Design, Synthesis, and Pharmacological Profiling of Cannabinoid 1 Receptor Allosteric Modulators: Preclinical Efficacy of C2-Group GAT211 Congeners for Reducing Intraocular Pressure

2021 ◽  
pp. 116421
Author(s):  
Sumanta Garai ◽  
Peter C. Schaffer ◽  
Robert B. Laprairie ◽  
David R. Janero ◽  
Roger G. Pertwee ◽  
...  
Keyword(s):  
Intraocular Pressure ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Cannabinoid 1 Receptor ◽  
Preclinical Efficacy

scholarly journals Design, Synthesis, and Preclinical Efficacy of Novel Nonretinoid Antagonists of Retinol-Binding Protein 4 in the Mouse Model of Hepatic Steatosis

2019 ◽  
Vol 62 (11) ◽  
pp. 5470-5500 ◽  
Author(s):  
Christopher L. Cioffi ◽  
Boglarka Racz ◽  
Andras Varadi ◽  
Emily E. Freeman ◽  
Michael P. Conlon ◽  
...  
Keyword(s):  
Mouse Model ◽  
Hepatic Steatosis ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Design Synthesis ◽  
Retinol Binding Protein 4 ◽  
Preclinical Efficacy

scholarly journals Design, Synthesis and Characterization of a New Series of Fluorescent Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulators

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1532
Author(s):  
Víctor Fernández-Dueñas ◽  
Mingcheng Qian ◽  
Josep Argerich ◽  
Carolina Amaral ◽  
Martijn D.P. Risseeuw ◽  
...  
Keyword(s):  
Binding Sites ◽  
Metabotropic Glutamate Receptor ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Metabotropic Glutamate ◽  
Animal Disease Models ◽  
Fluorescent Ligands ◽  
The Brain

In recent years, new drug discovery approaches based on novel pharmacological concepts have emerged. Allosteric modulators, for example, target receptors at sites other than the orthosteric binding sites and can modulate agonist-mediated activation. Interestingly, allosteric regulation may allow a fine-tuned regulation of unbalanced neurotransmitter’ systems, thus providing safe and effective treatments for a number of central nervous system diseases. The metabotropic glutamate type 5 receptor (mGlu5R) has been shown to possess a druggable allosteric binding domain. Accordingly, novel allosteric ligands are being explored in order to finely regulate glutamate neurotransmission, especially in the brain. However, before testing the activity of these new ligands in the clinic or even in animal disease models, it is common to characterize their ability to bind mGlu5Rs in vitro. Here, we have developed a new series of fluorescent ligands that, when used in a new NanoBRET-based binding assay, will facilitate screening for novel mGlu5R allosteric modulators.

Fulgazepam: A Fulgimide-Based Potentiator of GABAA Receptors

2019 ◽  
Author(s):  
Karin Rustler ◽  
Galyna Maleeva ◽  
Alexandre M. J. Gomila ◽  
Pau Gorostiza ◽  
Piotr Bregestovski ◽  
...  
Keyword(s):  
Protein Function ◽  
Biological Evaluation ◽  
Term Treatment ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Non Invasive ◽  
Long Term Treatment ◽  
Benzodiazepine Derivatives ◽  
Synthesis And Biological Evaluation

The <i>γ</i>-aminobutyric acid gated chloride channel represents the major mediator of inhibitory neurotransmission in the mammalian central nervous system and its dysfunction is related to severe diseases like epilepsy and depression, which can be relieved by the application of allosteric modulators. However, the drugs’ potential side-effects limit their application for long-term treatment. Applying light as external stimulus to modify the pharmacophore’s activity, as emerged in the field of photopharmacology, provides a non-invasive tool with high spatial and temporal resolution for the modulation of protein function. Herein, we report the design, synthesis, and biological evaluation of photochromic fulgimide-based benzodiazepine derivatives as light-controllable potentiators of GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs). A photocontrolled potentiator of GABA<sub>A</sub>Rs (Fulgazepam) has been identified that does not display agonist or antagonist activity and allows manipulating zebrafish larvae swimming.

Design, Synthesis, and Pharmacology of Novel 7-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of AMPA Receptors†

2007 ◽  
Vol 50 (13) ◽  
pp. 3153-3157 ◽  
Author(s):  
Pierre Francotte ◽  
Pascal de Tullio ◽  
Eric Goffin ◽  
Gaëlle Dintilhac ◽  
Emmanuel Graindorge ◽  
...  
Keyword(s):  
Ampa Receptors ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Positive Allosteric Modulators

scholarly journals Fulgazepam: A Fulgimide-Based Potentiator of GABAA Receptors

2019 ◽  
Author(s):  
Karin Rustler ◽  
Galyna Maleeva ◽  
Alexandre M. J. Gomila ◽  
Pau Gorostiza ◽  
Piotr Bregestovski ◽  
...  
Keyword(s):  
Protein Function ◽  
Biological Evaluation ◽  
Term Treatment ◽  
Allosteric Modulators ◽  
Design Synthesis ◽  
Non Invasive ◽  
Long Term Treatment ◽  
Benzodiazepine Derivatives ◽  
Synthesis And Biological Evaluation

The <i>γ</i>-aminobutyric acid gated chloride channel represents the major mediator of inhibitory neurotransmission in the mammalian central nervous system and its dysfunction is related to severe diseases like epilepsy and depression, which can be relieved by the application of allosteric modulators. However, the drugs’ potential side-effects limit their application for long-term treatment. Applying light as external stimulus to modify the pharmacophore’s activity, as emerged in the field of photopharmacology, provides a non-invasive tool with high spatial and temporal resolution for the modulation of protein function. Herein, we report the design, synthesis, and biological evaluation of photochromic fulgimide-based benzodiazepine derivatives as light-controllable potentiators of GABA<sub>A</sub> receptors (GABA<sub>A</sub>Rs). A photocontrolled potentiator of GABA<sub>A</sub>Rs (Fulgazepam) has been identified that does not display agonist or antagonist activity and allows manipulating zebrafish larvae swimming.

Sign in / Sign up

Export Citation Format

Share Document