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https://www.readbyqxmd.com/read/26994846/synthesis-and-biological-activities-of-indolizine-derivatives-as-alpha-7-nachr-agonists
#1
Yu Xue, Jingshu Tang, Xiaozhuo Ma, Qing Li, Bingxue Xie, Yuchen Hao, Hongwei Jin, Kewei Wang, Guisen Zhang, Liangren Zhang, Lihe Zhang
Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure-activity relationship studies provide insights to develop more potent novel α7 nAChR agonists...
June 10, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/26983414/a-mouse-model-of-the-15q13-3-microdeletion-syndrome-shows-prefrontal-neurophysiological-dysfunctions-and-attentional-impairment
#2
Simon R O Nilsson, Pau Celada, Kim Fejgin, Jonas Thelin, Jacob Nielsen, Noemí Santana, Christopher J Heath, Peter H Larsen, Vibeke Nielsen, Brianne A Kent, Lisa M Saksida, Tine B Stensbøl, Trevor W Robbins, Jesper F Bastlund, Timothy J Bussey, Francesc Artigas, Michael Didriksen
RATIONALE: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. OBJECTIVES: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays...
June 2016: Psychopharmacology
https://www.readbyqxmd.com/read/26242477/the-therapeutic-potential-of-%C3%AE-7-nicotinic-acetylcholine-receptor-%C3%AE-7-nachr-agonists-for-the-treatment-of-the-cognitive-deficits-associated-with-schizophrenia
#3
REVIEW
Corinne Beinat, Samuel D Banister, Marco Herrera, Vivian Law, Michael Kassiou
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...
July 2015: CNS Drugs
https://www.readbyqxmd.com/read/26044974/targeting-of-%C3%AE-7-nicotinic-acetylcholine-receptors-in-the-treatment-of-schizophrenia-and-the-use-of-auditory-sensory-gating-as-a-translational-biomarker
#4
REVIEW
Kenji Hashimoto
Accumulating evidence suggests that the α7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer's disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of α7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker...
2015: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/25880723/development-of-automated-patch-clamp-assay-for-evaluation-of-%C3%AE-7-nicotinic-acetylcholine-receptor-agonists-in-automated-qpatch-16
#5
Yuchen Hao, Jingshu Tang, KeWei Wang
The α7 nicotinic acetylcholine receptor (α7 nAChR) is an important and challenging target for drug discovery in the area of neuropsychiatric disorders. The current screening for chemicals targeting α7 nAChRs is primarily achieved by the use of low-throughput assay two-electrode voltage clamp (TEVC) in nonmammalian Xenopus oocytes. Automated patch clamp system has emerged as an attractive approach compared to conventional electrophysiology. To develop a mammalian cell-based functional assay in an automated electrophysiology system, we in this study generated a stable expression of α7 nAChRs in GH3 cells that originated from a rat pituitary tumor cell line and utilized automated QPatch-16 to test a set of tool compounds and chemicals identified as α7 agonists by TEVC...
April 2015: Assay and Drug Development Technologies
https://www.readbyqxmd.com/read/25794332/continuous-infusion-of-the-%C3%AE-7-nicotinic-acetylcholine-receptor-agonist-evp-6124-produces-no-signs-of-tolerance-at-memory-enhancing-doses-in-rats-a-pharmacokinetic-and-behavioral-study
#6
Nick P van Goethem, Jos Prickaerts, Devin Welty, Dorothy G Flood, Gerhard Koenig
We investigated whether the effects of acutely administered EVP-6124, an α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, on cognition were maintained after 6-day continuous minipump administration. Performance in a delay-dependent forgetting test was measured in the object recognition task after single-oral doses of 0.3 or 1 mg/kg, or at plasma steady-state concentrations (Css) of 0.6 or 2 ng/ml, which were similar to the efficacious plasma concentrations after single-oral dosing. The 0.3 mg/kg acute dose enhanced memory at a total plasma concentration of ∼0...
