Davis A

References (17)

Title : Organophosphate toxicity patterns: A new approach for assessing organophosphate neurotoxicity - Karaboga_2024_J.Hazard.Mater_470_134236
Author(s) : Karaboga S , Severac F , Collins ES , Stab A , Davis A , Souchet M , Herve G
Ref : J Hazard Mater , 470 :134236 , 2024
Abstract : Organophosphorus compounds or organophosphates (OPs) are widely used as flame retardants, plasticizers, lubricants and pesticides. This contributes to their ubiquitous presence in the environment and to the risk of human exposure. The persistence of OPs and their bioaccumulative characteristics raise serious concerns regarding environmental and human health impacts. To address the need for safer OPs, this study uses a New Approach Method (NAM) to analyze the neurotoxicity pattern of 42 OPs. The NAM consists of a 4-step process that combines computational modeling with in vitro and in vivo experimental studies. Using spherical harmonic-based cluster analysis, the OPs were grouped into four main clusters. Experimental data and quantitative structure-activity relationships (QSARs) analysis were used in conjunction to provide information on the neurotoxicity profile of each group. Results showed that one of the identified clusters had a favorable safety profile, which may help identify safer OPs for industrial applications. In addition, the 3D-computational analysis of each cluster was used to identify meta-molecules with specific 3D features. Toxicity was found to correspond to the level of phosphate surface accessibility. Substances with conformations that minimize phosphate surface accessibility caused less neurotoxic effect. This multi-assay NAM could be used as a guide for the classification of OP toxicity, helping to minimize the health and environmental impacts of OPs, and providing rapid support to the chemical regulators, whilst reducing reliance on animal testing.
ESTHER : Karaboga_2024_J.Hazard.Mater_470_134236
PubMedSearch : Karaboga_2024_J.Hazard.Mater_470_134236
PubMedID: 38613959

Title : Solvents and detergents compatible with enzyme kinetic studies of cholinesterases - Sands_2023_Chem.Biol.Interact_14ChEPon_110667
Author(s) : Sands D , Davis A , Banfield S , Pottie IR , Darvesh S
Ref : Chemico-Biological Interactions , :110667 , 2023
Abstract : Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that serve a wide range of physiological functions including the hydrolysis of the neurotransmitter acetylcholine and several other xenobiotics. The development of inhibitors for these enzymes has been the focus for the treatment of several conditions, such as Alzheimer's disease. Novel chemical entities are evaluated as potential inhibitors of AChE and BChE using enzyme kinetics. A common issue encountered in these studies is low aqueous solubility of the possible inhibitor. Additives such as cosolvents or detergents can be included in these studies improve the aqueous solubility. Typical cosolvents include acetonitrile or dimethyl sulfoxide while typical detergents include Polysorbate 20 (Tween 20) or 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate (CHAPS). When solubility is not improved, these molecules are often not evaluated further. To address this issue eleven cosolvents and six detergents that could facilitate aqueous solubility were evaluated to understand how they would affect cholinesterase enzymes using Ellman's assay. These studies show that propylene glycol, acetonitrile, methanol, Tween 20, Polysorbate 80 (Tween 80), polyoxyethylene 23 lauryl ether (Brij 35) and polyoxyethylene 10 oleoyl ether (Brij 96v) have the least inhibitory effects towards cholinesterase activity. It is concluded that these cosolvents and detergents should be considered as solubilizing agents for evaluation of potential cholinesterase inhibitors with low aqueous solubility.
ESTHER : Sands_2023_Chem.Biol.Interact_14ChEPon_110667
PubMedSearch : Sands_2023_Chem.Biol.Interact_14ChEPon_110667
PubMedID: 37579937

Title : Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca(2+) Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation - Malek_2022_Molecules_28_
Author(s) : Malek R , Simakov A , Davis A , Maj M , Bernard PJ , Wnorowski A , Martin H , Marco-Contelles J , Chabchoub F , Dallemagne P , Rochais C , Jozwiak K , Ismaili L
Ref : Molecules , 28 : , 2022
Abstract : Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
ESTHER : Malek_2022_Molecules_28_
PubMedSearch : Malek_2022_Molecules_28_
PubMedID: 36615267

Title : Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment - Seguy_2021_Pharmaceutics_13_
Author(s) : Seguy L , Guyon L , Maurel M , Verdie P , Davis A , Corvaisier S , Lisowski V , Dallemagne P , Groo AC , Malzert-Freon A
Ref : Pharmaceutics , 13 : , 2021
Abstract : BACKGROUND AND PURPOSE: The activation of 5-HT(4) receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer's disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood-brain barrier shuttle peptide. RESULTS: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 degreesC and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C(18)/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. CONCLUSION: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.
ESTHER : Seguy_2021_Pharmaceutics_13_
PubMedSearch : Seguy_2021_Pharmaceutics_13_
PubMedID: 34683919

