Callahan P.M.,Augusta University |
Bertrand D.,HiQScreen Sarl |
Bertrand S.,HiQScreen Sarl |
Plagenhoef M.R.,Augusta University |
Terry A.V.,Augusta University
Neuropharmacology | Year: 2017
Tropisetron, a 5-HT3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at α7 nicotinic acetylcholine receptors (α7 nAChRs). α7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric α7 nAChR and recently characterized heteromeric α7β2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at α7 nAChRs (EC50 ∼2.4 μM) with a similar effect at α7β2 nAChRs (EC50 ∼1.5 μM). Moreover, currents evoked by irregular pulses of acetylcholine (40 μM) at α7 and α7β2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a “priming” or co-agonist effect. Tropisetron (0.1–10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03–1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize α7 containing nAChRs to low levels of acetylcholine. © 2017 Elsevier Ltd
Prickaerts J.,Maastricht University |
Van Goethem N.P.,Maastricht University |
Chesworth R.,EnVivo Pharmaceuticals Inc. |
Chesworth R.,Epizyme |
And 10 more authors.
Neuropharmacology | Year: 2012
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 (0.1 mg/kg, i.p.) in an object recognition task (ORT). Although donepezil at 0.1 mg/kg, p.o. or EVP-6124 at 0.03 mg/kg, p.o. did not improve memory in this task, co-administration of these sub-efficacious doses fully restored memory. In a natural forgetting test, an ORT with a 24 h retention time, EVP-6124 improved memory at 0.3 mg/kg, p.o. This improvement was blocked by the selective α7 nAChR antagonist methyllycaconitine (0.3 mg/kg, i.p. or 10 μg, i.c.v.). In co-application experiments of EVP-6124 with acetylcholine, sustained exposure to EVP-6124 in functional investigations in oocytes caused desensitization at concentrations greater than 3 nM, while lower concentrations (0.3-1 nM) caused an increase in the acetylcholine-evoked response. These actions were interpreted as representing a co-agonist activity of EVP-6124 with acetylcholine on α7 nAChRs. The concentrations of EVP-6124 that resulted in physiological potentiation were consistent with the free drug concentrations in brain that improved memory performance in the ORT. These data suggest that the selective partial agonist EVP-6124 improves memory performance by potentiating the acetylcholine response of α7 nAChRs and support new therapeutic strategies for the treatment of cognitive impairment. © 2011 Elsevier Ltd. All rights reserved.
Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.1-5 | Award Amount: 14.64M | Year: 2008
Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimers and Parkinsons, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.
Agency: European Commission | Branch: FP7 | Program: CSA | Phase: ICT-2011.9.5 | Award Amount: 1.71M | Year: 2011
Guardian Angels (GA) are future zero-power, intelligent, autonomous systems-of-systems featuring sensing, computation, and communication beyond human aptitudes. GA will assist humans from their infancy to old age in complex life situations and environments. Zero-power reflects system-of-systems ability to scavenge energy in dynamic environments by disruptive harvesting techniques. The project prepares zero-power technologies based on future energy-efficient technologies, heterogeneous design, and disruptive energy scavengers.\nThree zero-power generations of GAs are foreseen: Physical Guardian Angels are zero-power, on-body networks or implantable devices that monitor vital health signals and take appropriate actions to preserve human health. Environmental Guardian Angels extend monitoring to dynamic environments, using disruptive scavengers, personalized data communication, and first thinking algorithms. They are personal assistants that protect their wearers from environment dangers. Emotional Guardian Angels are intelligent personal companions with disruptive zero-power, manmachine interfaces deployed at large scale. They sense and communicate using non-verbal languages playing an important role in health, education, and security worldwide. This project addresses the following scientific challenges for energy-efficient visionary Guardian Angel autonomous systems: (i) energy-efficient computing (down to E=10-100kT), (ii) and communication (approaching the limit of 1pJ/bit), (iii) low-power sensing, (iv) disruptive scavenging (bio-inspired, thermoelectric, etc, targeting energy densities of tens of mW/cm2), and (v) zero-power man-machine interfaces. A selection of emerging technologies based on energy efficiency is proposed. We will also develop design tools that integrate electrical, mechanical, optical, thermal, and chemical simulation tools over length and time scales currently not achievable.