June 2015: Behavioural Pharmacology
https://www.readbyqxmd.com/read/25586394/scopolamine-provocation-based-pharmacological-mri-model-for-testing-procognitive-agents
#7
COMPARATIVE STUDY
Nikolett Hegedűs, Judit Laszy, István Gyertyán, Pál Kocsis, Dávid Gajári, Szabolcs Dávid, Levente Deli, Zsófia Pozsgay, Károly Tihanyi
There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species...
April 2015: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/25495510/safety-and-clinical-effects-of-evp-6124-in-subjects-with-alzheimer-s-disease-currently-or-previously-receiving-an-acetylcholinesterase-inhibitor-medication
#8
REVIEW
William James Deardorff, Ahmad Shobassy, George T Grossberg
Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats...
January 2015: Expert Review of Neurotherapeutics
https://www.readbyqxmd.com/read/25438724/pharmacodynamics-pharmacokinetics-safety-and-tolerability-of-encenicline-a-selective-%C3%AE-7-nicotinic-receptor-partial-agonist-in-single-ascending-dose-and-bioavailability-studies
#9
RANDOMIZED CONTROLLED TRIAL
Ann J Barbier, Martijn Hilhorst, André Van Vliet, Peter Snyder, Michael G Palfreyman, Maria Gawryl, Nancy Dgetluck, Monica Massaro, Renger Tiessen, Wia Timmerman, Dana C Hilt
PURPOSE: Encenicline (EVP-6124) is a selective α7 nicotinic acetylcholine receptor partial agonist being developed for cognitive impairment in Alzheimer's disease and schizophrenia. We report on 2 single-dose studies to assess the relative bioavailability, pharmacokinetic profile, tolerability, and cognitive effects of encenicline in healthy volunteers. METHODS: A single ascending-dose study assessed the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of encenicline in healthy male volunteers...
February 1, 2015: Clinical Therapeutics
https://www.readbyqxmd.com/read/25145965/human-brain-imaging-of-%C3%AE-7-nachr-with-18-f-asem-a-new-pet-radiotracer-for-neuropsychiatry-and-determination-of-drug-occupancy
#10
Dean F Wong, Hiroto Kuwabara, Martin Pomper, Daniel P Holt, James R Brasic, Noble George, Boris Frolov, William Willis, Yongjun Gao, Heather Valentine, Ayon Nandi, Lorena Gapasin, Robert F Dannals, Andrew G Horti
PURPOSE: Using the α7-nAChR radiotracer, [(18)F]ASEM, we present the first successful human positron emission tomography (PET) studies. Rodent occupancy with three clinically employed α7-nAChR drugs confirms the specificity of the radiotracer. PROCEDURES: Five healthy male subjects were imaged for 90 min following IV [(18)F]ASEM. Two subjects were scanned for the second time (test/retest; TRV). Mouse biodistribution of [(18)F]ASEM was carried out in CD1 mice injected with using human equivalent doses of DMXB-A, EVP-6124, and varenicline to block specific binding...
October 2014: Molecular Imaging and Biology: MIB: the Official Publication of the Academy of Molecular Imaging
https://www.readbyqxmd.com/read/25064467/pcp-induced-deficits-in-murine-nest-building-activity-employment-of-an-ethological-rodent-behavior-to-mimic-negative-like-symptoms-of-schizophrenia
#11
Christian Spang Pedersen, Dorte Bratbo Sørensen, Anna I Parachikova, Niels Plath
Schizophrenia is a severe psychiatric disorder characterized by three symptom domains, positive (hallucinations, obsession), negative (social withdrawal, apathy, self-neglect) and cognitive (impairment in attention, memory and executive function). Whereas current medication ameliorates positive symptomatology, negative symptoms as well as cognitive dysfunctions remain untreated. The development of improved therapies for negative symptoms has proven particularly difficult, in part due to the inability of mimicking these in rodents...
