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

Abstract

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 NEt₃/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 IC₅₀=29.1 nM for the trans isomer and IC₅₀=294.2 nM for the cis counterpart. However, the IC₅₀ 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 IC₅₀=460 nM for trans and IC₅₀=1040 nM for cis. This functional property has not been previously observed for any other THC isomers.