P/F Project 3: “Designing novel functional chemical probes with high Cannabinoid receptor CB1/CB2 selectivity and specificity as probes for studying of cannabinoid related pathways” (PI: Peng Yang, PhD, Research Associate, Department of Pharmaceutical Sciences, University of Pittsburgh)

Specific Aims. Dr. Yang is a young investigator and his research focuses on the design, synthesis and potential uses of selective CB2 compounds. His latest review about CB2 and DA showed CB2 ligands could be developed as new treatments for DA by modulating the endocannabinoid system, which is a promising target for development of drug addiction. He already discovered and published two series of CB2 compounds with good CB1/CB2 selectivity, which have the potential for use as anti-osteoporosis agents. His ongoing work on this project is a continuation of the search for novel chemical probes with higher CB2 affinity and better CB1/CB2 selectivity, which will exhibit greater pharmacological effects. His project will benefit from the support of the CDAR Center, which will specifically focus on CB1/CB2 selectivity and affinity prediction, while Dr. Yang focuses on the exploration of more potential and selective CB2 agonists, antagonists, and inverse agonists, and their therapeutic uses. The top targets identified in silico will be synthesized by Dr. Yang, and further tested/validated for their CB1/CB2 affinity and functional activity (effect on cAMP production), using established methods in Dr. Yang’s lab. In addition, the P/F PI will also test the anti-osteoporosis potency of these compounds by using his established human, non-adherent, mononuclear, bone marrow cell model. In the present P/F project, we propose two specific aims:

Aim 1: To design and identify structurally diverse CB2 libraries with novel chemical scaffolds and better affinity/selectivity by using our well-defined pharmacophore models (CB1 and CB2) and CoMFA/QSAR models.

Aim 2: To synthesize these probes and further validate their CB1/CB2 affinity and biological activities, which are routine methods in our lab.