October 15, 2014: Behavioural Brain Research
https://www.readbyqxmd.com/read/24810107/the-novel-%C3%AE-7-nicotinic-acetylcholine-receptor-agonist-evp-6124-enhances-dopamine-acetylcholine-and-glutamate-efflux-in-rat-cortex-and-nucleus-accumbens
#12
Mei Huang, Anna R Felix, Dorothy G Flood, Chaya Bhuvaneswaran, Dana Hilt, Gerhard Koenig, Herbert Y Meltzer
BACKGROUND: Alpha7 and α4β2 nicotinic acetylcholine receptor (nAChR) agonists have been shown to improve cognition in various animal models of cognitive impairment and are of interest as treatments for schizophrenia, Alzheimer's disease, and other cognitive disorders. Increased release of dopamine (DA), acetylcholine (ACh), glutamate (Glu), and γ-aminobutyric acid (GABA) in cerebral cortex, hippocampus, and nucleus accumbens (NAC) has been suggested to contribute to their beneficial effects on cognition...
December 2014: Psychopharmacology
https://www.readbyqxmd.com/read/24419310/the-role-of-proof-of-concept-poc-studies-in-drug-development-using-the-evp-6124-poc-study-as-an-example
#13
Sheldon H Preskorn
The goal of early proof of concept studies, typically involving a small number of subjects and more latitude in statistical requirements, is to provide evidence that a drug is likely to be successful in later stages of drug development. Although often not published, such studies allow drug developers to make "Go/No Go" decisions about proceeding with larger, more expensive studies.
January 2014: Journal of Psychiatric Practice
https://www.readbyqxmd.com/read/24419307/normalizing-effects-of-evp-6124-an-%C3%AE-7-nicotinic-partial-agonist-on-event-related-potentials-and-cognition-a-proof-of-concept-randomized-trial-in-patients-with-schizophrenia
#14
RANDOMIZED CONTROLLED TRIAL
Sheldon H Preskorn, Maria Gawryl, Nancy Dgetluck, Michael Palfreyman, Lance O Bauer, Dana C Hilt
UNLABELLED: Cognitive impairment is a cause of significant disability in patients with schizophrenia. To date, no drug has been approved for this indication by the U.S. Food and Drug Administration. This article presents findings suggesting that a medication targeting the alpha-7 nicotinic acetylcholine receptor (α7 nAChR) might meet this need. This single-center, randomized, parallel-group, double-blind,placebo-controlled study examined 21 medically stable patients with schizophrenia or schizoaffective disorder treated with second generation antipsychotics...
January 2014: Journal of Psychiatric Practice
https://www.readbyqxmd.com/read/24062193/a-review-of-the-pharmacology-efficacy-and-tolerability-of-recently-approved-and-upcoming-oral-antipsychotics-an-evidence-based-medicine-approach
#15
REVIEW
Leslie Citrome
Evidence-based medicine (EBM) is a broad concept, but the key elements include the incorporation of clinical judgment (which requires clinical experience) together with relevant scientific evidence while remaining mindful of the individual patient's values and preferences. Using the framework and philosophy of EBM, this systematic review summarizes the pharmacology, efficacy, and tolerability of newly approved oral antipsychotics, including iloperidone, asenapine, and lurasidone, and outlines what is known about agents that are in late-stage clinical development, such as cariprazine, brexpiprazole, zicronapine, bitopertin, and EVP-6124...
November 2013: CNS Drugs
https://www.readbyqxmd.com/read/22085888/evp-6124-a-novel-and-selective-%C3%AE-7-nicotinic-acetylcholine-receptor-partial-agonist-improves-memory-performance-by-potentiating-the-acetylcholine-response-of-%C3%AE-7-nicotinic-acetylcholine-receptors
#16
Jos Prickaerts, Nick P van Goethem, Richard Chesworth, Gideon Shapiro, Frank G Boess, Christoph Methfessel, Olga A H Reneerkens, Dorothy G Flood, Dana Hilt, Maria Gawryl, Sonia Bertrand, Daniel Bertrand, Gerhard König
EVP-6124, (R)-7-chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide, is a novel partial agonist of α7 neuronal nicotinic acetylcholine receptors (nAChRs) that was evaluated here in vitro and in vivo. In binding and functional experiments, EVP-6124 showed selectivity for α7 nAChRs and did not activate or inhibit heteromeric α4β2 nAChRs. EVP-6124 had good brain penetration and an adequate exposure time. EVP-6124 (0.3 mg/kg, p.o.) significantly restored memory function in scopolamine-treated rats (0...
February 2012: Neuropharmacology
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