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Rollema H.,Rollema Biomedical Consulting | Russ C.,Pfizer | Lee T.C.,Pfizer | Hurst R.S.,Pfizer | Bertrand D.,HiQScreen
Nicotine and Tobacco Research | Year: 2014

Introduction: It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control. Methods: Concentration-dependent functional effects of varenicline and nicotine at human α3β4, α3α5β4, α7, and α4β2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype. Results: Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of α3β4, α4β2 (<2%), α7 (<0.05%), and α3α5β4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of α3β4 (48%) and α3α5β4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of α4β2 nAChRs (42%-56%) and α7 nAChRs (16%) as varenicline. Conclusions: Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic α3β4* nAChRs, while their functional profiles at α3β4, α3α5β4, α7, and α4β2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified. © The Author 2014. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved.

Reymond J.-L.,University of Bern | Van Deursen R.,University of Bern | Bertrand D.,HiQScreen
Biochemical Pharmacology | Year: 2011

The activity of ligand gated channels is crucial for proper brain function and dysfunction of a single receptor subtype have led to neurological impairments ranging from benign to major diseases such as epilepsy, startle diseases, etc. Molecular biology and crystallography allowed the characterization at the atomic scale of the first four transmembrane ligand gated channels and of proteins sharing a high degree of homology with the neurotransmitter-binding domain. Gaining an adequate knowledge of the structural features of the ligand binding pocket led to the possibilities of developing virtual screening based approaches and probing in silico the docking of very large numbers of molecules. Development of new computing tools further extended such possibilities and rendered possible the screening of the chemical universe database GDB-11, which contains all possible organic molecules up to 11 atoms of C, N, O and F. In the case of the nicotinic acetylcholine receptors molecules identified using such screening methods were synthesized and characterized in binding assays and their pose determined in crystal structure with the acetylcholine binding protein. However, in spite of these thorough approaches, functional studies revealed that these molecules had a greater affinity for the pore domain of the channel and acted as open channel blocker rather than binding site antagonist. In this work, we discuss the potential and current limitations of how progresses made with the crystal structures of ligand gated channels, or ligand binding proteins, can be used in combination with virtual screening and functional assays, to identify novel compounds. © 2011 Elsevier Inc.

Burgi J.J.,University of Bern | Awale M.,University of Bern | Boss S.D.,University of Bern | Schaer T.,HiQScreen | And 6 more authors.
ACS Chemical Neuroscience | Year: 2014

While a plethora of ligands are known for the well studied α7 and α4β2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related α3β2 nAChR expressed in the central nervous system and at the neuromuscular junction. Starting with the public database ChEMBL organized in the chemical space of Molecular Quantum Numbers (MQN, a series of 42 integer value descriptors of molecular structure), a visual survey of nearest neighbors of the α7 nAChR partial agonist N-(3R)-1- azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) pointed to N-(2-halobenzyl)-3-aminoquinuclidines as possible nAChR modulators. This simple "chemical space walk" was performed using a web-browser available at www.gdb.unibe.ch. Electrophysiological recordings revealed that these ligands represent a new and to date most potent class of positive allosteric modulators (PAMs) of the α3β2 nAChR, which also exert significant effects in vivo. The present discovery highlights the value of surveying chemical space neighbors of known drugs within public databases to uncover new pharmacology. © 2014 American Chemical Society.

Marger L.,HiQScreen | Schubert C.R.,Pfizer | Bertrand D.,HiQScreen
Biochemical Pharmacology | Year: 2014

