Anand Radhika, Anand Loveleena Kaur, Rashid Nadia, Painuli Ritu, Malik Fayaz, Singh Parvinder Pal
Natural Product & Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
J Nat Prod. 2024 Feb 23;87(2):167-175. doi: 10.1021/acs.jnatprod.3c00172. Epub 2024 Feb 14.
(-)--Δ-Tetrahydrocannabinol (-(-)-Δ-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (-(-)-Δ-THCO) and unnatural Δ-tetrahydrocannabiorcol (-(+)-Δ-THCO) were successfully synthesized starting from -limonene and -limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 μM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural -(+)-Δ-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.
(-)-Δ-四氢大麻酚[(-)-Δ-THC]已显示出神经保护潜力，但其药用价值因具有精神活性的特性而未得到充分开发。其低级同系物本质上无精神活性，但在神经保护潜力方面缺乏全面的科学验证。本研究描述了THC型化合物的无精神活性低级同系物的合成及其神经保护潜力。天然四氢大麻酚酸[(-)-Δ-THCO]和非天然Δ-四氢大麻酚酸[(-)-(+)-Δ-THCO]分别从(-)-苎烯和(+)-苎烯成功合成，并在细胞模型中研究其神经保护潜力。通过核磁共振(NMR)、异核多键相关(HMBC)、异核单量子相干(HQSC)、核欧沃豪斯效应光谱(NOESY)和全相关谱(COSY)实验确认了两种对映体的结构。结果表明，两种对映体在浓度高达50 μM时对处理的细胞均无毒。对映体的神经保护特性表明，处理可显著逆转皮质酮诱导的SH-SY5Y细胞毒性，并同时导致脑源性神经营养因子(BDNF)表达升高。还观察到，非天然的(-)-(+)-Δ-THCO比天然对映体表现出更好活性，其在神经病理学疾病中的潜在用途可进一步探索。
