Probing the ligand-binding pocket of the cannabinoid receptors: Design and synthesis of novel ligands

Cannabinoids and related compounds act through the cannabinoid receptors CB-1 and CB-2 to produce diverse physiological effects. Cannabinoids have potential therapeutic implications in several pathological conditions such as inflammation, asthma, obesity, Parkinson's disease, hemorrhagic shock and cancer. Our research was focused on three major conditions for which cannabinoids hold great promise for drug development, namely, obesity, inflammation and cancer.; For targeting obesity, we designed and synthesized a series of N-1 and C-5 cycloalkyl-substituted pyrazole analogs. We hypothesized that the relative orientations of the N-1 and C-5 substituents play a critical role in determining cannabinoid receptor binding affinity and selectivity. Our receptor binding studies suggested that the C-5 cycloalkyl-substituted pyrazole analogs were good leads for development of CB-2 selective ligands. NMR solution structure studies on these compounds suggested that the torsional parameter tau 2 is an important determinant of CB-1/CB-2 binding affinity and selectivity. Also, the presence of a volume excluded region in the CB-2 receptor was demonstrated. One of our analogs with the 4-methyl phenyl group at the C-5 position showed comparable activity to our lead compound SR 141716A.; In our second project we developed aromatic side chain analogs of Delta 8-THC for targeting inflammation and cancer. We hypothesized that introduction of an aromatic side chain would alter the electronic properties of both the side chain and ring A of Delta8-THC as well as help in probing potential pi-pi interactions with the aromatic amino acids that are present in the CB-1 receptor. A pilot study resulted in a highly potent and selective CB-2 ligand which had a dimethyl phenyl side chain. We utilized this analog as the lead for development of a series of substituted phenyl as well as thiophenyl side chain analogs of Delta8-THC for augmenting CB-2 selectivity and affinity. Our receptor binding studies suggested that introduction of electron withdrawing groups and bulky groups help in improving CB-2 affinity. Our thiophenyl analog displayed very high potencies at both the receptor sub types with a CB-2 affinity that is comparable to some of the most potent CB-2 analogs that have been reported so far. Initial in-vitro studies suggest that our dimethyl phenyl analog is more efficacious and safe than carmustine for treatment of gliomas. AP-1 inhibitory studies on some of our analogs indicate that these compounds hold promise for targeting inflammation.