Similarities and differences upon binding of naturally occurring Δ9-tetrahydrocannabinol-derivatives to cannabinoid CB1 and CB2 receptors

• DOI: 10.1016/j.phrs.2021.105970
• Publication Date: 2021-11-07T06:23:09Z
• Authors: Iu Raïch; Rafael Rivas-Sant...; Alejandro Lillo; Jaume Lillo; Irene Reyes-Resina; Xavier Nadal; Carlos Ferreiro-Vera; Verónica Sánchez ...; Maria Majellaro; Eddy Sotelo; Gemma Navarro; Rafael Franco
• Keywords: GPR18; Functional selectivity; Cannabinoid Receptor Agonists; Tetrahydrocannabinol

We have here assessed, using Δ9-tetrahydrocannabinol (Δ9-THC) for comparison, the effect of Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and Δ9-tetrahydrocannabivarin (Δ9-THCV) that is mediated by human versions CB1, CB2, CB1-CB2 receptor functional units, expressed in a heterologous system. Binding to CB1 CB2 receptors was addressed living cells means homogeneous assay. A biphasic competition curve binding receptor, obtained Δ9-THCV expressing two receptors. Signaling studies included cAMP level determination, activation mitogen-activated protein kinase pathway ß-arrestin recruitment were performed. The signaling triggered Δ9-THCA via individual or heteromers disclosed differential bias, i.e. bias observed given phytocannabinoid depended on (CB1, CB1-CB2) compound used as reference calculate factor (Δ9-THC, selective agonist non-selective agonist). These results are consistent with different modes leading selectivity depending structure, state (monomeric heteromeric) cannabinoid receptor. In addition, studying Gi-coupling we showed able revert agonist, but only Δ9-THCV, not Δ9-THCA, reverted arachidonyl-2′-chloroethylamide (ACEA 100 nM) Overall, these indicate cannabinoids may variety qualitatively effects engaged upon