Chemistry, Crystal Structure, and In Vitro Receptor Binding of Δ10-THC Isomers.

Introduction: The psychoactive properties of Δ10-THC isomers ( trans- and cis- Δ10-THC) are poorly understood. To shed more light on the biological effects of these compounds, we studied in vitro receptor binding of Δ10-THC isomers at cannabinoid CB1 and CB2 receptors. Materials and Methods: We first optimized and simplified catalytic synthesis of trans- and cis- Δ10-THC to allow their safe and cheap large-scale synthesis. In our synthesis, BuLi was replaced with KO t Bu, and DMSO/anisole or NEt 3 /heptane solvent systems were used instead of HMPA/toluene. Single crystal X-ray analysis confirmed the structure of both isomers and the configuration of their chiral centers. Results: In the radioligand replacement assay, both isomers showed strong affinity toward the CB1 receptor, with IC 50 =29.1 nM for the trans isomer and IC 50 =294.2 nM for the cis counterpart. However, the IC 50 values were significantly higher than that of Δ9-THC (2.1 nM), a naturally occurring psychoactive component of cannabis sativa , suggesting a lower affinity of Δ10-THCs toward this receptor. In function assays, in contrast to Δ9-THC, both isomers failed to show any agonist properties at concentrations up to 10 μM suggesting a lack of THC-like psychoactivity for trans- and cis- Δ10-THC. Conclusions: Our results established Δ10-THC isomers among antagonists of the CB1 receptor as both cis and trans isomers antagonized CP55,490 with IC 50 =460 nM for trans and IC 50 =1040 nM for cis . This functional property has not been previously observed for any other THC isomers.