Williams M

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Full name : Williams Michael

First name : Michael

Mail : Feinberg School of Medicine, Northwestern University, Chicago, IL

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Country : USA

Email : mazarine1643@comcast.net

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References (33)

Title : A Murine Model of Hyperlipidemia-Induced Heart Failure with Preserved Ejection Fraction - Williams_2024_J.Vis.Exp__
Author(s) : Williams M , Kamiar A , Condor Capcha JM , Rasmussen MA , Alitter Q , Kanashiro Takeuchi R , Mitsuru Takeuchi L , Hare JM , Shehadeh LA
Ref : J Vis Exp , : , 2024
Abstract : The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.
ESTHER : Williams_2024_J.Vis.Exp__
PubMedSearch : Williams_2024_J.Vis.Exp__
PubMedID: 38619239

Title : Lipase hypersecretion syndrome: A rare cutaneous manifestation of advanced pancreatic acinar cell carcinoma - Nizam_2020_Clin.Case.Rep_8_905
Author(s) : Nizam W , Shah AA , Rajack F , Ramdath A , Naab T , Williams M
Ref : Clin Case Rep , 8 :905 , 2020
Abstract : Careful recognition of cutaneous lesions in patients with malignancies may aid in avoiding additional morbidity during end of life care.
ESTHER : Nizam_2020_Clin.Case.Rep_8_905
PubMedSearch : Nizam_2020_Clin.Case.Rep_8_905
PubMedID: 32477543

Title : Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity - Mullane_2019_Curr.Protoc.Pharmacol__e57
Author(s) : Mullane K , Williams M
Ref : Curr Protoc Pharmacol , :e57 , 2019
Abstract : The only drugs currently approved for the treatment of Alzheimer's Disease (AD) are four acetylcholinesterase inhibitors and the NMDA antagonist memantine. Apart from these drugs, which have minimal to no clinical benefit, the 40-year search for effective therapeutics to treat AD has resulted in a clinical failure rate of 100% not only for compounds that prevent brain amyloid deposition or remove existing amyloid plaques but also those acting by a variety of other putative disease-associated mechanisms. This indicates that the preclinical data generated from current AD targets to support the selection, optimization, and translation of new chemical entities (NCEs) and biologics to clinical trials is seriously compromised. While many of these failures reflect flawed hypotheses or a lack of adequate characterization of the preclinical pharmacodynamic and pharmacokinetic (PD/PK) properties of lead NCEs-including their bioavailability and toxicity-the conceptualization, validation, and interrogation of the current animal models of AD represent key limitations. The overwhelming majority of these AD models are transgenic, based on aspects of the amyloid hypothesis and the genetics of the familial form of the disease. As a result, these generally lack construct and predictive validity for the sporadic form of the human disease. The 170 or so transgenic models, perhaps the largest number ever focused on a single disease, use rodents, mainly mice, and in addition to amyloid also address aspects of tau causality with more complex multigene models including other presumed causative factors together with amyloid. This overview discusses the current animal models of AD in the context of both the controversies surrounding the causative role of amyloid in the disease and the need to develop validated models of cognitive function/dysfunction that more appropriately reflect the phenotype(s) of human aged-related dementias. (c) 2019 by John Wiley & Sons, Inc.
ESTHER : Mullane_2019_Curr.Protoc.Pharmacol__e57
PubMedSearch : Mullane_2019_Curr.Protoc.Pharmacol__e57
PubMedID: 30802363

Title : Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Soreze 2009 - Oji_2010_J.Am.Acad.Dermatol_63_607
Author(s) : Oji V , Tadini G , Akiyama M , Blanchet Bardon C , Bodemer C , Bourrat E , Coudiere P , DiGiovanna JJ , Elias P , Fischer J , Fleckman P , Gina M , Harper J , Hashimoto T , Hausser I , Hennies HC , Hohl D , Hovnanian A , Ishida-Yamamoto A , Jacyk WK , Leachman S , Leigh I , Mazereeuw-Hautier J , Milstone L , Morice-Picard F , Paller AS , Richard G , Schmuth M , Shimizu H , Sprecher E , Van Steensel M , Taieb A , Toro JR , Vabres P , Vahlquist A , Williams M , Traupe H
Ref : J Am Acad Dermatol , 63 :607 , 2010
Abstract : BACKGROUND: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. OBJECTIVE: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. METHODS: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Soreze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. RESULTS: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. LIMITATIONS: As more becomes known about these diseases in the future, modifications will be needed. CONCLUSION: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research.
ESTHER : Oji_2010_J.Am.Acad.Dermatol_63_607
PubMedSearch : Oji_2010_J.Am.Acad.Dermatol_63_607
PubMedID: 20643494