Title : Development of Novel Potential Pleiotropic Compounds of Interest in Alzheimer's Disease Treatment through Rigidification Strategy - Lecoutey_2021_Molecules_26_
Author(s) : Lecoutey C , Legay R , Davis A , Sopkova-de Oliveira Santos J , Dallemagne P , Rochais C
Ref : Molecules , 26 : , 2021
Abstract : The development of Multi-Target Directed Ligand is of clear interest for the treatment of multifactorial pathology such as Alzheimer's disease (AD). In this context, acetylcholinesterase (AChE) inhibitors have been modulated in order to generate novel pleiotropic compounds targeting a second protein of therapeutic interest in AD. Among them, donecopride was the first example of a dual acetylcholinesterase inhibitor and 5-HT(4) receptor agonist. In order to explore the structural diversity around this preclinical candidate we have explored the preparation of novel constrained analogs through late-stage rigidification strategy. A series of phenylpyrazoles was prepared in a late-stage functionalization process and all compounds were evaluated in vitro towards AChE and 5-HTRs. A docking study was performed in order to better explain the observed SAR towards AChE, 5-HT(4)R and 5-HT(6)R and this study led to the description of novel ligand targeting both AChE and 5-HT(6)R.
ESTHER : Lecoutey_2021_Molecules_26_
PubMedSearch : Lecoutey_2021_Molecules_26_
PubMedID: 33926141

Title : Disproportionality analysis in VigiBase as a drug repositioning method for the discovery of potentially useful drugs in Alzheimer's disease - Chretien_2021_Br.J.Clin.Pharmacol_87_2830
Author(s) : Chretien B , Jourdan JP , Davis A , Fedrizzi S , Bureau R , Sassier M , Rochais C , Alexandre J , Lelong-Boulouard V , Dolladille C , Dallemagne P
Ref : British Journal of Clinical Pharmacology , 87 :2830 , 2021
Abstract : Drug repositioning aims to propose new indications for marketed drugs. Although several methods exist, the utility of pharmacovigilance databases for this purpose is unclear. We conducted a disproportionality analysis in the World Health Organization pharmacovigilance database VigiBase to identify potential anticholinesterase drug candidates for repositioning in Alzheimer's disease (AD). METHODS: Disproportionality analysis is a validated method for detecting significant associations between drugs and adverse events (AEs) in pharmacovigilance databases. We applied this approach in VigiBase to establish the safety profile displayed by the anticholinesterase drugs used in AD and searched the database for drugs with similar safety profiles. The detected drugs with potential activity against acetylcholinesterase and butyrylcholinesterases (BuChEs) were then evaluated to confirm their anticholinesterase potential. RESULTS: We identified 22 drugs with safety profiles similar to AD medicines. Among these drugs, 4 (clozapine, aripiprazole, sertraline and S-duloxetine) showed a human BuChE inhibition rate of over 70% at 10(-5) M. Their human BuChE half maximal inhibitory concentration values were compatible with clinical anticholinesterase action in humans at their normal doses. The most active human BuChE inhibitor in our study was S-duloxetine, with a half maximal inhibitory concentration of 1.2 microM. Combined with its ability to inhibit serotonin (5-HT) reuptake, the use of this drug could represent a novel multitarget directed ligand therapeutic strategy for AD. CONCLUSION: We identified 4 drugs with repositioning potential in AD using drug safety profiles derived from a pharmacovigilance database. This method could be useful for future drug repositioning efforts.
ESTHER : Chretien_2021_Br.J.Clin.Pharmacol_87_2830
PubMedSearch : Chretien_2021_Br.J.Clin.Pharmacol_87_2830
PubMedID: 33274491

Title : First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease - Guieu_2020_Molecules_26_
Author(s) : Guieu B , Lecoutey C , Legay R , Davis A , Sopkova de Oliveira Santos J , Altomare CD , Catto M , Rochais C , Dallemagne P
Ref : Molecules , 26 : , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease towards which pleiotropic approach using Multi-Target Directed Ligands is nowadays recognized as probably convenient. Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC(50) = 0.4 microM) and (h)MAO-B (IC(50) = 6.4 microM).
ESTHER : Guieu_2020_Molecules_26_
PubMedSearch : Guieu_2020_Molecules_26_
PubMedID: 33375412

