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Adhesion G protein-coupled receptors (aGPCRs) have emerged as potential therapeutic targets in multiple cancers and in neurologic diseases. However, there are few modulatory compounds that act on these receptors. The majority of aGPCRs are orphans and a general activation mechanism has only recently been defined: aGPCRs are activated by a tethered agonist. aGPCRs constitutively cleave themselves during biosynthesis to generated two-part receptors comprising an extracellular domain (ECD) and a 7-transmembrane spanning domain (7TM). ECD dissociation reveals the tethered agonist initiating G protein signaling. Synthetic peptides that mimic the tethered agonist region can activate aGPCRs. We hypothesized that small molecules could act in the same way as peptide agonists. High throughput screening of the 2000-compound Spectrum Collection library using the serum response element luciferase gene reporter assay revealed two related classes of small molecules that could activate the aGPCR GPR56/ADGRG1. The most potent compound identified was 3- α -acetoxydihydrodeoxygedunin, or 3- α -DOG. 3- α -DOG activated engineered, low-activity GPR56 7TM in independent biochemical and cell-based assays with an EC 50 of ∼5 μ M. The compound also activated a subset of aGPCRs but not two class A GPCRs tested. The mode of 3- α -DOG-mediated receptor activation is that of partial agonist. 3- α -DOG activated GPR56 less efficaciously than peptide agonist and could antagonize both the peptide agonist and the endogenous tethered agonist, which are pharmacological hallmarks of partial agonists. Taken together, we have uncovered a novel group of aGPCR partial agonists that will serve as invaluable resources for understanding this unique class receptors.

Gedunin- and Khivorin-Derivatives Are Small-Molecule Partial Agonists for Adhesion G Protein-Coupled Receptors GPR56/ADGRG1 and GPR114/ADGRG5