Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study

Winterer, Georg; Gallinat, Juergen; Brinkmeyer, Jürgen; Musso, Francesco; Kornhuber, Johannes; Thuerauf, Norbert; Rujescu, Dan; Favis, Reyna; Sun, Yu; Franc, Monique A.; Ouwerkerk‐Mahadevan, Sivi; Janssens, Luc; Timmers, Maarten; Streffer, Johannes

doi:10.1016/j.neuropharm.2012.06.040

Cited by 60 publications

(55 citation statements)

References 80 publications

(84 reference statements)

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“…Only two reports have examined the effects of α7 nAChR medications on MMN, both being conducted in SZ patients. While JNJ-39393406, an α7 PAM, failed to alter MMN (Winterer et al 2013), the α7 partial agonist EVP-6124 increased the frequency deviant MMN in a dosedependent manner (Preskorn et al 2014).…”

Section: Introductionmentioning

confidence: 93%

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

Knott

Impey

Choueiry

et al. 2015

Neuropsychiatr Electrophysiol

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Background: Alpha 7 nicotinic acetylcholine receptors (α7 nAChR) are prioritized molecular targets for the development of new pharmacological treatments for impaired cognition in schizophrenia. The use of schizophrenia-associated biomarkers both as endpoints and for segmentation of homogeneous populations for early detection of cognitive enhancing agents has been advanced to enhance the drug discovery process. Methods: In this study, the mismatch negativity (MMN) event-related brain potential (ERP), considered one of the few fully developed biomarkers in schizophrenia, was employed: a) to stratify 24 healthy volunteers into subgroups exhibiting low, medium, or high auditory sensory discrimination based on pre-attentive detection of deviant auditory features, and b) to assess their acute response to a low (500 mg) and moderate dose (1000 mg) of CDP-choline, a dietary supplement with selective agonist actions at α7 nAChRs.

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Section: Introductionmentioning

confidence: 93%

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

Knott

Impey

Choueiry

et al. 2015

Neuropsychiatr Electrophysiol

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“…24 Examples of both positive and negative allosteric modulators are currently in clinical trials. 25,26 One advantage of using allostery as a mode of action lies in the ability of the therapeutic to not interfere competitively with the native enzyme function, in contrast with the current modes of action for treatments that serve as reversible AChE inhibitors (for pretreatment) or active-site oxime reactivators. In addition, using a PAM as a chemical countermeasure against OP intoxication could potentially reduce the onset of poisoning symptoms, increase the chances of patient survival, and assist in the efficacy of oxime and nonoxime AChE reactivators.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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 IC 50 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.

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“…PAMs of a 7 that have entered clinical trials for the treatment of schizophrenia, JNJ-39393406 and galantamine, are described in Table 1. JNJ-39393406 behaves as a PAM of the a 7 receptor, with no action at 5-HT 3 channels [66]. Repetitive application of the natural ligand (ACh or choline) in the presence of JNJ-39393406 does not lead to a loss of receptor activation.…”

Section: Positive Allosteric Modulators Of the A 7 Receptormentioning

confidence: 99%

“…Repetitive application of the natural ligand (ACh or choline) in the presence of JNJ-39393406 does not lead to a loss of receptor activation. JNJ-39393406 lowers the agonist and nicotine threshold for activation of a 7 nAChRs 10-to 20-fold and increases the maximum agonist response 17-to 20-fold [66]. JNJ-39393406 was first evaluated in two phase I trials investigating the safety, tolerability and pharmacokinetics of solid formulations [108,109].…”

Section: Positive Allosteric Modulators Of the A 7 Receptormentioning

confidence: 99%

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

et al. 2015

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Homomeric α7 nicotinic acetylcholine receptors (α7 nAChRs) have implications in the regulation of cognitive processes such as memory and attention, and have shown promise as a therapeutic target for the treatment of the cognitive deficits associated with schizophrenia. Multiple α7 nAChR agonists have entered human trials; however, unfavorable side effects and pharmacokinetic issues have hindered the development of a clinical α7 nAChR agonist. Currently, EVP-6124 is in phase III clinical trials, and several other α7 nAChR agonists (GTS-21 and AQW051) are in earlier stages of development. This review will summarize the recent advances and failures of α7 nAChR agonists in clinical trials for the treatment of the aforementioned pathology.

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Allosteric alpha-7 nicotinic receptor modulation and P50 sensory gating in schizophrenia: A proof-of-mechanism study

Cited by 60 publications

References 80 publications

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

An acute dose, randomized trial of the effects of CDP-Choline on Mismatch Negativity (MMN) in healthy volunteers stratified by deviance detection level

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

The Therapeutic Potential of α7 Nicotinic Acetylcholine Receptor (α7 nAChR) Agonists for the Treatment of the Cognitive Deficits Associated with Schizophrenia

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