scholarly journals Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joerg F. Hipp ◽  
Frederic Knoflach ◽  
Robert Comley ◽  
Theresa M. Ballard ◽  
Michael Honer ◽  
...  
Keyword(s):  
Receptor Occupancy ◽  
Allosteric Modulator ◽  
Receptor Subtypes ◽  
Target Engagement ◽  
Phase Ii Trials ◽  
Open Label ◽  
Preclinical Pharmacology ◽  
Clinical Benefits ◽  
Negative Allosteric Modulator

AbstractGABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.

scholarly journals The Opportunities and Use of Imaging to Measure Target Engagement

2019 ◽  
Vol 25 (2) ◽  
pp. 127-136
Author(s):  
Juliana Maynard ◽  
Philippa Hart
Keyword(s):  
Ex Vivo ◽  
Clinical Success ◽  
Receptor Occupancy ◽  
Accurate Information ◽  
Target Engagement ◽  
Drug Molecule ◽  
Drug Discovery And Development ◽  
Ex Vivo Imaging

Lack of efficacy and poor safety outcomes are deemed to be the greatest causes of clinical failure of novel therapeutics. The use of biomarkers that give accurate information on target engagement, providing confidence that pharmacological activity in the target organ is being achieved, is key in optimizing clinical success. Without a measurement of target engagement, it can be very difficult to discern the basis for any lack of efficacy of a drug molecule within the pharmaceutical industry. Target engagement can be measured in both an in vitro and in vivo setting, and in recent years imaging measurements have been used frequently in drug discovery and development to assess target engagement and receptor occupancy in both human and animal models. From this perspective, we assess and look at the advancements in both in vivo and ex vivo imaging to demonstrate the enormous potential that imaging has as an application to provide a greater understanding of target engagement with a correlative therapeutic impact.

scholarly journals Protease-activated receptor-2 ligands reveal orthosteric and allosteric mechanisms of receptor inhibition

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Amanda J. Kennedy ◽  
Linda Sundström ◽  
Stefan Geschwindner ◽  
Eunice K. Y. Poon ◽  
Yuhong Jiang ◽  
...  
Keyword(s):  
Competitive Inhibitor ◽  
Activation Mechanism ◽  
Allosteric Modulator ◽  
Remote Site ◽  
Receptor Inhibition ◽  
Protease Activation ◽  
Negative Allosteric Modulator ◽  
Allosteric Mechanisms ◽  
Protease Activated Receptor 2

AbstractProtease-activated receptor-2 (PAR2) has been implicated in multiple pathophysiologies but drug discovery is challenging due to low small molecule tractability and a complex activation mechanism. Here we report the pharmacological profiling of a potent new agonist, suggested by molecular modelling to bind in the putative orthosteric site, and two novel PAR2 antagonists with distinctly different mechanisms of inhibition. We identify coupling between different PAR2 binding sites. One antagonist is a competitive inhibitor that binds to the orthosteric site, while a second antagonist is a negative allosteric modulator that binds at a remote site. The allosteric modulator shows probe dependence, more effectively inhibiting peptide than protease activation of PAR2 signalling. Importantly, both antagonists are active in vivo, inhibiting PAR2 agonist-induced acute paw inflammation in rats and preventing activation of mast cells and neutrophils. These results highlight two distinct mechanisms of inhibition that potentially could be targeted for future development of drugs that modulate PAR2.

scholarly journals GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET

NeuroImage ◽  
2017 ◽  
Vol 150 ◽  
pp. 279-291 ◽  
Author(s):  
Adrienne Müller Herde ◽  
Dietmar Benke ◽  
William T. Ralvenius ◽  
Linjing Mu ◽  
Roger Schibli ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Mouse Brain ◽  
Receptor Occupancy ◽  
Receptor Subtypes ◽  
Regional Mapping ◽  
Gabaa Receptor Subtypes

scholarly journals Author response: Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

2017 ◽  
Author(s):  
Joan Font ◽  
Marc López-Cano ◽  
Serena Notartomaso ◽  
Pamela Scarselli ◽  
Paola Di Pietro ◽  
...  
Keyword(s):  
Optical Control ◽  
Author Response ◽  
Allosteric Modulator ◽  
Mglu5 Receptor ◽  
Negative Allosteric Modulator

scholarly journals In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal nAChRs

2010 ◽  
Vol 59 (6) ◽  
pp. 511-517 ◽  
Author(s):  
Galya R. Abdrakhmanova ◽  
Bruce E. Blough ◽  
Carey Nesloney ◽  
Hernán A. Navarro ◽  
M. Imad Damaj ◽  
...  
Keyword(s):  
Allosteric Modulator ◽  
Negative Allosteric Modulator ◽  
In Vivo Characterization

scholarly journals Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Joan Font ◽  
Marc López-Cano ◽  
Serena Notartomaso ◽  
Pamela Scarselli ◽  
Paola Di Pietro ◽  
...  
Keyword(s):  
Light Emitting Diode ◽  
Optical Control ◽  
Allosteric Modulator ◽  
Light Illumination ◽  
Spatiotemporal Resolution ◽  
Peripheral Tissues ◽  
Metabotropic Glutamate ◽  
Mglu5 Receptor ◽  
Negative Allosteric Modulator

Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug’s release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders.

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