nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin crossed a blood–brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5‐HT2A receptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5‐HT2A‐mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles.

Conclusions and Implications:

Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

2024-01-17·ACS chemical neuroscience

Psychedelic-like Activity of Norpsilocin Analogues

Article

作者: Williamson, Samuel E ; Burkhartzmeyer, Elise K ; Glatfelter, Grant C ; Baumann, Michael H ; Sherwood, Alexander M

Primary metabolites of mushroom tryptamines, psilocybin and baeocystin (i.e., psilocin and norpsilocin), exhibit potent agonist activity at the serotonin 2A receptor (5-HT_2A) in vitro but differ in their 5-HT_2A-mediated effects in vivo. In particular, psilocin produces centrally mediated psychedelic effects in vivo, whereas norpsilocin, differing only by the loss of an N-methyl group, is devoid of psychedelic-like effects. These observations suggest that the secondary methylamine group in norpsilocin impacts its central nervous system (CNS) bioavailability but not its receptor pharmacodynamics. To test this hypothesis, eight norpsilocin derivatives were synthesized with varied secondary alkyl-, allyl-, and benzylamine groups, primarily aiming to increase their lipophilicity and brain permeability. Structure-activity relationships for the norpsilocin analogues were evaluated using the mouse head-twitch response (HTR) as a proxy for CNS-mediated psychedelic-like effects. HTR studies revealed that extending the N-methyl group of norpsilocin by a single methyl group, to give the corresponding secondary N-ethyl analogue (4-HO-NET), was sufficient to produce psilocin-like activity (median effective dose or ED₅₀ = 1.4 mg/kg). Notably, N-allyl, N-propyl, N-isopropyl, and N-benzyl derivatives also induced psilocin-like HTR activity (ED₅₀ = 1.1-3.2 mg/kg), with variable maximum effects (26-77 total HTR events). By contrast, adding bulkier tert-butyl or cyclohexyl groups in the same position did not elicit psilocin-like HTRs. Pharmacological assessments of the tryptamine series in vitro demonstrated interactions with multiple serotonin receptor subtypes, including 5-HT_2A, and other CNS signaling proteins (e.g., sigma receptors). Overall, our data highlight key structural requirements for CNS-mediated psychedelic-like effects of norpsilocin analogues.

2023-06-01·Computational biology and chemistry

In silico characterization of the psilocybin biosynthesis pathway

Article

作者: Irvine, William ; Tyler, Marshall ; Delgoda, Rupika

Nearly all mushrooms of the Psilocybe genus contain the natural product psilocybin, which is a psychoactive alkaloid derived from l-tryptophan. Considering their use in ancient times, as well as their psychedelic properties, these mushrooms have re-emerged with psychotherapeutic potential for treating depression, which has triggered increased pharmaceutical interest. However, the psilocybin biosynthesis pathway was only recently defined and, as such, little exists in the way of structural data. Accordingly, the aim of this study was to structurally characterize this pathway by generating homology models for the four Psilocybe cubensis enzymes involved in psilocybin biosynthesis (PsiD, a decarboxylase; PsiH, a monooxygenase; PsiK, a phosphotransferase; PsiM, a methyltransferase). Following initial model generation and alignment with the identified structural templates, repeated refinement of the models was carried out using secondary structure prediction, geometry evaluation, energy minimization, and molecular dynamics simulations in water. The final models were then evaluated using molecular docking interactions with their substrates, i.e., psilocybin precursors (l-tryptophan, tryptamine, 4-hydroxytryptamine, and norbaeocystin/baeocystin), all of which generated feasible binding modes for the expected biotransformation. Further plausibility of the psilocybin → aeruginascin, 4-hydroxytryptamine → norpsilocin, and tryptamine → N,N-dimethyltryptamine conversions, all mediated by the generated model for PsiM, suggests valid routes of formation for these key secondary metabolites. The structural characterization of these enzymes and their binding modes which emerged from this study can lead to a better understanding of psilocybin synthesis, thereby paving the way for the development of novel substrates and selective inhibitors, as well as improved biotechnological manipulation and production of psilocybin in vitro.

