Synthesis and Evaluation of Natural and Unnatural Tetrahydrocannabiorcol for Its Potential Use in Neuropathologies.

(-)- trans -Δ 9 -Tetrahydrocannabinol ( trans -(-)-Δ 9 -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 ( trans -(-)-Δ 9 -THCO) and unnatural Δ 9 -tetrahydrocannabiorcol ( trans -(+)-Δ 9 -THCO) were successfully synthesized starting from R -limonene and S -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 trans -(+)-Δ 9 -THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.