OTHER PROJECT INFORMATION – SUMMARY/ABSTRACT This project serves as the ligand development component of a comprehensive collaborative effort to fundamentally expand our understanding of the selective and functional modulation of the two cannabinoid receptors, CB1 and CB2. During the current funding period, we have made substantial progress in exploring the functional and structural properties of CB1 and CB2 through the development of suitable irreversible novel ligands. These have been used to obtain structural and functional information on CB1 and CB2 through our Ligand Assisted Protein Structure (LAPS) approach. Results originating from LAPS were further refined with the assistance of CB1 and CB2 X-ray and cryo-EM structures in complex with our high-affinity ligands. Based on our early work we were successful in developing neutral CB1 receptor antagonists that are being tested as potential medications for alcohol and opioid addiction (centrally active) as well as for pulmonary, liver and kidney fibrotic conditions (peripherally active). We have made advances towards the goals of the current cycle by distinguishing structural features of functional selectivity and developing functionally selective ligands. Additionally, we have identified novel approaches for developing ligands with distinct pharmacological profiles. These are now being integrated into our current submission. This project will provide the basis for the development of ligands that are involved in the preferential modulation of CB1 and the selective activation of CB2. We propose to accomplish our goals with the following specific aims: The first aim encompasses the development of a) orthosteric agonists exhibiting functional selectivity for CB1 and b) CB1 positive allosteric modulators with irreversible binding characteristics. The second aim encompasses the development of a) CB2 agonists with no or minimal efficacy for CB1 and b) bifunctional ligands that behave as CB2 agonists/CB1 antagonists (Yin-Yang). The results and ligands produced under the auspices of this project will serve as a basis for the development of novel medications with improved pharmacological profiles for the treatment of addictive, inflammatory and fibrotic disorders.