Title : Progress in Alzheimer's disease drug discovery: an update - Williams_2009_Curr.Opin.Investig.Drugs_10_23
Author(s) : Williams M
Ref : Curr Opin Investig Drugs , 10 :23 , 2009
Abstract : While Alzheimer's disease (AD) represents a major healthcare challenge, with 25 to 34 million individuals currently affected worldwide and triple this number of patients projected by 2050, the drugs currently approved for the palliative treatment of AD, the cholinesterase inhibitors and the NMDA antagonist memantine, have demonstrated questionable efficacy, highlighting an urgent need for new therapies. Efforts in targeting the removal of amyloid plaques from the brain of patients with AD have been disappointing, with neither plaque-removing vaccines nor the gamma-secretase modulator, tarenflurbil demonstrating clinical benefit, thus questioning the validity of the amyloid cascade hypothesis that has driven AD research for the past decade. The lack of progress in mechanistic approaches (the amyloid and tau hypotheses) to developing new AD drugs indicates that some of the basic assumptions of AD causality and the search for effective drugs are probably in need of major reassessment and redirection.
ESTHER : Williams_2009_Curr.Opin.Investig.Drugs_10_23
PubMedSearch : Williams_2009_Curr.Opin.Investig.Drugs_10_23
PubMedID: 19127484