项与 Baeocystin(Pilz Bioscience) 相关的新闻（医药）

2022-06-16

·BioSpace

Nova Mentis Files Patent on Diagnosing, Monitoring and Treating Neurological Diseases with Psychoactive Tryptamine Derivatives

mRNA Diagnostic Index to Measure Drug Treatment Response Vancouver, British Columbia--(News - June 16, 2022) - Nova Mentis Life Science Corp. (CSE: NOVA) (FSE: HN3Q) (OTCQB: NMLSF) ("NOVA" or the "Company"), a biotechnology company and global leader in first-in-class psilocybin-based therapeutics and complementary diagnostics for neuroinflammatory disorders is pleased to announce it is bolstering its IP with the filing of provisional patent applications to protect data it obtained during its psilocybin preclinical studies and provide protection for the Company's therapeutic paradigm for treating neuroinflammatory disorders with psilocybin and psilocybin-based tryptamine derivatives. "The filing of these patent applications represent a major milestone in NOVA's psilocybin research program," stated Dr. Marvin S. Hausman MD, Chairman of NOVA's Scientific Advisory Board. "The Company is now in a position to reveal the breakthrough preclinical psilocybin results uncovered in its treatment of fragile X syndrome (FXS). Oral repetitive doses of microdose psilocybin showed a more robust improvement in memory than the same doses given by injection. Metabolic changes of psilocybin within the small intestine and perhaps the microbiome may represent a new paradigm in the application of psilocybin to the treatment of autism spectrum disorder (ASD). The data is scheduled to be published in a peer reviewed journal and presented at the upcoming 18th NFXF International Fragile X Conference in July 2022." The provisional patent applications filed with the U.S. Patent and Trademark Office relates to diagnosis, monitoring and treating neuroinflammatory diseases and conditions with psychoactive tryptamine derivatives. NOVA's psilocybin formulation was evaluated in two distinct rat models of autism in the laboratory of Dr. Viviana Trezza, Rome, Italy, and demonstrated psilocybin proof of efficacy and safety. In February 2022, the Company announced it had successfully completed a preclinical study that confirmed oral microdose psilocybin as a potential treatment option for ASD and FXS. The research found that a repeated low dose of NOVA's proprietary psilocybin drug (NM-1001) significantly modulated behavioural and cognitive defects, such as recognition memory, in a genetic model of FXS. Neuroinflammatory conditions - especially those that have the added complexity of disrupted emotional states and behaviours - are still difficult to diagnose accurately and treat effectively. NOVA's research program is designed to generate clinical biomarker data that characterize aberrant gene expression and cellular communication in neurological disease or injury and provide insights into possible interventions and disease monitoring. The ability to penetrate the unique genetic language underlying the development of chronic diseases and assess therapeutic responses will assist NOVA in obtaining psychedelic drug approval with the regulatory agencies. In July 2021, NOVA filed a U.S. provisional patent application for a proprietary manufacturing process for the production of psilocybin and tryptamine analogues, baeocystin and aeruginascin. In May and November 2021, the Company filed US provisional patent applications describing a diagnostic/therapeutic combination of mRNA molecules that encode proteins involved in the development of neurogenerative diseases, FXS and ASD. About Nova Mentis Life Science Corp. Nova Mentis Life Science Corp. is a Canadian-based biotechnology company and global leader in developing diagnostics and psilocybin-based therapeutics for neuroinflammatory disorders. Nova is the first biotech company to achieve orphan drug designation in both the United States and European Union for the use of psilocybin in the treatment of Fragile X Syndrome (FXS). Our goal is to diagnose and treat debilitating chronic conditions that have unmet medical needs, such as autism spectrum disorder (ASD) and FXS. For further information on the Company, please visit or email info@novamentis.ca. On Behalf of the Board Will Rascan, President & CEO Nova Mentis Life Science Corp. Phone: 778-819-0244 Toll Free: 1-833-542-5323 Twitter: @novamentislsc Instagram: @novamentislsc Facebook: @novamentislsc Neither the Canadian Securities Exchange nor its Market Regulator (as that term is defined in the policies of the Canadian Securities Exchange) accepts responsibility for the adequacy or accuracy of this release. This news release contains statements that constitute "forward-looking statements." Such forward looking statements involve known and unknown risks, uncertainties and other factors that may cause Nova Mentis Life Science's actual results, performance or achievements, or developments in the industry to differ materially from the anticipated results, performance or achievements expressed or implied by such forward-looking statements. Forward looking statements are statements that are not historical facts and are generally, but not always, identified by the words "expects," "plans," "anticipates," "believes," "intends," "estimates," "projects," "potential" and similar expressions, or that events or conditions "will," "would," "may," "could" or "should" occur. To view the source version of this press release, please visit

孤儿药First in Class信使RNA

100 项与 Baeocystin(Pilz Bioscience) 相关的药物交易

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