The divalent cation, zinc is the second most abundant metal in the human body and is indispensable for life. Zinc concentrations must however, be tightly regulated as deficiencies are associated with multiple pathological conditions while an excess can be toxic. Zinc plays an important role as a cofactor in protein folding and function, e.g. catalytic interactions, DNA recognition by zinc finger proteins and modulation ion channel activity. There are 24 mammalian proteins specific for zinc transport that are subdivided in two groups with opposing functions: ZnT proteins reduce cytosolic zinc concentration while ZIP proteins increase it. The mammalian brain contains a significant amount of zinc, with 5-15% concentrated in synaptic vesicles of glutamatergic neurons alone. Accumulated in these vesicles by the ZnT3 transporter, zinc is released into the synaptic cleft at concentrations from nanomolar at rest to high micromolar during active neurotransmission. Low concentrations of zinc modulate the activity of a multitude of voltage- or ligand-gated ion channels, indicating that this divalent cation must be taken into account in the analysis of the pathophysiology of CNS disorders including epilepsy, schizophrenia and Alzheimer's disease. In the context of the latest findings, we review the role of zinc in the central nervous system and discuss the relevance of the most recent association between the zinc transporter, ZIP8 and schizophrenia. An enhanced understanding of zinc transporters in the context of ion channel modulation may offer new avenues in identifying novel therapeutic entities that target neurological disorders. © 2014 Elsevier Inc. All rights reserved.

Chen S.,Ecole Polytechnique Federale de Lausanne | Gopalakrishnan R.,Ecole Polytechnique Federale de Lausanne | Schaer T.,HiQScreen | Marger F.,HiQScreen | And 4 more authors.
Nature chemistry | Year: 2014

The disulfide bonds that form between two cysteine residues are important in defining and rigidifying the structures of proteins and peptides. In polypeptides containing multiple cysteine residues, disulfide isomerization can lead to multiple products with different biological activities. Here, we describe the development of a dithiol amino acid (Dtaa) that can form two disulfide bridges at a single amino acid site. Application of Dtaas to a serine protease inhibitor and a nicotinic acetylcholine receptor inhibitor that contain disulfide constraints enhanced their inhibitory activities 40- and 7.6-fold, respectively. X-ray crystallographic and NMR structure analysis show that the peptide ligands containing Dtaas have retained their native tertiary structures. We furthermore show that replacement of two cysteines by Dtaas can avoid the formation of disulfide bond isomers. With these properties, Dtaas are likely to have broad application in the rational design or directed evolution of peptides and proteins with high activity and stability.

Wallace T.L.,SRI International | Bertrand D.,HiQScreen
Expert Opinion on Therapeutic Targets | Year: 2013

Introduction: Schizophrenia is a profoundly debilitating disease that represents not only an individual, but a societal problem. Once characterized solely by the hyperactivity of the dopaminergic system, therapies directed to dampen dopaminergic neurotransmission were developed. However, these drugs do not address the significant impairments in cognition and the negative symptoms of the disease, and it is now apparent that disequilibrium of many neurotransmitter systems is involved. Despite enormous efforts, minimal progress has been made toward the development of safer, more effective therapies to date. Areas covered: The high preponderance of smoking in schizophrenics suggests that nicotine may provide symptomatic improvement, which has led to investigation for selective molecules targeted to individual nicotinic receptor (nAChR) subtypes. Of special interest is activation of the homomeric α7nAChR, which is widely distributed in the brain and has been implicated in the pathophysiology of schizophrenia through numerous approaches. Expert opinion: Preclinical and clinical data suggest that neuronal α7nAChRs play an important role in cognitive functions. Moreover, some, but not all, early clinical trials conducted with α7nAChR agonists show cognitive benefits in schizophrenics. These encouraging results suggest that development of compounds targeting α7nAChRs will represent a valuable tool to mitigate symptoms associated with schizophrenia, and open new strategies for better pharmacological treatment of these patients. © 2013 Informa UK, Ltd.

