Photoswitching the Efficacy of a Small‐Molecule Ligand for a Peptidergic GPCR: from Antagonism to Agonism

Abstract

For optical control of GPCR function, we set out to develop small-molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene-containing CXCR3 ligands. G protein activation assays and real-time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron-donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling.

A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor

“…[1a] GPCRs constitute one of the largest families of transmembrane proteins,t heir dysfunction is associated with ap lethora of diseases and consequently GPCRs are one of the most successful classes of drug targets. [5] Recently,v arious GPCRs have been successfully targeted using photopharmacology approaches,i ncluding mopioid, [6] CXCR3, [7] CB1, [8] H 3 R, [9] mGlu5, [10] and GLP1. [11] Yet, almost all these examples include at least one but more frequently two antagonistic/partial agonist isomeric forms.In contrast, freely diffusible affinity and potencyp hotoswitches in which both isomers act as full agonists are scarce, [1a] even though such compounds would be very useful for photopharmacology approaches and complementary to agonist-toantagonist switches.…”

Strategies and considerations of G-protein-coupled receptor photopharmacology

“…Intriguingly, alloswitch-1 was based on the scaffold of a potent mGlu4 PAM, but with the strategic addition of an azobenzene core its activity switched to negative cooperativity with glutamate at the mGlu5, and this NAM activity is reversibly controlled by irradiation with different wavelengths of light (Pittolo et al, 2014) (Figure 3B). Furthermore, in a recent communication by Gomez-Santacana et al, (2018), photoswitchable orthosteric-targeting ligands for the chemokine receptor CXCR3 were rationally designed to have efficacy photoswitches in a [ 35 S]GTPγS binding assay. They showed that depending on the light condition, orthosteric-targeting small molecules could bind to the CXCR3 and demonstrate either full, partial or no agonism at the receptor (Gomez-Santacana, de Munnik, Vijayachandran, Da Costa Pereira, & Bebelman, 2018).…”

“…Furthermore, in a recent communication by Gomez-Santacana et al, (2018), photoswitchable orthosteric-targeting ligands for the chemokine receptor CXCR3 were rationally designed to have efficacy photoswitches in a [ 35 S]GTPγS binding assay. They showed that depending on the light condition, orthosteric-targeting small molecules could bind to the CXCR3 and demonstrate either full, partial or no agonism at the receptor (Gomez-Santacana, de Munnik, Vijayachandran, Da Costa Pereira, & Bebelman, 2018). This study illustrates that not only allosteric PCLs, but also orthosteric PCLs can be designed to have subtle structural differences, which result in significant changes in pharmacological activity.…”

A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G‐Protein‐Coupled Receptor

“…GPCRs constitute one of the largest families of transmembrane proteins, their dysfunction is associated with a plethora of diseases and consequently GPCRs are one of the most successful classes of drug targets . Recently, various GPCRs have been successfully targeted using photopharmacology approaches, including μ‐opioid, CXCR3, CB1, H 3 R, mGlu5, and GLP1 . Yet, almost all these examples include at least one but more frequently two antagonistic/partial agonist isomeric forms.…”