scholarly journals High‐throughput screening for novel allosteric modulators of the D1 dopamine receptor (662.4)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Jennie Conroy ◽  
R. Free ◽  
Trevor Doyle ◽  
Noel Southall ◽  
Lisa Hazelwood ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
High Throughput ◽  
High Throughput Screening ◽  
Allosteric Modulators ◽  
D1 Dopamine Receptor

scholarly journals High‐throughput screening for identification of novel allosteric modulators of the D 3 dopamine receptor

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
A Moritz ◽  
R. Free ◽  
W. Weiner ◽  
M. Bachani ◽  
J. Conroy ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
High Throughput ◽  
High Throughput Screening ◽  
Allosteric Modulators

scholarly journals Discovery of Selective Cannabinoid CB2 Receptor Agonists by High-Throughput Screening

2017 ◽  
Vol 23 (4) ◽  
pp. 375-383 ◽  
Author(s):  
Lisa M. Ogawa ◽  
Neil T. Burford ◽  
Yu-Hsien Liao ◽  
Caitlin E. Scott ◽  
Ashley M. Hine ◽  
...  
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Immune Modulation ◽  
Cannabinoid Receptors ◽  
Endocannabinoid System ◽  
Allosteric Modulators ◽  
Peripheral Tissues ◽  
Selective Agonists

The endocannabinoid system (ECS) plays a diverse role in human physiology ranging from the regulation of mood and appetite to immune modulation and the response to pain. Drug development that targets the cannabinoid receptors (CB1 and CB2) has been explored; however, success in the clinic has been limited by the psychoactive side effects associated with modulation of the neuronally expressed CB1 that are enriched in the CNS. CB2, however, are expressed in peripheral tissues, primarily in immune cells, and thus development of CB2-selective drugs holds the potential to modulate pain among other indications without eliciting anxiety and other undesirable side effects associated with CB1 activation. As part of a collaborative effort among industry and academic laboratories, we performed a high-throughput screen designed to discover selective agonists or positive allosteric modulators (PAMs) of CB2. Although no CB2 PAMs were identified, 167 CB2 agonists were discovered here, and further characterization of four select compounds revealed two with high selectivity for CB2 versus CB1. These results broaden drug discovery efforts aimed at the ECS and may lead to the development of novel therapies for immune modulation and pain management with improved side effect profiles.

scholarly journals High-Throughput Screening for Positive Allosteric Modulators Identified Potential Therapeutics against Acetylcholinesterase Inhibition

2015 ◽  
Vol 20 (9) ◽  
pp. 1142-1149 ◽  
Author(s):  
Richard R. Chapleau ◽  
Craig A. McElroy ◽  
Christopher D. Ruark ◽  
Emily J. Fleming ◽  
Amy B. Ghering ◽  
...  
Keyword(s):  
Side Effects ◽  
High Throughput ◽  
High Throughput Screening ◽  
Standard Of Care ◽  
Acetylcholinesterase Inhibition ◽  
Therapeutic Window ◽  
Ache Inhibitor ◽  
Allosteric Modulators ◽  
Current Standard ◽  
Positive Allosteric Modulators

The current standard of care for treatment of organophosphate (OP) poisoning includes pretreatment with the weak reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide. Because this drug is an AChE inhibitor, similar side effects exist as with OP poisoning. In an attempt to provide a therapeutic capable of mitigating AChE inhibition without such side effects, high-throughput screening was performed to identify a compound capable of increasing the catalytic activity of AChE. Herein, two such novel positive allosteric modulators (PAMs) of AChE are presented. These PAMs increase AChE activity threefold, but they fail to upshift the apparent IC50 of a variety of OPs. Further development and optimization of these compounds may lead to pre- and/or postexposure therapeutics with broad-spectrum efficacy against pesticide and nerve agent poisoning. In addition, they could be used to complement the current therapeutic standard of care to increase the activity of uninhibited AChE, potentially increasing the efficacy of current therapeutics in addition to altering the therapeutic window.

scholarly journals Identification of Positive Allosteric Modulators of the D1 Dopamine Receptor That Act at Diverse Binding Sites

2018 ◽  
Vol 94 (4) ◽  
pp. 1197-1209 ◽  
Author(s):  
Kathryn D. Luderman ◽  
Jennie L. Conroy ◽  
R. Benjamin Free ◽  
Noel Southall ◽  
Marc Ferrer ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Binding Sites ◽  
Allosteric Modulators ◽  
D1 Dopamine Receptor ◽  
Positive Allosteric Modulators

scholarly journals An Integrated Approach for Screening and Identification of Positive Allosteric Modulators of N-Methyl-D-Aspartate Receptors

2016 ◽  
Vol 21 (5) ◽  
pp. 468-479 ◽  
Author(s):  
Enrique Jambrina ◽  
Rok Cerne ◽  
Emery Smith ◽  
Louis Scampavia ◽  
Maria Cuadrado ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Therapeutic Interventions ◽  
Calcium Flux ◽  
Electrophysiological Recording ◽  
Small Subset ◽  
Allosteric Modulators ◽  
Chemical Library ◽  
Subtype Selectivity ◽  
Positive Allosteric Modulators

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors that play an important role in synaptic plasticity and learning and memory formation. Malfunctioning of NMDARs, in particular the reduction in NMDAR activity, is thought to be implicated in major neurological disorders. NMDAR positive allosteric modulators (PAMs) represent potential therapeutic interventions for restoring normal NMDAR function. We report a novel screening approach for identification and characterization of NMDAR-PAMs. The approach combines high-throughput fluorescence imaging with automated electrophysiological recording of glutamate-evoked responses in HEK-293 cells expressing NR1/NR2A NMDAR subunits. Initial high-throughput screening (HTS) of a chemical library containing >810,000 compounds using a calcium flux assay in 1536-well plate format identified a total of 864 NMDAR-PAMs. Concentration response determination in both calcium flux and automated electrophysiological assays found several novel chemical series with EC50 values between 0.49 and 10 µM. A small subset (six series) was selected and analyzed for pharmacological properties, subtype selectivity, mode of action, and activity at native NMDARs. Our approach demonstrates the successful application of HTS functional assays that led to identification of NMDAR-PAMs providing the foundation for further medicinal chemistry work that may lead to novel therapies for treatment of cognitive impairment associated with Alzheimer’s disease and schizophrenia.

High-Throughput Screening for Modulators of the D2 Dopamine Receptor Yields Unique and Selective Pharmacological Chemotypes

2014 ◽  
pp. 115
Author(s):  
R. Benjamin Free ◽  
Jennie L. Conroy ◽  
Rebecca A. Roof ◽  
Trevor Doyle ◽  
Yang Han ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
High Throughput ◽  
High Throughput Screening ◽  
D2 Dopamine Receptor

ChemInform Abstract: Synthesis and SAR of Novel, 4-(Phenylsulfamoyl)phenylacetamide mGlu4 Positive Allosteric Modulators (PAMs) Identified by Functional High-Throughput Screening (HTS).

ChemInform ◽  
2010 ◽  
Vol 42 (1) ◽  
pp. no-no
Author(s):  
Darren W. Engers ◽  
Patrick R. Gentry ◽  
Richard Williams ◽  
Julie D. Bolinger ◽  
C. David Weaver ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Allosteric Modulators ◽  
Positive Allosteric Modulators
Sign in / Sign up

Export Citation Format

Share Document