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

Abstract

Adhesion G protein-coupled receptors (aGPCRs) have emerged as potential therapeutic targets in multiple cancers and in neurological 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 comprised of 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 similarly 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-a-acetoxydihydrodeoxygedunin, or 3-a-DOG. 3-a-DOG activated engineered, low-activity GPR56 7TM in independent biochemical and cell-based assays with an EC 50 of ~5 µM. The compound also activated a subset of aGPCRs but not two Class A GPCRs tested. The mode of 3-a-DOG-mediated receptor activation is as a partial agonist. 3-a-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.

Adhesion G protein–coupled receptors—Candidate metabotropic mechanosensors and novel drug targets

“…In an independent screen, three surrogate ligands, ezetimibe (an inhibitor of cholesterol absorption), flunarizine (a nonselective calcium channel blocker and histamine H1 receptor blocker) and the non‐steroidal oestrogen zeranol, were found to activate β‐arrestin recruitment through ADGRG3 . Later on, dihydromunduletone was shown to antagonize the tethered agonist activity of ADGRG1 and ADGRG5/GPR114, while 3‐α‐acetoxydihydrodeoxygedunin and structurally related gedunin and khivorin derivatives were singled out as partial agonists for the same aGPCR . Synaptamide, a docosahexaenoic acid metabolite, was reported to bind ADGRF1/GPR110 and activate a Stachel ‐independent cAMP response .…”

GPR56/ADGRG1 is associated with response to antidepressant treatment

“…Following activation of the GPR56 receptor by its ligands, the extracellular and transmembrane domains of GPR56 dissociate to reveal a tethered-peptide-agonist 11 . Based on this mechanism, synthetic peptides (i.e., P7 "TYFAVLM-NH2" and P19 "TYFAVLMQLSPALVPAELL-NH2"), comprising the specific portion of the tethered-peptide-agonist, have been generated and demonstrate GPR56 agonist properties 11,12 . We bilaterally infused these peptides and their inactive controls in the mouse PFC to explore the behavioral effects of GPR56 activation.…”

“…Gpr56 agonist: To test the antidepressant-like effect of Gpr56 agonists, we bilaterally infused synthetic peptides (P7 and P19) as well as control or an inactive modified peptide (P19 Y ->N: "TNFAVLMQLSPALVPAELL-NH2") previously described 12 , both in the PFC and in the NAcc of mice. Mice were anesthetized with a ketamine/xylazine mixture (100/10 mg/kg, i.p.)…”

Trendbericht Biochemie Teil 3: Adhäsions‐GPCR ‐‐ Hindernisse und Perspektiven

“…Breit angelegte Screenings lieferten bereits erste agonistische und antagonistische Substanzen, die jedoch noch nicht rezeptorspezifisch sind. [23][24][25] Die intrazelluläre Signalleitung ist gleichfalls durch eine ungewöhnliche Bandbreite gekennzeichnet. Außer der klassischen funktionellen Interaktion mit G-Proteinen 26,27) sind mittlerweile Bindung an Arrestine, 28) Wechselbeziehungen mit dem Cytoskelett 29) sowie der Austausch mit Molekülen des wnt-Signalwegs [30][31][32] beschrieben.…”