Paradoxical pharmacological effects of deoxy-tetrahydrocannabinol analogs lacking high CB1 receptor affinity

The present study investigated the role of peripheral cannabinoid (CB(2)) receptors in producing hypomobility, antinociception and hypothermia in mice. Results revealed that the CB(2)-selective antagonist, SR144528, did not block cannabimimetic effects of a potent delta(8)-tetrahydrocannabinol (THC) analog in mice. While most of a series of CB(2)-selective 1-deoxy-THC analogs were active in vivo only if they also had good affinity for CB(1) receptors, four of these analogs showed in vivo activity even though their affinities for CB(1) receptors were poor. Further, this activity was blocked by the CB(1) antagonist SR141716A, but not by SR144528. One of the deoxy analogs also stimulated [(35)S]GTPgammaS binding, an effect that was blocked by SR141716A. These results provide further evidence that these cannabimimetic effects are not mediated through action at CB(2) receptors. In addition, some of these analogs may be very low efficacy agonists at CB(1) receptors that act as full agonists in vivo, but lack the ability to displace high affinity and high efficacy binding ligands in vitro.