Photoswitchable allosteric modulators for metabotropic glutamate receptors

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

“…Due to these distinct structural features and mandatory dimerization, the class C GPCRs have been the most complex of the GPCRs in terms of understanding their activation mechanism [ 31 , 32 , 33 , 34 , 35 ]. Using several methods such as crystallization [ 30 ], lipid cubic phase [ 36 ], and most commonly single particle Cryo-EM, structures of over 20 human class C GPCRs have been solved to date [ 37 ], comprising metabotropic glutamate receptors (mGluR1–5,mGluR7) [ 36 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ], gamma-aminobutyric acid receptors (GABA 1 and GABA 2) [ 23 , 24 , 47 ], calcium-sensing receptors (CaS) [ 48 , 49 , 50 ], the extra-cellular domain of taste receptors (TAS1R1–TAS1R3) [ 51 , 52 , 53 , 54 , 55 ], and orphan receptors (GPR158, GPR179, GPR156) [ 56 , 57 , 58 , 59 , 60 ]. Similarly to other GPCR structures, class C GPCR structures are solved with inclusion of cholesterol or cholesteryl hemisuccinate (CHS) to the detergent mix during crystallization and recently, Cryo-EM ( Table 1 ).…”

Visible-Light-Controlled Histone Deacetylase Inhibitors for Targeted Cancer Therapy

“…While the design of cages is simpler as it can employ well-validated drugs, the reversibility of photoswitches allows for greater control of biological function, as both the initiation and termination of drug effects and its dose can be locally controlled by light. Among the known photochromic moieties, azobenzenes are the most popular. − They can isomerize between the more stable trans configuration to cis under illumination with a particular wavelength, which is dependent on the type and substitution of the aryl groups. This results in a large change in polarity, geometry, and end-to-end distance, which can lead to a difference in target engagement.…”

“…Among the known photochromic moieties, azobenzenes are the most popular. 11 − 14 They can isomerize between the more stable trans configuration to cis under illumination with a particular wavelength, which is dependent on the type and substitution of the aryl groups. This results in a large change in polarity, geometry, and end-to-end distance, which can lead to a difference in target engagement.…”

Optical Control of Adenosine A2A Receptor Using Istradefylline Photosensitivity

“…25,26 Increasing interest is being shown in GPCR photopharmacology, 27,28 which offers the possibility to modulate and understand GPCR physiology and pathology with a higher spatiotemporal control than that offered by classical pharmacological approaches. Photopharmacology has been applied to many GPCRs including dopamine, 29 cannabinoid, 30,31 opioid, 32,33 glutamate, 34 and adrenergic receptors. 35,36 Concerning adenosine receptors, a photoactivatable A 2A R antagonist, MRS7145, 37 a nonselective photoswitchable partial agonist, MRS5543, 38 and an adenosine-based photoswitchable agonist, AA-3 39 have been reported.…”

“…Combined with optical technologies, photopharmacology is a powerful fundamental research tool to explore the physiopathological function of endogenous regulatory systems, with micrometric spatial resolution and millisecond temporal resolution, opening new pharmacotherapeutic opportunities toward precision medicine. , Increasing interest is being shown in GPCR photopharmacology, , which offers the possibility to modulate and understand GPCR physiology and pathology with a higher spatiotemporal control than that offered by classical pharmacological approaches. Photopharmacology has been applied to many GPCRs including dopamine, cannabinoid, , opioid, , glutamate, and adrenergic receptors. , Concerning adenosine receptors, a photoactivatable A 2A R antagonist, MRS7145, a nonselective photoswitchable partial agonist, MRS5543, and an adenosine-based photoswitchable agonist, AA-3 have been reported. Exploration of the pathophysiological function of A 2A R and its therapeutic potential may benefit from additional selective A 2A R photochromic ligands.…”