Agency: European Commission | Branch: FP7 | Program: CP | Phase: ICT-2007.3.6 | Award Amount: 5.16M | Year: 2008
NEMSIC addresses the future intelligent sensor and actuator systems in which solid-state semiconductor micro/nanodevices and micro/nano-mechanical devices are co-integrated for new functionalities and increased performance.The project proposes the exploration and development of low power sensing micro/nanosystems based on Nano-Electro-Mechanical (NEM) structures integrated on a Silicon-On-Insulator (SOI) or Silicon-On-Nothing (SON) technological platform. The applications that drive the technological NEM-based smart system demonstrators are gas (COx, NOx, SOx) and biological sensing (DNA, proteins and other molecules), dedicated to critical environment monitoring and applications in the fields of genetics, pharmacology and drug discovery. NEM technology will be combined with silicon CMOS technology involving novelty and scientific/technical challenges at three levels: (i) system level, addressing the challenge of true nano-micro interfaces, where signals detected by arrays of nanostructures are processed by smartly designed low power CMOS circuitry, (ii) device level, where novel true hybrid NEM-FET devices support new highly sensitive detection scheme and power management via sleep switches and (iii) technology level, where nanotechnology processes (top down processed nanobeams and nanogaps, featuring sub-100nm dimensions) will be developed and combined with advanced functionalization techniques for dedicated sensing that stays compatible with CMOS in future IC-embedded or post-IC approaches. The reliability of the NEM structures, combined with prospects for 0-level packaging are studied as key challenges for the success of such Nano-electro-mechanical-system-integrated-circuits (NEMSIC).Finally, NEMSIC is expected to provide the end-users with flexible design methodologies based on advanced but well-controlled SOI or SON technology platforms, with predictable performances and associated cost effectiveness.
Terry A.V.,Georgia Regents University |
Callahan P.M.,Georgia Regents University |
Bertrand D.,HiQScreen Sarl
Journal of Pharmacology and Experimental Therapeutics | Year: 2015
The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(+) and S-(-) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at α4β2 or α7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at α7 nAChRs exposed to 1.0 mMR-(+)-or S-(-)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(+)-or S-(-)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-β-erythroidine, indicating that both α7 and α4β2 nAChRs contribute to the response. These results indicate that cotinine may sensitize α7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Bertrand D.,HiQScreen Sarl |
Lee C.-H.L.,Abbvie Inc. |
Flood D.,FORUM Pharmaceuticals Inc |
Marger F.,HiQScreen Sarl |
Donnelly-Roberts D.,Abbvie Inc.
Pharmacological Reviews | Year: 2015
Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important inmany higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes inmultiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states. © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Pucci L.,CNR Institute of Neuroscience |
Grazioso G.,University of Milan |
Dallanoce C.,University of Milan |
Rizzi L.,University of Milan |
And 7 more authors.
FASEB Journal | Year: 2011
α6β2* Nicotinic acetylcholine receptors are expressed in selected central nervous system areas, where they are involved in striatal dopamine (DA) release and its behavioral consequences, and other still uncharacterized brain activities. α6β2* receptors are selectively blocked by the α-conotoxins MII and PIA, which bear a characteristic N-terminal amino acid tail [arginine (R), aspartic acid (D), and proline (P)]. We synthesized a group of PIA-related peptides in which R1 was mutated or the RDP motif gradually removed. Binding and striatal DA release assays of native rat α6β2* receptors showed that the RDP sequence, and particularly residue R1, is essential for the activity of PIA. On the basis of molecular modeling analyses, we synthesized a hybrid peptide (RDPMII) that had increased potency (7-fold) and affinity (13-fold) for α6β2* receptors but not for the very similar α3β2* subtype. As docking studies also suggested that E11 of MII might be a key residue engendering α6β2* vs. α3β2* selectivity, we prepared MII[E11R] and RDPMII[ E11R] peptides. Their affinity and potency for native α6β2* receptors were similar to those of their parent analogues, whereas, for the oocyte expressed rat α3β2* subtype, they showed a 31- and 14-fold lower affinity and 21- and 3.5-fold lower potency. Thus, MII[E11R] and RDP-MII[E11R] are potent antagonists showing a degree of α6β2* vs. α3β2* selectivity in vivo. © FASEB.
Hurst R.,Pfizer |
Rollema H.,Rollema Biomedical Consulting |
Bertrand D.,HiQScreen Sarl
Pharmacology and Therapeutics | Year: 2013
Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic. © 2012 Elsevier Inc.
Bertrand D.,HiQScreen Sarl |
Bertrand S.,HiQScreen Sarl |
Neveu E.,HiQScreen Sarl |
Antimicrobial Agents and Chemotherapy | Year: 2010
Adverse effects have limited the clinical use of telithromycin. Preferential inhibition of the nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (α3β2 and NMJ), the ciliary ganglion of the eye (α3β4 and α7), and the vagus nerve innervating the liver (α7) could account for the exacerbation of myasthenia gravis, the visual disturbance, and the liver failure seen with telithromycin use. The studies presented here enable the prediction of expected side effects of macrolides in development, such as solithromycin (CEM-101). Copyright © 2010, American Society for Microbiology. All Rights Reserved.