Abstract
Cannabinoids exert their effects through interaction with two cannabinoid receptors CB1 and CB2. Activation of these receptors produces copious pharmacological effects. However, activation of the CB1 receptor with orthosteric agonists induces psychotropic effects, which limited the application of CB1 ligands for therapeutic gain. Allosteric modulators, which bind to sites different from where orthosteric ligands bind, provided a novel approach to regulate the function of CB1 through biased signaling. Biased signaling of allosteric modulators offered unique possibility to separate therapeutically relevant signaling pathways from adverse events. Currently, several CB1 allosteric modulators have been identified and represented by negative allosteric modulator Org27569 and positive allosteric modulator ZCZ01. Preliminary investigations suggested that CB1 allosteric modulators possess better signaling bias and less adverse effects in comparison with CB1 orthosteric ligands. Thus, discovery and development of CB1 allosteric modulators lead to new opportunities for discovering safer and more effective cannabinoid-based medications.