Allosteric Optical Control of a Class B G‐Protein‐Coupled Receptor

Abstract

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G‐protein‐coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light‐activated positive allosteric modulator of the glucagon‐like peptide‐1 receptor (GLP‐1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca2+, cAMP, and insulin responses to glucagon‐like peptide‐1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small‐molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP‐1R.

Potent Prearranged Positive Allosteric Modulators of the Glucagon‐like Peptide‐1 Receptor

“…In the present study, we describe a photopharmacology‐inspired strategy for the rational design of potent GLP‐1R PAMs based upon the allosteric photoswitch PhotoETP . By restricting degrees of freedom using stilbenes, it could be shown that compounds prearranged as their trans ‐isomer were more potent than other PAMs, including BETP .…”

“…Recently, we described allosteric optical control of the glucagon‐like peptide‐1 receptor (GLP‐1R), a prototypical class B GPCR involved in the maintenance of blood glucose levels and a blockbuster target for type 2 diabetes treatment . As peptide ligands that target the GLP‐1R must be injected, the development of orally available small‐molecule GLP‐1R activators is a priority.…”

“…As peptide ligands that target the GLP‐1R must be injected, the development of orally available small‐molecule GLP‐1R activators is a priority. In our previous work, an azobenzene‐containing molecular photoswitch termed PhotoETP was designed and synthesized, based upon an “azologue” of the known GLP‐1R positive allosteric modulator (PAM) 4‐(3‐(benzyloxy)phenyl)‐2‐(ethylsulfinyl)‐6‐(trifluoro‐methyl)pyrimidine ( BETP ) . Notably, signaling responses to glucagon‐like peptide‐1 (GLP‐1) degradation products could be sculpted by the application of blue light to induce formation of the trans ‐isomer .…”

“…a) BETP possesses an O ‐benzyl ether that can freely rotate and adopt various conformations, occupying a large space, as denoted in the lower drawing. b) PhotoETP endows GLP‐1R with light sensitivity when the azobenzene is locked in its active trans ‐state under blue light illumination (blue circle), which is interchangeable with UV light to its inactive cis ‐state (gray circle). c) Novel stilbene congeners are constantly locked (orange circle) in their respective state and do not exhibit photostationary states.…”

Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits

“…A photoswitchable small molecule mu opioid agonist fentanyl has also been developed as well using this approach [69]. Diffusible photoswitches have also been developed to allosterically modulate metabotrophic glutamate receptors [70,71**]. Additional, neuropeptide photo-ligand mimics are in development and offer exciting extensions of this early work.…”