GPR22 Inhibitors

GPR22 is a G-protein coupled receptor (GPCR) that, when activated, can signal through multiple pathways including those mediated by Gi/o, Gq, and Gs proteins. The inhibitors listed above have been identified based on their ability to disrupt specific aspects of these signaling pathways, thereby inhibiting the functional activity of GPR22. For instance, Pertussis Toxin and GDP-beta-S are both capable of inhibiting the interaction between Gi/o proteins and GPR22, with Pertussis Toxin causing irreversible modification of G proteins and GDP-beta-S acting as a GDP analog preventing the necessary GTP exchange for activation. On the other hand, YM-254890 and U73122 target the Gq-mediated pathways by inhibiting the function of Gq proteins and phospholipase C, respectively, leading to a reduction in the signaling cascade that involves calcium mobilization, a process GPR22 can initiate. Additionally, clozapine and suramin function as antagonists of GPR22 by preventing ligand binding, while ML297 indirectly modulates cellular excitability controlled by GPR22 through activation of GIRK channels. Cholera Toxin, through its action on Gs proteins, could lead to a state of receptor desensitization, thus dampening GPR22 activity. Go 6983 and M119K affect signaling downstream of GPR22 activation, with Go 6983 inhibiting protein kinase C, which is involved in the phosphorylation of target proteins post-GPR22 activation, and M119K inhibiting the G-protein beta-gamma subunit functions. BIM-46174 disrupts G-protein signaling more broadly by inhibiting Gα-Gβγ reassociation, a step essential for GPR22 function. Lastly, Palmitoyl-DL-carnitine's disruption of lipid rafts alters the membrane domains crucial for GPR22 localization and function, thereby providing an indirect means of inhibition. Each of these compounds, through their unique interactions with either the GPR22 itself or its associated signaling molecules, contribute to the portfolio of potential GPR22 inhibitors.