October 17th, 2019
Although a number of cannabinoid analogs had been synthesized beginning in the 1960’s, the discovery of the first cannabinoid receptor (CB1) took several decades. This happened through the joint efforts of a number of laboratories, and it involved the use of photoaffinity labelling of radioligands and imaging. The need for obtaining structural information on both CB1 and CB2 to serve as templates in target-based discovery led to computational efforts based on mutational studies for receptor modeling. More extended structural work involving the use of covalent ligands, targeted mutations and proteomic approaches in our laboratory, under the designation of Ligand Assisted Protein Structure (LAPS), provided more detailed experimental data and identified helix 6 in both receptors as being a key site involved in their activation/deactivation, validating some of the earlier computational efforts. An intensive effort involving Scripps, iHuman in Shanghai, and our laboratory, the Center for Drug Discovery led to the crystal structure of the CB1 receptor, first in its inactive form using a suitably designed antagonist for crystallization and subsequently in its activated form, using two irreversible agonists. This work provided detailed information on the binding motif of CB1 ligands . It also validated the concept of a double-toggle (HX6 - Hx3) mechanism of activation. These first two successes were followed by the very recent crystallization of the CB2 receptor, which provided some initial evidence for the complementarity of the two receptors and introduced the activation/deactivation(ying-yang)receptor concept, which now serves as a basis for the development of CB2 agonist/CB1 antagonist therapeutic medications.The availability of detailed structural information of a number of CB1 and CB2 ligand complexes, coupledwith data on ligand-receptor dynamics, opens the door for the design of cannabinergic drugs with greater structural and functional specificity.