Title : The genome of the model beetle and pest Tribolium castaneum - Richards_2008_Nature_452_949
Author(s) : Richards S , Gibbs RA , Weinstock GM , Brown SJ , Denell R , Beeman RW , Gibbs R , Bucher G , Friedrich M , Grimmelikhuijzen CJ , Klingler M , Lorenzen M , Roth S , Schroder R , Tautz D , Zdobnov EM , Muzny D , Attaway T , Bell S , Buhay CJ , Chandrabose MN , Chavez D , Clerk-Blankenburg KP , Cree A , Dao M , Davis C , Chacko J , Dinh H , Dugan-Rocha S , Fowler G , Garner TT , Garnes J , Gnirke A , Hawes A , Hernandez J , Hines S , Holder M , Hume J , Jhangiani SN , Joshi V , Khan ZM , Jackson L , Kovar C , Kowis A , Lee S , Lewis LR , Margolis J , Morgan M , Nazareth LV , Nguyen N , Okwuonu G , Parker D , Ruiz SJ , Santibanez J , Savard J , Scherer SE , Schneider B , Sodergren E , Vattahil S , Villasana D , White CS , Wright R , Park Y , Lord J , Oppert B , Brown S , Wang L , Weinstock G , Liu Y , Worley K , Elsik CG , Reese JT , Elhaik E , Landan G , Graur D , Arensburger P , Atkinson P , Beidler J , Demuth JP , Drury DW , Du YZ , Fujiwara H , Maselli V , Osanai M , Robertson HM , Tu Z , Wang JJ , Wang S , Song H , Zhang L , Werner D , Stanke M , Morgenstern B , Solovyev V , Kosarev P , Brown G , Chen HC , Ermolaeva O , Hlavina W , Kapustin Y , Kiryutin B , Kitts P , Maglott D , Pruitt K , Sapojnikov V , Souvorov A , Mackey AJ , Waterhouse RM , Wyder S , Kriventseva EV , Kadowaki T , Bork P , Aranda M , Bao R , Beermann A , Berns N , Bolognesi R , Bonneton F , Bopp D , Butts T , Chaumot A , Denell RE , Ferrier DE , Gordon CM , Jindra M , Lan Q , Lattorff HM , Laudet V , von Levetsow C , Liu Z , Lutz R , Lynch JA , da Fonseca RN , Posnien N , Reuter R , Schinko JB , Schmitt C , Schoppmeier M , Shippy TD , Simonnet F , Marques-Souza H , Tomoyasu Y , Trauner J , Van der Zee M , Vervoort M , Wittkopp N , Wimmer EA , Yang X , Jones AK , Sattelle DB , Ebert PR , Nelson D , Scott JG , Muthukrishnan S , Kramer KJ , Arakane Y , Zhu Q , Hogenkamp D , Dixit R , Jiang H , Zou Z , Marshall J , Elpidina E , Vinokurov K , Oppert C , Evans J , Lu Z , Zhao P , Sumathipala N , Altincicek B , Vilcinskas A , Williams M , Hultmark D , Hetru C , Hauser F , Cazzamali G , Williamson M , Li B , Tanaka Y , Predel R , Neupert S , Schachtner J , Verleyen P , Raible F , Walden KK , Angeli S , Foret S , Schuetz S , Maleszka R , Miller SC , Grossmann D
Ref : Nature , 452 :949 , 2008
Abstract : Tribolium castaneum is a member of the most species-rich eukaryotic order, a powerful model organism for the study of generalized insect development, and an important pest of stored agricultural products. We describe its genome sequence here. This omnivorous beetle has evolved the ability to interact with a diverse chemical environment, as shown by large expansions in odorant and gustatory receptors, as well as P450 and other detoxification enzymes. Development in Tribolium is more representative of other insects than is Drosophila, a fact reflected in gene content and function. For example, Tribolium has retained more ancestral genes involved in cell-cell communication than Drosophila, some being expressed in the growth zone crucial for axial elongation in short-germ development. Systemic RNA interference in T. castaneum functions differently from that in Caenorhabditis elegans, but nevertheless offers similar power for the elucidation of gene function and identification of targets for selective insect control.
ESTHER : Richards_2008_Nature_452_949
PubMedSearch : Richards_2008_Nature_452_949
PubMedID: 18362917
Gene_locus related to this paper: trica-ACHE1 , trica-ACHE2 , trica-d2a0g9 , trica-d2a0h0 , trica-d2a0w9 , trica-d2a0x0 , trica-d2a0x1 , trica-d2a0x3 , trica-d2a0x4.1 , trica-d2a0x4.2 , trica-d2a0x6 , trica-d2a2b8 , trica-d2a2h1 , trica-d2a3c3 , trica-d2a3g9 , trica-d2a5y5 , trica-d2a309 , trica-d2a514 , trica-d2a515 , trica-d2a516 , trica-d2a577 , trica-d2a578 , trica-d6w6x8 , trica-d6w7f9 , trica-d6w7h2 , trica-d6w8e7 , trica-d6w9c0 , trica-d6w855 , trica-d6wac8 , trica-d6wan4 , trica-d6wd50 , trica-d6wd73 , trica-d6wd74 , trica-A0A139WM97 , trica-d6wfu3 , trica-d6wgl2 , trica-d6wj57 , trica-d6wj59 , trica-d6wjs3 , trica-d6wl31 , trica-d6wnv1 , trica-d6wpl0 , trica-d6wqd6 , trica-d6wqr4 , trica-d6ws52 , trica-d6wsm0 , trica-d6wu38 , trica-d6wu39 , trica-d6wu40 , trica-d6wu41 , trica-d6wu44 , trica-d6wvk5 , trica-d6wvz7 , trica-d6wwu9 , trica-d6wwv0 , trica-d6wxz0 , trica-d6wyy1 , trica-d6wyy2 , trica-d6x0z2 , trica-d6x0z5 , trica-d6x0z6 , trica-d6x4b2 , trica-d6x4e8 , trica-d6x4e9 , trica-d6x197 , trica-d7eip7 , trica-d7eld3 , trica-d7us45 , trica-q5wm43 , trica-q5zex9 , trica-d6wie5 , trica-d6w7t0 , trica-d6x4h0 , trica-d6x4h1 , trica-a0a139wae8 , trica-a0a139wc96 , trica-d6x325 , trica-d2a4s2 , trica-d6wvw8