Title : Rational design of novel benzisoxazole derivatives with acetylcholinesterase inhibitory and serotoninergic 5-HT4 receptors activities for the treatment of Alzheimer's disease - Lalut_2020_Sci.Rep_10_3014
Author(s) : Lalut J , Payan H , Davis A , Lecoutey C , Legay R , Sopkova-de Oliveira Santos J , Claeysen S , Dallemagne P , Rochais C
Ref : Sci Rep , 10 :3014 , 2020
Abstract : A rigidification strategy was applied to the preclinical candidate donecopride, an acetylcholinesterase inhibitor possessing 5-HT4R agonist activity. Inspired by promising bioactive benzisoxazole compounds, we have conducted a pharmacomodulation study to generate a novel series of multitarget directed ligands. The chemical synthesis of the ligand was optimized and compounds were evaluated in vitro against each target and in cellulo. Structure-activity relationship was supported by docking analysis in human acetylcholinesterase binding site. Among the synthesized compounds, we have identified a novel hybrid 32a (3-[2-[1-(cyclohexylmethyl)-4-piperidyl]ethyl]-4-methoxy-1,2-benzoxazole) able to display nanomolar acetylcholinesterase inhibitory effects and nanomolar Ki for 5-HT4R.
ESTHER : Lalut_2020_Sci.Rep_10_3014
PubMedSearch : Lalut_2020_Sci.Rep_10_3014
PubMedID: 32080261

Title : Pleiotropic prodrugs: Design of a dual butyrylcholinesterase inhibitor and 5-HT(6) receptor antagonist with therapeutic interest in Alzheimer's disease - Toublet_2020_Eur.J.Med.Chem_210_113059
Author(s) : Toublet FX , Lalut J , Hatat B , Lecoutey C , Davis A , Since M , Corvaisier S , Freret T , Sopkova-de Oliveira Santos J , Claeysen S , Boulouard M , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 210 :113059 , 2020
Abstract : Beside acetylcholinesterase, butyrylcholinesterase could be considered as a putative target of interest for the symptomatic treatment of Alzheimer's disease (AD). As a result of complexity of AD, no molecule has been approved since 2002. Idalopirdine, a 5-HT(6) receptors antagonist, did not show its effectiveness in clinical trial despite its evaluation as adjunct to cholinesterase inhibitors. Pleiotropic molecules, known as multitarget directed ligands (MTDLs) are currently developed to tackle the multifactorial origin of AD. In this context, we have developed a pleiotropic carbamate 7, that behaves as a covalent inhibitor of BuChE (IC(50) = 0.97 M). The latter will deliver after hydrolysis, compound 6, a potent 5-HT(6) receptors antagonist (K(i) = 11.4 nM) related to idalopirdine. In silico and in vitro evaluation proving our concept were performed completed with first in vivo results that demonstrate great promise in restoring working memory.
ESTHER : Toublet_2020_Eur.J.Med.Chem_210_113059
PubMedSearch : Toublet_2020_Eur.J.Med.Chem_210_113059
PubMedID: 33310288

Title : Pharmacotechnical Development of a Nasal Drug Delivery Composite Nanosystem Intended for Alzheimer's Disease Treatment - Adnet_2020_Pharmaceutics_12_
Author(s) : Adnet T , Groo AC , Picard C , Davis A , Corvaisier S , Since M , Bounoure F , Rochais C , Pluart LL , Dallemagne P , Malzert-Freon A
Ref : Pharmaceutics , 12 : , 2020
Abstract : Direct nose-to-brain delivery has been raised as a non-invasive powerful strategy to deliver drugs to the brain bypassing the blood-brain barrier (BBB). This study aimed at preparing and characterizing an innovative composite formulation, associating the liposome and hydrogel approaches, suitable for intranasal administration. Thermosensitive gel formulations were obtained based on a mixture of two hydrophilic polymers (Poloxamer 407, P407 and Poloxamer 188, P188) for a controlled delivery through nasal route via liposomes of an active pharmaceutical ingredient (API) of potential interest for Alzheimer's disease. The osmolarity and the gelation temperature (T degrees sol-gel) of formulations, defined in a ternary diagram, were investigated by rheometry and visual determination. Regarding the issue of assays, a mixture composed of P407/P188 (15/1%, w/w) was selected for intranasal administration in terms of T degrees sol-gel and for the compatibility with the olfactory mucosal (280 +/- 20 mOsmol, pH 6). Liposomes of API were prepared by the thin film hydration method. Mucoadhesion studies were performed by using mucin disc, and they showed the good natural mucoadhesive characteristics of in situ gel formulations, which increased when liposomes were added. The study demonstrated successful pharmacotechnical development of a promising API-loaded liposomes in a thermosensitive hydrogel intended for nasal Alzheimer's disease treatment.
ESTHER : Adnet_2020_Pharmaceutics_12_
PubMedSearch : Adnet_2020_Pharmaceutics_12_
PubMedID: 32168767

