The CB1 cannabinoid receptor is a widely distributed G-protein coupled receptor in human central and peripheral system. It is the most abundant GPCR in the brain. Ligands for the CB1 receptors have shown a broad scope of pharmacological properties such as analgesic, antiinflammatory, and antineoplastic effects. However, direct activation of the CB1 receptors has been linked to psychotropic effects. This limited the therapeutic application of CB1 agonists. Additionally, a CB1 inverse agonist (Rimonabant) marketed as an anti-obesity drug has been found liable of inducing psychoactive effects. Recently, several allosteric modulators for the CB1 receptors have been identified. These discoveries brought new opportunities for targeting the CB1 receptor for a variety of diseases, particularly for some disorders in the central nervous system. ORG27569 is the first allosteric modulator identified for the CB1 receptor. This compound was proven capable to regulate the functions of the CB1 receptor in a pathway-specific manner. This implied a new approach to modulate the functions of physiologically and pharmacologically important CB1 receptor. However, ORG27569 showed relatively weak binding capability (KB= 217.3 nM) and allostery (α = 6.95) to the CB1 receptor. To be therapeutically useful, allosteric modulators are desired to have high binding affinity and potent allostery on the CB1 receptors. Therefore, we designed novel analogs of ORG27569 with the aims of studying the structure-iv activity relationship (SAR) of this class of compounds and developing potent allosteric modulators for the CB1 receptor. In this project, we have designed and synthesized several classes of ORG27569 analogs, from which we found that the presence of the indole ring is more influential for modulator’s binding affinity (KB) and the C3 alkyl substitution has significant impact on the allostery of ligand. In this process, we identified a robust CB1 allosteric modulator LDK1240 which exhibited high binding cooperativity factor (α=16.7) and acted as potent antagonist on the agonist-induced GTPγS binding. In this thesis, we report the synthesis and pharmacological characterization of these novel indole-2-carboxamides.
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