<br>Norpsilocin 类似物的迷幻活性,ACS Chemical Neuroscience

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Norpsilocin 类似物的迷幻活性
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2024-01-08 , DOI: 10.1021/acschemneuro.3c00610
Alexander M Sherwood ₁ , Elise K Burkhartzmeyer ₁ , Samuel E Williamson ₁ , Michael H Baumann ₂ , Grant C Glatfelter ₂

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蘑菇色胺、赛洛西宾和贝奥囊素（即赛洛辛和去甲赛洛辛）的初级代谢物在体外对血清素 2A 受体 (5-HT _2A ) 表现出有效的激动剂活性，但在体内的5-HT _2A介导作用有所不同。特别地，赛洛辛在体内产生中枢介导的致幻作用，而去甲赛洛辛的不同之处仅在于失去了N-甲基基团，不具有致幻样作用。这些观察结果表明，诺赛洛星中的仲甲胺基团影响其中枢神经系统 (CNS) 生物利用度，但不影响其受体药效学。为了检验这一假设，合成了八种具有不同仲烷基、烯丙基和苄胺基团的去甲西洛辛衍生物，主要目的是增加其亲脂性和脑通透性。使用小鼠头部抽搐反应（HTR）作为中枢神经系统介导的迷幻样作用的代表来评估去甲西洛星类似物的结构-活性关系。 HTR 研究表明，通过单个甲基扩展 psilocin 的N -甲基基团，得到相应的二级N -乙基类似物 (4-HO-NET)，足以产生 psilocin 样活性（中位有效剂量或 ED ₅₀ = 1.4 毫克/千克）。值得注意的是， N-烯丙基、 N-丙基、 N-异丙基和N-苄基衍生物也诱导赛洛辛样 HTR 活性 (ED ₅₀ = 1.1–3.2 mg/kg)，最大效应各不相同（总共 26–77 个 HTR 事件）。相比之下，在同一位置添加体积较大的叔丁基或环己基并不会引发赛洛辛样 HTR。色胺系列的体外药理学评估表明与多种血清素受体亚型（包括 5-HT _2A ）和其他 CNS 信号蛋白（例如 sigma 受体）有相互作用。总体而言，我们的数据强调了诺赛洛星类似物中枢神经系统介导的迷幻样作用的关键结构要求。

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Psychedelic-like Activity of Norpsilocin Analogues

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.

更新日期：2024-01-08

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