Title : Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer's Disease - Toublet_2019_Molecules_24_
Author(s) : Toublet FX , Lecoutey C , Lalut J , Hatat B , Davis A , Since M , Corvaisier S , Freret T , Sopkova de Oliveira Santos J , Claeysen S , Boulouard M , Dallemagne P , Rochais C
Ref : Molecules , 24 : , 2019
Abstract : Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.
ESTHER : Toublet_2019_Molecules_24_
PubMedSearch : Toublet_2019_Molecules_24_
PubMedID: 31370232

Title : Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1 receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase - Lalut_2019_Eur.J.Med.Chem_162_234
Author(s) : Lalut J , Santoni G , Karila D , Lecoutey C , Davis A , Nachon F , Silman I , Sussman JL , Weik M , Maurice T , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 162 :234 , 2019
Abstract : Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the sigma1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.
ESTHER : Lalut_2019_Eur.J.Med.Chem_162_234
PubMedSearch : Lalut_2019_Eur.J.Med.Chem_162_234
PubMedID: 30447434
Gene_locus related to this paper: torca-ACHE

Title : A Novel in vivo Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HT4R) Agonist and Serotonergic Subtype 6 Receptor (5-HT6R) Inverse Agonist Activities, With a Potential Interest Against Alzheimer's Disease - Hatat_2019_Front.Aging.Neurosci_11_148
Author(s) : Hatat B , Yahiaoui S , Lecoutey C , Davis A , Freret T , Boulouard M , Claeysen S , Rochais C , Dallemagne P
Ref : Front Aging Neurosci , 11 :148 , 2019
Abstract : This work describes the conception, synthesis, in vitro and in vivo biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT4 receptors, block 5-HT6 receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT4 and blockage of 5-HT6 receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT4 receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPalpha. Finally, we identified a pleiotropic compound, [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-(3-methylbenzyl)piperidin-4-yl)propan- 1-one fumaric acid salt (10)], which displayed in vivo an anti-amnesic effect in a model of scopolamine-induced deficit of working memory at a dose of 0.3 mg/kg.
ESTHER : Hatat_2019_Front.Aging.Neurosci_11_148
PubMedSearch : Hatat_2019_Front.Aging.Neurosci_11_148
PubMedID: 31316368

Title : Design, synthesis, and pharmacological evaluation of multitarget-directed ligands with both serotonergic subtype 4 receptor (5-HT4R) partial agonist and 5-HT6R antagonist activities, as potential treatment of Alzheimer's disease - Yahiaoui_2016_Eur.J.Med.Chem_121_283
Author(s) : Yahiaoui S , Hamidouche K , Ballandonne C , Davis A , de Oliveira Santos JS , Freret T , Boulouard M , Rochais C , Dallemagne P
Ref : Eur Journal of Medicinal Chemistry , 121 :283 , 2016
Abstract : 5-HT4 receptor (5-HT4R) activation and blockade of the 5-HT6 receptor (5-HT6R) are known to enhance the release of numerous neurotransmitters whose depletion is implicated in Alzheimer's disease (AD). Furthermore, 5-HT4R agonists seem to favor production of the neurotrophic soluble amyloid protein precursor alpha (sAPPalpha). Consequently, combining 5-HT4R agonist/5-HT6R antagonist activities in a single chemical compound would constitute a novel approach able to display both a symptomatic and disease-modifying effect in AD. Seventeen novel derivatives of RS67333 (1) were synthesized and evaluated as potential dual-target compounds. Among them, four agents showed nanomolar and submicromolar affinities toward 5-HT4R and 5-HT6R, respectively; one of them, 7m, was selected on the basis of its in vitro affinity (Ki5-HT4R = 5.3 nM, Ki5-HT6R = 219 nM) for further in vivo experiments, where 7m showed an antiamnesic effect in the mouse at 1 mg/kg ip.
ESTHER : Yahiaoui_2016_Eur.J.Med.Chem_121_283
PubMedSearch : Yahiaoui_2016_Eur.J.Med.Chem_121_283
PubMedID: 27266998