Title : Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science - editorial comments -
Author(s) : Gopalakrishnan M , Bertrand D , Williams M
Ref : Biochemical Pharmacology , 74 :1091 , 2007
PubMedID: 17889037

Title : Neuronal nicotinic receptors: a perspective on two decades of drug discovery research - Arneric_2007_Biochem.Pharmacol_74(8)_1092
Author(s) : Arneric SP , Holladay M , Williams M
Ref : Biochemical Pharmacology , 74 :1092 , 2007
Abstract : Neuronal nicotinic acetylcholine receptors (nAChRs) have been a target for drug discovery efforts, primarily for CNS indications, for the past two decades. While nicotine and related natural products have been used for smoking cessation in various formulations (e.g., gum, spray, patches), it was only in 2006 with the launch of varenicline (Chantix) by Pfizer for smoking cessation that a new chemical entity (NCE) originating from a rational medicinal chemistry effort targeting neuronal AChRs was approved. The current overview outlines the chronology of drug discovery efforts in nAChRs from the cloning of the receptor family in the 1980s, to initial research efforts at SIBIA, R.J. Reynolds and Abbott, to the current industry-wide interest in nAChR agonists as novel therapeutics for pain, schizophrenia and Alzheimer's Disease. Key events in the evolution of the nAChR field were the development of high throughput electrophysiological screening tools that provided the means to enable lead optimization efforts in medicinal chemistry and the discovery by John Daly at the NIH of the frog alkaloid, epibatidine, that provided the framework for the discovery of ABT-594, an alpha4beta2 agonist that is 200 times more potent than morphine as an analgesic. Over the next decade, it is anticipated that additional NCEs including antagonists and allosteric modulators (both positive and negative), interacting with various nAChR subtypes, will be advanced to the clinic in areas of high unmet medical need, e.g., pain, neurodegeneration, to provide novel medications with improved efficacy.
ESTHER : Arneric_2007_Biochem.Pharmacol_74(8)_1092
PubMedSearch : Arneric_2007_Biochem.Pharmacol_74(8)_1092
PubMedID: 17662959

Title : Genome-based drug discovery: prioritizing disease-susceptibility\/disease-associated genes as novel drug targets for schizophrenia - Williams_2003_Curr.Opin.Investig.Drugs_4_31
Author(s) : Williams M
Ref : Curr Opin Investig Drugs , 4 :31 , 2003
Abstract : The search for new classes of antipsychotics based on novel targets identified from linkage/linkage association in diseased cohorts and microarray approaches using tissue from affected individuals is a high priority in central nervous system research. Genes linked to schizophrenia, a disease affecting 1% of the population, have been identified on nearly every chromosome of the human genome leading to a diverse choice of targets for validation. Interestingly, while the majority of currently used antipsychotic medications act by blocking dopamine receptors, there have been few genetic studies implicating the dopamine receptor family in disease etiology. Recently, four genes have been identified that encode dysbindin, neuroregulin, D-amino acid oxidase and G72, respectively, that support previous studies suggesting that schizophrenia may result from a hypofunction of glutamatergic neurotransmission. Linkage and microarray studies have similarly supported studies implicating the alpha 7 neuronal nicotinic receptor in the etiology of schizophrenia. Microarray studies using brain tissue from schizophrenic patients have shown changes in gene expression that number in the thousands, involving a number of proteins related to synaptic structure and function (PSYN gene group) and cellular metabolism. The majority of these proteins are not traditional drug discovery targets, nor are their functional roles in schizophrenia obvious, providing a challenge to validate them from the drug target identification/drug discovery perspective. The current state-of-the-art in genome-based approaches to schizophrenia, target discovery highlights a need for a multidisciplinary, integrative, null hypothesis-based approach to sort through these novel genes as drug targets.
ESTHER : Williams_2003_Curr.Opin.Investig.Drugs_4_31
PubMedSearch : Williams_2003_Curr.Opin.Investig.Drugs_4_31
PubMedID: 12625025

