scholarly journals Positive Allosteric Modulators Differentially Affect Full versus Partial Agonist Activation of the Glycine Receptor

2012 ◽  
Vol 342 (1) ◽  
pp. 61-70 ◽  
Author(s):  
Dean Kirson ◽  
Jelena Todorovic ◽  
S. John Mihic
Keyword(s):  
Partial Agonist ◽  
Glycine Receptor ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulators

Identification of Positive Allosteric Modulators of Glycine Receptors from a High-Throughput Screen Using a Fluorescent Membrane Potential Assay

2016 ◽  
Vol 21 (10) ◽  
pp. 1042-1053 ◽  
Author(s):  
Clara Stead ◽  
Adam Brown ◽  
Cathryn Adams ◽  
Sarah J. Nickolls ◽  
Gareth Young ◽  
...  
Keyword(s):  
Membrane Potential ◽  
High Throughput ◽  
Glycine Receptor ◽  
Functional Characterization ◽  
In Vitro Assays ◽  
Allosteric Modulators ◽  
Inhibitory Neurotransmission ◽  
Starting Point ◽  
Positive Allosteric Modulators

Glycine receptor 3 (GlyRα3) is a ligand-gated ion channel of the cys-loop family that plays a key role in mediating inhibitory neurotransmission and regulation of pain signaling in the dorsal horn. Potentiation of GlyRα3 function is therefore of interest as a putative analgesic mechanism with which to target new therapeutics. However, to date, positive allosteric modulators (PAMs) of this receptor with sufficient selectivity to enable target validation studies have not been described. To address this lack of pharmacological tools, we developed a suite of in vitro assays comprising a high-throughput fluorescent membrane potential screen and a medium-throughput electrophysiology assay using IonFlux HT together with conventional manual patch clamp. Using these assays, we conducted a primary screening campaign and report the structures of hit compounds identified as GlyR PAMs. Our functional characterization data reveal a hit compound with high efficacy relative to current known potentiators and selectivity over GABAAR, another major class of inhibitory neurotransmission receptors of importance to pain. These small-molecule GlyR PAMs have high potential both as early tool compounds to enable pharmacological studies of GlyR inhibitory neurotransmission and as a starting point for the development of potent, selective GlyRα3 PAMs as novel analgesics.

scholarly journals Effects of alpha 7 positive allosteric modulators in murine inflammatory and chronic neuropathic pain models

2013 ◽  
Vol 65 ◽  
pp. 156-164 ◽  
Author(s):  
Kelen Freitas ◽  
Sudeshna Ghosh ◽  
F. Ivy Carroll ◽  
Aron H. Lichtman ◽  
M. Imad Damaj
Keyword(s):  
Neuropathic Pain ◽  
Allosteric Modulators ◽  
Chronic Neuropathic Pain ◽  
Pain Models ◽  
Positive Allosteric Modulators ◽  
Alpha 7

scholarly journals Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

2021 ◽  
Vol 22 (2) ◽  
pp. 973
Author(s):  
Marta Ximenis ◽  
José Mulet ◽  
Salvador Sala ◽  
Francisco Sala ◽  
Manuel Criado ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Allosteric Modulators ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Curcumin Analogues ◽  
Curcumin Derivatives ◽  
Curcumin Analogs ◽  
Naturally Occurring ◽  
Α7 Nachr ◽  
Positive Allosteric Modulators ◽  
Α7 Nachrs

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

scholarly journals Discovery of small molecule positive allosteric modulators of the secretin receptor

2021 ◽  
pp. 114451
Author(s):  
Daniela G. Dengler ◽  
Kaleeckal G. Harikumar ◽  
Sirkku Pollari ◽  
Qing Sun ◽  
Brock T. Brown ◽  
...  
Keyword(s):  
Small Molecule ◽  
Allosteric Modulators ◽  
Secretin Receptor ◽  
Positive Allosteric Modulators
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