The endocannabinoid signaling system has emerged as an important target for therapeutic drug development, although the design of receptor-selective ligands has remained a challenge. The present findings represent an important step toward the rational design of drugs interacting with cannabinoid receptors, both in terms of their CB1 and CB2 selectivity and their mode of action as agonists or antagonists/inverse agonists.

First, resolution of the crystal structure of the CB2 receptor in complex with our high-affinity antagonist AM10257 has revealed that the CB2 antagonist-binding pocket is distinct, relatively smaller than the CB1 antagonist-binding pocket, and more similar with regard to size and the ligand-interacting residues to the CB1 agonist-binding pocket. This provides a rational explanation for the empirical findings of a high degree of CB1 and CB2 selectivity among cannabinoid receptor antagonists designed to date, and it also may account for the present finding that two structurally distinct CB2 antagonists display CB1 partial agonist activity. Given their lack of CB1 antagonist activity, CB2 antagonists should not elicit neuropsychiatric side effects similar to those that thwarted the clinical use of globally acting CB1 antagonists, such as rimonabant ().

Han et al., 2015 Han S.

Zhang F.F.

Qian H.Y.

Chen L.L.

Pu J.B.

Xie X.

Chen J.Z. Development of Quinoline-2,4(1H,3H)-diones as Potent and Selective Ligands of the Cannabinoid Type 2 Receptor.

Lucchesi et al., 2014 Lucchesi V.

Hurst D.P.

Shore D.M.

Bertini S.

Ehrmann B.M.

Allara M.

Lawrence L.

Ligresti A.

Minutolo F.

Saccomanni G.

et al. CB2-selective cannabinoid receptor ligands: synthesis, pharmacological evaluation, and molecular modeling investigation of 1,8-Naphthyridin-2(1H)-one-3-carboxamides.

A second important finding revealed a molecular mechanism critical for CB2 activation. This was achieved through molecular docking and functional studies using a rationally designed pair of structurally related ligands that unexpectedly acted as a CB2 antagonist (MRI2687) or agonist (MRI2594) because of the length difference of their arm 1, which resulted in diverse interactions with the toggle switch residue Trp258. Apart from providing strong support for the role of Trp258in the activation of CB2, the overlapping binding pose of these two compounds also highlights a close similarity of the interacting residues involved in the binding of CB2 agonists and antagonists. This conclusion is also supported by previous homology-based studies of other CB2 agonist and inverse agonist pairs based on different chemical scaffolds (). Because of the aforementioned similarity between the CB2 antagonist and CB1 agonist binding pockets, by inference, the CB1 and CB2 agonist binding pockets are also likely similar. Such structural observations may explain the low level of CB1 and CB2 selectivity and the related psychotropic effects that are associated with CB1 activation for some of the classical cannabinoids and their synthetic analogs. Nevertheless, structure-based rational drug design could mitigate this problem by exploiting the subtle differences in interactions with critical residues within both receptors. Although the agonist-bound structure of CB2 remains to be determined, the knowledge obtained from the antagonist-bound CB2 crystal structure, along with the findings relating to the opposing effects of CB2 and CB1, should aid in the rational design of CB2-interactive ligands with improved functional selectivity.