Title : The sequence of the human genome - Venter_2001_Science_291_1304
Author(s) : Venter JC , Adams MD , Myers EW , Li PW , Mural RJ , Sutton GG , Smith HO , Yandell M , Evans CA , Holt RA , Gocayne JD , Amanatides P , Ballew RM , Huson DH , Wortman JR , Zhang Q , Kodira CD , Zheng XH , Chen L , Skupski M , Subramanian G , Thomas PD , Zhang J , Gabor Miklos GL , Nelson C , Broder S , Clark AG , Nadeau J , McKusick VA , Zinder N , Levine AJ , Roberts RJ , Simon M , Slayman C , Hunkapiller M , Bolanos R , Delcher A , Dew I , Fasulo D , Flanigan M , Florea L , Halpern A , Hannenhalli S , Kravitz S , Levy S , Mobarry C , Reinert K , Remington K , Abu-Threideh J , Beasley E , Biddick K , Bonazzi V , Brandon R , Cargill M , Chandramouliswaran I , Charlab R , Chaturvedi K , Deng Z , Di Francesco V , Dunn P , Eilbeck K , Evangelista C , Gabrielian AE , Gan W , Ge W , Gong F , Gu Z , Guan P , Heiman TJ , Higgins ME , Ji RR , Ke Z , Ketchum KA , Lai Z , Lei Y , Li Z , Li J , Liang Y , Lin X , Lu F , Merkulov GV , Milshina N , Moore HM , Naik AK , Narayan VA , Neelam B , Nusskern D , Rusch DB , Salzberg S , Shao W , Shue B , Sun J , Wang Z , Wang A , Wang X , Wang J , Wei M , Wides R , Xiao C , Yan C , Yao A , Ye J , Zhan M , Zhang W , Zhang H , Zhao Q , Zheng L , Zhong F , Zhong W , Zhu S , Zhao S , Gilbert D , Baumhueter S , Spier G , Carter C , Cravchik A , Woodage T , Ali F , An H , Awe A , Baldwin D , Baden H , Barnstead M , Barrow I , Beeson K , Busam D , Carver A , Center A , Cheng ML , Curry L , Danaher S , Davenport L , Desilets R , Dietz S , Dodson K , Doup L , Ferriera S , Garg N , Gluecksmann A , Hart B , Haynes J , Haynes C , Heiner C , Hladun S , Hostin D , Houck J , Howland T , Ibegwam C , Johnson J , Kalush F , Kline L , Koduru S , Love A , Mann F , May D , McCawley S , McIntosh T , McMullen I , Moy M , Moy L , Murphy B , Nelson K , Pfannkoch C , Pratts E , Puri V , Qureshi H , Reardon M , Rodriguez R , Rogers YH , Romblad D , Ruhfel B , Scott R , Sitter C , Smallwood M , Stewart E , Strong R , Suh E , Thomas R , Tint NN , Tse S , Vech C , Wang G , Wetter J , Williams S , Williams M , Windsor S , Winn-Deen E , Wolfe K , Zaveri J , Zaveri K , Abril JF , Guigo R , Campbell MJ , Sjolander KV , Karlak B , Kejariwal A , Mi H , Lazareva B , Hatton T , Narechania A , Diemer K , Muruganujan A , Guo N , Sato S , Bafna V , Istrail S , Lippert R , Schwartz R , Walenz B , Yooseph S , Allen D , Basu A , Baxendale J , Blick L , Caminha M , Carnes-Stine J , Caulk P , Chiang YH , Coyne M , Dahlke C , Mays A , Dombroski M , Donnelly M , Ely D , Esparham S , Fosler C , Gire H , Glanowski S , Glasser K , Glodek A , Gorokhov M , Graham K , Gropman B , Harris M , Heil J , Henderson S , Hoover J , Jennings D , Jordan C , Jordan J , Kasha J , Kagan L , Kraft C , Levitsky A , Lewis M , Liu X , Lopez J , Ma D , Majoros W , McDaniel J , Murphy S , Newman M , Nguyen T , Nguyen N , Nodell M , Pan S , Peck J , Peterson M , Rowe W , Sanders R , Scott J , Simpson M , Smith T , Sprague A , Stockwell T , Turner R , Venter E , Wang M , Wen M , Wu D , Wu M , Xia A , Zandieh A , Zhu X
Ref : Science , 291 :1304 , 2001
Abstract : A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.
ESTHER : Venter_2001_Science_291_1304
PubMedSearch : Venter_2001_Science_291_1304
PubMedID: 11181995
Gene_locus related to this paper: human-AADAC , human-ABHD1 , human-ABHD10 , human-ABHD11 , human-ACHE , human-BCHE , human-LDAH , human-ABHD18 , human-CMBL , human-ABHD17A , human-KANSL3 , human-LIPA , human-LYPLAL1 , human-NDRG2 , human-NLGN3 , human-NLGN4X , human-NLGN4Y , human-PAFAH2 , human-PREPL , human-RBBP9 , human-SPG21

