Department of Psychology, Miami University, Oxford, Ohio, USA.
Department of Chemical, Paper, and Biomedical Engineering, Miami University, Oxford, Ohio, USA.
Br J Pharmacol. 2024 Oct;181(19):3627-3641. doi: 10.1111/bph.16466. Epub 2024 Jun 2.
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.
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.
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-HT 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-HT-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.
Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.
对新型抗抑郁药的需求促使人们重新评估迷幻药物的治疗潜力。一些存在于含“魔法”蘑菇的裸盖菇素中的色胺与裸盖菇素有化学相似性。早期的研究表明，它们可能具有相同的生物学靶点。然而，很少有研究探索它们的药理学和行为学效应。
我们比较了裸盖菇素、去磷酸裸盖菇素和去磷酸aeruginascin 与裸盖菇素，以确定它们是否由相同的酶代谢，是否类似地穿透血脑屏障，是否作为类似受体的配体，并以类似的方式调节啮齿动物的行为。我们还评估了每种化合物的稳定性以及最佳的储存和处理条件。
体外酶动力学测定发现，所有化合物通过碱性磷酸酶去磷酸化和单胺氧化酶代谢的速率几乎相同。此外，我们发现只有裸盖菇素和去磷酸裸盖菇素的去磷酸化产物与去磷酸裸盖菇素类似地穿过血脑屏障模拟物，类似于去磷酸化形式的裸盖菇素，裸盖菇素。在体外细胞成像测定中，发现去磷酸化的 norbaeocystin 以与裸盖菇素和 norpsilocin 相似的效力激活 5-HT 受体。行为上，只有裸盖菇素在大鼠中引起头部抽搐反应，这是 5-HT 介导的迷幻作用和致幻潜力的标志物。然而，与裸盖菇素一样，去磷酸 norbaeocystin 改善了强迫游泳试验的结果。所有化合物对肾脏和肝脏健康指标的变化都很小，表明安全性良好。
总的来说，这项工作表明，其他天然存在的色胺，特别是去磷酸 norbaeocystin，可能与裸盖菇素有重叠的治疗潜力，但不会引起幻觉。
