scholarly journals Pronounced antiepileptic activity of the subtype-selective GABAA -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model

2018 ◽  
Vol 25 (2) ◽  
pp. 255-260 ◽  
Author(s):  
Venceslas Duveau ◽  
Derek L. Buhl ◽  
Alexis Evrard ◽  
Céline Ruggiero ◽  
Betty Mandé-Niedergang ◽  
...  
Keyword(s):  
Absence Epilepsy ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Antiepileptic Activity ◽  
Subtype Selective

scholarly journals Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAAReceptor Positive Allosteric Modulator

2017 ◽  
Vol 8 (6) ◽  
pp. 1305-1312 ◽  
Author(s):  
Lakeisha A. Lewter ◽  
Janet L. Fisher ◽  
Justin N. Siemian ◽  
Kashi Reddy Methuku ◽  
Michael M. Poe ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Antinociceptive Effects ◽  
Subtype Selective

scholarly journals Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats

2019 ◽  
Vol 30 (5) ◽  
pp. 452-461 ◽  
Author(s):  
Megan J. Moerke ◽  
Guanguan Li ◽  
Lalit K. Golani ◽  
James Cook ◽  
S. Stevens Negus
Keyword(s):  
Gabaa Receptor ◽  
Allosteric Modulator ◽  
Positive Allosteric Modulator ◽  
Subtype Selective

scholarly journals A Comparison of the 2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Sarah Nickolls ◽  
Hannah Mace ◽  
Rebecca Fish ◽  
Michelle Edye ◽  
Rachel Gurrell ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Side Effect ◽  
Allosteric Modulator ◽  
Allosteric Modulators ◽  
Side Effect Profile ◽  
Preclinical Models ◽  
Positive Allosteric Modulator ◽  
Pain Medications ◽  
Pain Models ◽  
Subtype Selective

receptors containingα2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specificαsubunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy atα2/3 or efficacy atα5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

scholarly journals A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers

2021 ◽  
Vol 118 (33) ◽  
pp. e2105848118
Author(s):  
Jordi Haubrich ◽  
Joan Font ◽  
Robert B. Quast ◽  
Anne Goupil-Lamy ◽  
Pauline Scholler ◽  
...  
Keyword(s):  
Small Molecules ◽  
Metabotropic Glutamate Receptor ◽  
Brain Diseases ◽  
Allosteric Modulator ◽  
Receptor Subtypes ◽  
Positive Allosteric Modulator ◽  
Metabotropic Glutamate ◽  
Glutamate Binding ◽  
Subtype Selective ◽  
G Protein Coupled

There is growing interest in developing biologics due to their high target selectivity. The G protein–coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.

Photosensitive epilepsy

Neurology ◽  
2019 ◽  
Vol 92 (15) ◽  
pp. e1786-e1795 ◽  
Author(s):  
Rachel Gurrell ◽  
Donal Gorman ◽  
Mark Whitlock ◽  
Adam Ogden ◽  
David S. Reynolds ◽  
...  
Keyword(s):  
Anticonvulsant Activity ◽  
Photic Stimulation ◽  
Allosteric Modulator ◽  
Complete Suppression ◽  
Positive Allosteric Modulator ◽  
Double Blind ◽  
Intermittent Photic Stimulation ◽  
Photosensitive Epilepsy ◽  
Subtype Selective

ObjectiveThe objective of this phase 2a study was to assess the activity of PF-06372865, a positive allosteric modulator (PAM) of α2/3/5 subunit-containing GABAA receptors with minimal activity at α1-containing receptors, which are believed to mediate many of the adverse events associated with benzodiazepines, in the epilepsy photosensitivity model as a proof-of-principle of efficacy.MethodsSeven participants with a photoparoxysmal response to intermittent photic stimulation (IPS) at baseline were randomized in a double-blind, 4-period cross-over study examining single doses of 17.5 and 52.5 mg PF-06372865, 2 mg lorazepam (active control), and placebo. Standardized photosensitivity ranges (SPRs) to IPS were recorded at screening, predose, and 1, 2, 4, and 6 hours postdose. The primary endpoint was the average least squares mean change in the SPR in the participant's most sensitive eye condition, across all time points.ResultsBoth doses of PF-06372865 produced a marked and statistically significant mean reduction in SPR compared to placebo, which was similar in degree to lorazepam. There was complete suppression of SPR in 6/7 participants following PF-06372865 or lorazepam administration. PF-06372865 was safe and well-tolerated.ConclusionPF-06372865 demonstrated highly robust efficacy. This demonstrates anticonvulsant activity of a novel α2/3/5-subtype selective GABAA PAM in humans. Further study of the antiepileptic properties of PF-06372865 is warranted.Clinicaltrials.gov identifierNCT02564029.Classification of evidenceThis study provides Class II evidence that for people with a stable photoparoxysmal response to intermittent photic stimulation, PF-06372865 reduces the SPR.

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