Wallace T.L.,SRI International | Bertrand D.,HiQScreen
Biochemical Pharmacology | Year: 2013

The prefrontal cortex (PFC) is responsible for integrating cortical and subcortical inputs to execute essential cognitive functions such as attention, working memory planning and decision-making. The importance of this brain region in regulating complex cognitive processes is underscored by a decline in PFC-mediated ability observed in aging and disease. The cholinergic system plays a vital role in cognitive function and treatments (e.g., cholinesterase inhibitors) to improve cholinergic neurotransmission provide the standard-of-care for diseases such as Alzheimer's. Nicotinic receptors (nAChRs) are a primary site of action for acetylcholine (ACh), and the resulting pro-cognitive effects observed by stimulating nAChRs with nicotine has long been appreciated by tobacco users, prompting investigation of therapeutic development for diseases (e.g., schizophrenia, Alzheimer or attention-deficit- hyperactivity disorder) by targeting the neuronal nAChR system. Noteworthy, improvements in attention, working memory and executive processes mediated by the PFC have been reported following nicotinic agonist exposure. Relevance of these ligand gated channels in higher brain function is further supported by the association of cognitive deficits reported in humans with mutations in CHRNB2 or CHRNA7 the genes encoding for the nicotinic receptor β2 and α7 subunits, respectively. In this work we review, in light of the latest findings, how nicotinic agonists may be acting in the PFC to influence cognitive function. © 2013 Elsevier Inc. All rights reserved.

Blum L.C.,University of Bern | Van Deursen R.,University of Bern | Bertrand S.,HiQScreen | Mayer M.,HiQScreen | And 3 more authors.
Journal of Chemical Information and Modeling | Year: 2011

The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBD MQN) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at www.gdb.unibe.ch. This virtual screening procedure selected 31 504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in Xenopus oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery. © 2011 American Chemical Society.

Brethous L.,University of Bern | Garcia-Delgado N.,University of Bern | Schwartz J.,University of Bern | Bertrand S.,HiQScreen | And 2 more authors.
Journal of Medicinal Chemistry | Year: 2012

The Chemical Universe Generated Databases up to 11 atoms of CNOF (GDB-11) and up to 13 atoms of CNOClS (GDB-13) were used to enumerate analogues of the diamine part of two known α7 nicotinic receptor agonists and construct libraries of virtual analogues of these drugs. The libraries were scored using structure-based (docking to the nicotine binding site of the acetylcholine binding protein 1uw6.pdb) or ligand-based (similarity to the parent drugs) methods, and the top-scoring virtual ligands were inspected for easily accessible synthetic targets. In total, 21 diamines were prepared and acylated with aromatic carboxylic or oxycarbonic acids to produce 85 analogues of the parent drugs. The compounds were profiled by electrophysiology in Xenopus oocytes expressing human nicotinic acetylcholine receptor (nAChR) subtypes α7, α3β2, α4β2, α3β4, or α4β4. Characterization of selected compounds revealed eight inhibitors of the α7 nicotinic receptor and three positive allosteric modulators of the α3β2 nAChR. © 2012 American Chemical Society.

Knoflach F.,Hoffmann-La Roche | Hernandez M.-C.,Hoffmann-La Roche | Bertrand D.,HiQScreen
Biochemical Pharmacology | Year: 2016

GABAA receptors are ligand-gated ion channels that form a fundamental component of inhibitory neurotransmission in the central and peripheral nervous systems. However, since the initial recordings of inhibitory electrical activity of neurons in response to GABA, these receptors have been found to play a more complex role and can, under some circumstances, function in an excitatory manner. This has been demonstrated via electrophysiological recordings conducted in both mature and developing neurons from different brain regions, as well as in various subcellular locations such as dendritic and axonal membranes.The balance between the inhibitory and excitatory effects mediated by GABAA receptor activation depends not only on multiple factors that govern the equilibrium of the transmembrane chloride gradient, but also on bicarbonate concentration. Moreover, electrophysiological and fluorescence measurements have revealed that a spatial distribution of the chloride gradient exists within neurons, which locally influences the effects mediated by GABAA receptor activation. In recent years, it has also become apparent that intra-neuronal chloride concentration is partially regulated by cation-chloride co-transporters (CCCs), in particular NKCC1 and KCC2.The aim of the present commentary is to discuss, in light of the latest findings, potential implications of the tight spatial and temporal regulation of chloride equilibrium in health and disease, as well as its relevance for the therapeutic effects of molecules acting at GABAA receptors. © 2016 Elsevier Inc.

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