The 11-hydroxy Metabolite Of Δ9-Tetrahydrocannabivarin Behaves As An Apparent CB1 and CB2 Receptor Neutral Antagonist

Maria Grazia Cascio, Pietro Marini, Daniele Bolognini, Roger G. Pertwee. University of Aberdeen, Aberdeen, UK

We have reported previously that the phytocannabinoid, Δ9-tetrahydrocannabivarin (Δ9-THCV), can behave as a CB1 receptor antagonist (Pertwee et al., 2007), and as a CB2 receptor partial agonist (Bolognini et al., 2010). We now report results from experiments directed at investigating the ability of the Δ9-THCV metabolite, 11-OH-Δ9-THCV, to target cannabinoid CB1 and CB2 receptors.

In our investigation, we performed both [3H]CP55940 displacement binding assays with membranes obtained from MF1 mouse whole brain, hCB1 and hCB2 CHO cells, and [35S]GTPγS binding assays, performed with these membranes or with MF1 mouse spleen membranes, using methods we have described previously (Cascio et al., 2010; Bolognini et al., 2010). Mean apparent KB values for 11-OH-Δ9-THCV (1 µM) were calculated by Schild analysis.

Table: Ki (nM), maximum displacement (%), Emax (%) and KB (nM) values, with 95% confidence limits (CL), for 11-OH-Δ9-THCV determined using mouse brain, mouse spleen, human CB1 CHO cell or human CB2 CHO cell membranes

When tested alone, 11-OH-Δ9-THCV (1nM-10µM) did not affect [35S]GTPγS binding to either mouse brain or hCB2 CHO cell membranes. Also, at 1 µM, 11-OH-Δ9-THCV induced a rightward, but not a downward, shift of the log concentration-response curve of CP55940 in mouse brain membranes, hCB2 CHO cell and mouse spleen membranes, thus behaving as an apparent CB1 and CB2 “neutral” antagonist. KB values are reported in the Table above. Consequently, 11-OH-Δ9-THCV may be an important lead compound for a much needed neutral CB2 receptor antagonist. It will be important, therefore, to establish whether, like Δ9-THCV (Bolognini et al., 2010), 11-OH-Δ9-THCV behaves as a CB2 partial agonist when the measured response is CB2-mediated inhibition of cyclic AMP production.

Funded by GW Pharmaceuticals

Pertwee RG et al, Br J Pharmacol 150:586, 2007

Bolognini D et al, Br J Pharmacol 160:677, 2010

Cascio MG et al, Br J Pharmacol 159:129, 2010