The oxytosis/ferroptosis regulated cell death pathway is an emerging field of research owing to its pathophysiological relevance to a wide range of neurological disorders, including Alzheimer's and Parkinson's diseases and traumatic brain injury. Developing novel neurotherapeutics to inhibit oxytosis/ferroptosis offers exciting opportunities for the treatment of these and other neurological diseases. Previously, we discovered cannabinol (CBN) as a unique, potent inhibitor of oxytosis/ferroptosis by targeting mitochondria and modulating their function in neuronal cells. To further elucidate which key pharmacophores and chemical space are essential to the beneficial effects of CBN, we herein introduce a fragment-based drug discovery strategy in conjunction with cell-based phenotypic screens using oxytosis/ferroptosis to determine the structure-activity relationship of CBN. The resulting information led to the development of four new CBN analogs, CP1-CP4, that not only preserve the sub-micromolar potency of neuroprotection and mitochondria-modulating activities seen with CBN in neuronal cell models but also have better druglike properties. Moreover, compared to CBN, the analog CP1 shows improved efficacy in the model of mild traumatic brain injury. Together these studies identify the key molecular scaffolds of cannabinoids that contribute to neuroprotection against oxytosis/ferroptosis. They also highlight the advantageous approach of combining cell-based assays and rapid studies using models for evaluating new therapeutic compounds.

中文翻译：

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基于片段的药物发现和新型大麻酚催氧作用/铁死亡抑制剂的生物学评估，用于治疗神经系统疾病


催氧/铁死亡调节的细胞死亡途径是一个新兴的研究领域，因为它与多种神经系统疾病（包括阿尔茨海默病、帕金森病和创伤性脑损伤）具有病理生理学相关性。开发新型神经治疗药物来抑制催氧作用/铁死亡为治疗这些疾病和其他神经系统疾病提供了令人兴奋的机会。此前，我们发现大麻酚 (CBN) 通过靶向线粒体并调节其在神经元细胞中的功能，作为一种独特的、有效的催氧作用/铁死亡抑制剂。为了进一步阐明哪些关键药效基团和化学空间对于 CBN 的有益作用至关重要，我们在此引入基于片段的药物发现策略，结合使用氧化作用/铁死亡的基于细胞的表型筛选来确定 CBN 的结构-活性关系。由此产生的信息导致了四种新 CBN 类似物 CP1-CP4 的开发，它们不仅保留了 CBN 在神经元细胞模型中所见的神经保护和线粒体调节活性的亚微摩尔效力，而且还具有更好的药物特性。此外，与 CBN 相比，类似物 CP1 在轻度创伤性脑损伤模型中显示出更高的疗效。这些研究共同确定了大麻素的关键分子支架，有助于神经保护以防止氧化中毒/铁死亡。他们还强调了将基于细胞的测定与使用评估新治疗化合物的模型进行快速研究相结合的有利方法。