Cannabinoid receptors respond to multiple endogenous fatty acid derivatives and are often divided into neuronal-associated CB1 receptors and immune cell-associated CB2 receptors. Both receptors are GPCR, coupled predominantly to Gi, and have cytoprotective properties. The predominant psychotropic agent in Cannabis, THC, acts as a partial agonist at both receptors. CB1 patho/physiological responses are often characterised as analgesic, rewarding, orexigenic, hypothermic and amnestic, while CB2 receptors are mostly associated with anti-inflammatory effects.
In many countries, synthetic cannabinoids have become a social issue, with a prevalence of use amongst the homeless and incarcerated, with even a number of deaths attributed to these agents. Although all the molecular mechanisms of action of these synthetic cannabinoids are yet to be defined, one feature they have in common is a high potency and high efficacy profile at CB1 receptors. Kumar and colleagues  report a CB1 receptor:Gi complex, where the receptor is bound to a synthetic cannabinoid, MDMB-FUBINACA. The authors report an agonist binding-evoked conformational switch involving residues in TM3 and TM6, which they suggest underlies the high affinity of this synthetic cannabinoid. Furthermore, they conduct in silico simulations to suggest a lateral path of entry for the synthetic cannabinoid between TM1 and TM7 rather than the ‘traditional’ extracellular point of ingress. This lateral diffusion model has been suggested for a number of lipid-binding GPCR.
There is a second cannabinoid receptor crystal structure in the same journal, which focusses on the CB2 receptor . Based on the primary sequences of the two human receptors, there is limited structural identity between CB1 and CB2 (~40 %), although the overlap is much higher in the transmembrane domains, as might be expected, given they bind a number of structurally-diverse ligands with little discrimination (e.g. CP55940, WIN55212-2 and HU210). Li et al report the first crystal structure of the CB2 receptor. In this version, a novel high affinity antagonist/inverse agonist AM10257 was bound to the receptor for crystallisation. The resultant structure shows a number of similarities with the antagonist-bound structure of the CB1 receptor, although notably the extracellular portions of the two receptors diverged markedly. Slightly surprisingly, a close resemblance to the agonist-bound CB1 receptor was identified, which lead them to investigate CB1 receptor function of the novel CB2 antagonist, which turned out to be a low efficacy CB1 receptor agonist.
Comments by Steve Alexander (@mqzspa)
 Kumar KK et al. (2018). Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell, pii: S0092-8674(18)31565-4. doi: 10.1016/j.cell.2018.11.040. [Epub ahead of print]. [PMID:30639101].
 Li X et al. (2018). Crystal Structure of the Human Cannabinoid Receptor CB2. Cell, pii: S0092-8674(18)31625-8. doi: 10.1016/j.cell.2018.12.011. [Epub ahead of print]. [PMID:30639103].