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The histamine H1 G protein-coupled receptor (GPCR) plays an important role in allergy and inflammation. Existing drugs that address the H1 receptor differ in their chemical structure, pharmacology, and side effects. Light-controllable spatial and temporal activity regulation of photochromic H1 ligands may contribute to a better mechanistic understanding and the development of improved correlations between ligand structure and pharmacologic effects. We report photochromic H1 receptor ligands, which were investigated in an organ-pharmacological assay. Initially, five photochromic azobenzene derivatives of reported dual H1 -H4 receptor antagonists were designed, synthesized, photochemically characterized, and organ-pharmacologically tested on the isolated guinea pig ileum. Among them, one compound [trans-19: (Z)-1-(4-chlorophenyl)-1-(4-methylpiperazin-1-yl)-N-(4-((E)-phenyldiazenyl)phenyl)methanimine] retained the antagonistic activity of its non-photochromic lead, and trans-cis isomerization by irradiation induced a fourfold difference in the pharmacological response. Further structural optimization resulted in two bathochromically shifted derivatives of 19 [NO2 -substituted 35 {(Z)-1-(4-chlorophenyl)-1-(4-methylpiperazin-1-yl)-N-(4-((E)-(4-nitrophenyl)diazenyl)phenyl)methanimine} and SO3 - -substituted 41 {4-((E)-(4-(((Z)-(4-chlorophenyl)(4-methylpiperazin-1-yl)methylene)amino)phenyl)diazenyl)benzenesulfonate}], which do not require the use of UV light for photoisomerization and which also have improved solubility and show reduced tissue impairment. The trans isomers of both compounds showed a remarkable increase in antagonistic activity relative to their lead trans-19; furthermore, a 46-fold difference in activity on the isolated guinea pig ileum was observed between trans- and cis-35.

Visual Abstract, Photopharmacology is a unique approach that through a combination of photochemistry methods and advanced life science techniques allows the study and control of specific biological processes, ranging from intracellular pathways to brain circuits. Recently, a first photochromic channel blocker of anion-selective GABAA receptors, the azobenzene-nitrazepam-based photochromic compound (Azo-NZ1), has been described. In the present study, using patch-clamp technique in heterologous system and in mice brain slices, site-directed mutagenesis and molecular modeling we provide evidence of the interaction of Azo-NZ1 with glycine receptors (GlyRs) and determine the molecular basis of this interaction. Glycinergic synaptic neurotransmission determines an important inhibitory drive in the vertebrate nervous system and plays a crucial role in the control of neuronal circuits in the spinal cord and brain stem. GlyRs are involved in locomotion, pain sensation, breathing, and auditory function, as well as in the development of such disorders as hyperekplexia, epilepsy, and autism. Here, we demonstrate that Azo-NZ1 blocks in a UV-dependent manner the activity of α2 GlyRs (GlyR2), while being barely active on α1 GlyRs (GlyR1). The site of Azo-NZ1 action is in the chloride-selective pore of GlyR at the 2’ position of transmembrane helix 2 and amino acids forming this site determine the difference in Azo-NZ1 blocking activity between GlyR2 and GlyR1. This subunit-specific modulation is also shown on motoneurons of brainstem slices from neonatal mice that switch during development from expressing “fetal” GlyR2 to “adult” GlyR1 receptors.

International audience; Glycine receptors (GlyRs) are indispensable for maintaining excitatory/inhibitory balance in neuronal circuits that control reflexes and rhythmic motor behaviors. Here we have developed Glyght, a GlyR ligand controlled with light. It is selective over other Cys-loop receptors, is active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understanding inhibitory circuits in intact animals and to developing drug-based phototherapies.

The desire to photocontrol molecular properties ranging from materials to pharmacology using light as an external trigger with high spatiotemporal resolution led to the development of a broad range of photochromic scaffolds. Among them, azobenzenes are synthetically well accessible and show excellent fatigue resistance. Their photochromic properties vary with the substitution pattern and for different heteroarenes. However, the photochromism of 3(5)-substituted-1H-pryazoles has not yet been investigated, although this compound class offers interesting possibilities of metal ion coordination and hydrogen bond formation via its NH moiety. Herein, we present the results of an experimental and computational investigation of arylazo-3(5)-arylazo-1H-pyrazoles. To elucidate their properties, solvent and substitution effects on their light absorption, thermal half-lives, photostationary states, fatigue, and quantum yields were determined.

The desire to photocontrol molecular properties ranging from materials to pharmacology using light as an external trigger with high spatiotemporal resolution led to the development of a broad range of photochromic scaffolds. Among them, azobenzenes are synthetically well accessible and show excellent fatigue resistance. Their photochromic properties vary with the substitution pattern and for different heteroarenes. However, the photochromism of 3(5)-substituted-1

Optogenetic and photopharmacological tools to manipulate neuronal inhibition have limited efficacy and reversibility. We report the design, synthesis, and biological evaluation of Fulgazepam, a fulgimide derivative of benzodiazepine that behaves as a pure potentiator of ionotropic γ‐aminobutyric acid receptors (GABAARs) and displays full and reversible photoswitching in vitro and in vivo. The compound enables high‐resolution studies of GABAergic neurotransmission, and phototherapies based on localized, acute, and reversible neuroinhibition., Fulgazepam: Herein, the design, synthesis, and biological evaluation of Fulgazepam, a fulgimide derivative of benzodiazepine that behaves as a pure potentiator of ionotropic γ‐aminobutyric acid receptors (GABAARs) and displays full and reversible photoswitching in vitro and in vivo, is reported.

Azobenzenes are of particular interest as a photochromic scaffold for biological applications because of their high fatigue resistance, their large geometrical change between extended (trans) and bent (cis) isomer, and their diverse synthetic accessibility. Despite their wide-spread use, there is no reported photochromic inhibitor of the well-investigated enzyme β-galactosidase, which plays an important role for biochemistry and single molecule studies. Herein, we report the synthesis of photochromic competitive β-galactosidase inhibitors based on the molecular structure of 2-phenylethyl β-d-thiogalactoside (PETG) and 1-amino-1-deoxy-β-d-galactose (β-d-galactosylamine). The thermally highly stable PETG-based azobenzenes show excellent photochromic properties in polar solvents and moderate to high photostationary states (PSS). The optimized compound 37 is a strong competitive inhibitior of β-galactosidase from Escherichia coli and its inhibition constant (Ki) changes between 60 nM and 290 nM upon irradiation with light. Additional docking experiments supported the observed structure-activity relationship.

Glycine receptors (GlyRs) are indispensable to maintain excitatory/inhibitory balance in neuronal circuits controlling reflex and rhythmic motor behaviors. Here we have developed Glyght, the first GlyR ligand controlled with light. It is selective over other cys-loop receptors, active in vivo, and displays an allosteric mechanism of action. The photomanipulation of glycinergic neurotransmission opens new avenues to understand inhibitory circuits in intact animals, and to develop drug-based phototherapies.

The histamine H

Optogenetic and photopharmacological tools to manipulate neuronal inhibition have limited efficacy and reversibility. We report the design, synthesis, and biological evaluation of Fulgazepam, a fulgimide derivative of benzodiazepine that behaves as a pure potentiator of ionotropic γ-aminobutyric acid receptors (GABA A Rs) and displays full and reversible photoswitching in vitro and in vivo. The compound enables high-resolution studies of GABAergic neurotransmission, and phototherapies based on localized, acute, and reversible neuroinhibition.