Title : Synthesis and evaluation of novel serotonin 4 receptor radiotracers for single photon emission computed tomography - Lalut_2016_Eur.J.Med.Chem_116_90
Author(s) : Lalut J , Tournier BB , Cailly T , Lecoutey C , Corvaisier S , Davis A , Ballandonne C , Since M , Millet P , Fabis F , Dallemagne P , Rochais C
Ref : Eur Journal of Medicinal Chemistry , 116 :90 , 2016
Abstract : Despite its implication in several physiological and pathological processes the serotonin subtype-4 receptor (5-HT4R) has seen limited effort for the development of radiolabeling agent especially concerning single photon emission computed tomography (SPECT). Bearing an ester function, the available ligands are rapidly susceptible to hydrolysis which limits their use in vivo. In this study the synthesis of iodinated benzamide and ketone analogs were described. Their affinity for the 5-HT4R and their lipophilicity were evaluated and the most promising derivatives were evaluated ex vivo for their binding to the receptor and for their ability to displace the reference ligand [(125)I]-SB207710.
ESTHER : Lalut_2016_Eur.J.Med.Chem_116_90
PubMedSearch : Lalut_2016_Eur.J.Med.Chem_116_90
PubMedID: 27060761

Title : Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) - Gault_1998_Genomics_52_173
Author(s) : Gault J , Robinson M , Berger R , Drebing C , Logel J , Hopkins J , Moore T , Jacobs S , Meriwether J , Choi MJ , Kim EJ , Walton K , Buiting K , Davis A , Breese C , Freedman R , Leonard S
Ref : Genomics , 52 :173 , 1998
Abstract : The human alpha7 neuronal nicotinic acetylcholine receptor gene (HGMW-approved symbol CHRNA7) has been characterized from genomic clones. The gene is similar in structure to the chick alpha7 gene with 10 exons and conserved splice junction positions. The size of the human gene is estimated to be larger than 75 kb. A putative promoter 5' of the translation start in exon 1 has been cloned and sequenced. The promoter region lacks a TATA box and has a high GC content (77%). Consensus Sp1, AP-2, Egr-1, and CREB transcription factor binding sites appear to be conserved between bovine and human genes. The alpha7 nAChR gene was found to be partially duplicated, with both loci mapping to the chromosome 15q13 region. A yeast artificial chromosome contig was constructed over a genetic distance of 5 cM that includes both alpha7 loci and the region between them. Four novel exons are described, located in genomic clones containing the partially duplicated gene. The duplicated sequences, including the novel exons, are expressed in human brain.
ESTHER : Gault_1998_Genomics_52_173
PubMedSearch : Gault_1998_Genomics_52_173
PubMedID: 9782083

Title : Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus - Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
Author(s) : Freedman R , Coon H , Myles-Worsley M , Orr-Urtreger A , Olincy A , Davis A , Polymeropoulos M , Holik J , Hopkins J , Hoff M , Rosenthal J , Waldo MC , Reimherr F , Wender P , Yaw J , Young DA , Breese CR , Adams C , Patterson D , Adler LE , Kruglyak L , Leonard S , Byerley W
Ref : Proc Natl Acad Sci U S A , 94 :587 , 1997
Abstract : Inheritance of a defect in a neuronal mechanism that regulates response to auditory stimuli was studied in nine families with multiple cases of schizophrenia. The defect, a decrease in the normal inhibition of the P50 auditory-evoked response to the second of paired stimuli, is associated with attentional disturbances in schizophrenia. Decreased P50 inhibition occurs not only in most schizophrenics, but also in many of their nonschizophrenic relatives, in a distribution consistent with inherited vulnerability for the illness. Neurobiological investigations in both humans and animal models indicated that decreased function of the alpha 7-nicotinic cholinergic receptor could underlie the physiological defect. In the present study, a genome-wide linkage analysis, assuming autosomal dominant transmission, showed that the defect is linked [maximum logarithm of the odds (lod) score = 5.3 with zero recombination] to a dinucleotide polymorphism at chromosome 15q13-14, the site of the alpha 7-nicotinic receptor. Despite many schizophrenics' extremely heavy nicotine use, nicotinic receptors were not previously thought to be involved in schizophrenia. The linkage data thus provide unique new evidence that the alpha 7-nicotinic receptor gene may be responsible for the inheritance of a pathophysiological aspect of the illness.
ESTHER : Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
PubMedSearch : Freedman_1997_Proc.Natl.Acad.Sci.U.S.A_94_587
PubMedID: 9012828