Salehi Arash, Ghanadian Mustafa, Zolfaghari Behzad, Jassbi Amir Reza, Fattahian Maryam, Reisi Parham, Csupor Dezső, Khan Ikhlas A, Ali Zulfiqar
Department of Pharmacognosy, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
Pharmaceuticals (Basel). 2023 May 14;16(5):747. doi: 10.3390/ph16050747.
This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of and (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na channels. Aconitine () and 3-acetyl aconitine () can desensitize Na channels after persistent activation. Lappaconitine (), N-deacetyllapaconitine (), 6-benzoylheteratisine (), and 1-benzoylnapelline () deactivate these channels. Methyllycaconitine (), mainly found in species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (), (), and mesaconitine () from species have a drastic analgesic effect. Among them, compound has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity.
本研究对二萜生物碱（DAs）进行了叙述性综述，二萜生物碱是一类极其重要的天然产物，主要存在于乌头属和翠雀属（毛茛科）的某些物种中。由于其众多复杂的结构和多样的生物活性，尤其是在中枢神经系统（CNS）中的活性，二萜生物碱长期以来一直是研究的焦点。这些生物碱通过四环或五环二萜类化合物的胺化反应产生，根据骨架结构中的碳原子数和结构差异分为三类46种。二萜生物碱的主要化学特征是其含有β - 氨基乙醇、甲胺或乙胺官能团的杂环系统。尽管A环中的叔氮作用和多环复杂结构在药物 - 受体亲和力中非常重要，但计算机模拟研究强调了C13、C14和C8中某些侧链的作用。二萜生物碱在临床前研究中大多通过钠通道显示出抗癫痫作用。乌头碱（）和3 - 乙酰乌头碱（）在持续激活后可使钠通道脱敏。拉帕乌头碱（）、去甲酰基拉帕乌头碱（）、6 - 苯甲酰异atisine（）和1 - 苯甲酰那pel线（）使这些通道失活。主要存在于藜芦属物种中的甲基lycaconitine（）对α7烟碱型乙酰胆碱受体（nAChR）的结合位点具有极高的亲和力，并有助于多种神经功能和神经递质的释放。几种来自乌头属物种的二萜生物碱，如布氏乌头碱A（）、（）和中乌头碱（）具有显著的镇痛作用。其中，化合物在中国已使用数十年。它们的作用可通过增加强啡肽A的释放、激活β - 肾上腺素能系统中的抑制性去甲肾上腺素能神经元以及通过使上述应激的钠通道失活来阻止疼痛信息的传递来解释。乙酰胆碱酯酶抑制、神经保护、抗抑郁和抗焦虑活性是某些二萜生物碱已被研究的其他中枢神经系统作用。然而，尽管有各种中枢神经系统作用，但由于其二萜生物碱的神经毒性，从二萜生物碱开发新药的近期进展并不显著。