Title : Alkaloids from frog skin: the discovery of epibatidine and the potential for developing novel non-opioid analgesics -
Author(s) : Daly JW , Garraffo HM , Spande TF , Decker MW , Sullivan JP , Williams M
Ref : Nat Prod Rep , 17 :131 , 2000
PubMedID: 10821107

Title : Neuronal nicotinic acetylcholine receptors as novel drug targets -
Author(s) : Lloyd GK , Williams M
Ref : Journal of Pharmacology & Experimental Therapeutics , 292 :461 , 2000
PubMedID: 10640281

Title : Activation of voltage-operated Ca2+-channels in human small cell lung carcinoma by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone - Sheppard_2000_Int.J.Oncol_16_513
Author(s) : Sheppard BJ , Williams M , Plummer HK , Schuller HM
Ref : Int J Oncol , 16 :513 , 2000
Abstract : The nicotine-derived tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung cancer in all animal species tested and is thought to contribute significantly to the high lung cancer burden associated with smoking. NNK has recently been identified as a high affinity ligand for neuronal nicotinic acetylcholine receptors comprised of alpha7 subunits (alpha7 nAChR), and expressed in human small cell lung carcinoma (SCLC). As agonist-binding to this receptor in mammalian cells often results in membrane depolarization and activation of voltage-operated Ca2+-channels (VOCCs), we hypothesized that NNK may exert similar effects in SCLC. Using flow cytometry to monitor the influx of Ca2+, reverse transcription polymerase chain reaction (RT-PCR) to determine the expression of VOCC-specific messenger RNA, as well as analysis of DNA synthesis or determination of cell number, our data demonstrate that binding of NNK to the alpha7 nAChR in SCLC cells caused influx of Ca2+ via VOCCs of the L-, N-, and P-type. In turn, this led to a significant increase in DNA synthesis and cell number which was inhibited by a site-selective antagonist for the alpha7 nAChR and by Ca2+-channel blockers of the L-, N-, or P-types of VOCCs. Our findings suggest that the chronic activation of VOCC-mediated Ca2+ influx by NNK in smokers is an important event that may affect numerous Ca2+-dependent signal transduction pathways, thus contributing significantly to the development of SCLC.
ESTHER : Sheppard_2000_Int.J.Oncol_16_513
PubMedSearch : Sheppard_2000_Int.J.Oncol_16_513
PubMedID: 10675483

Title : The identification of novel structural compound classes exhibiting high affinity for neuronal nicotinic acetylcholine receptors and analgesic efficacy in preclinical models of pain - Meyer_2000_Eur.J.Pharmacol_393_171
Author(s) : Meyer MD , Decker MW , Rueter LE , Anderson DJ , Dart MJ , Kim KH , Sullivan JP , Williams M
Ref : European Journal of Pharmacology , 393 :171 , 2000
Abstract : Neuronal nicotinic acetylcholine receptors represent a new and potentially useful target for the development of novel non-opioid, non-NSAID (nonsteroidal antiinflammatory drug) analgesic agents. A variety of nicotinic acetylcholine receptor agonists such as nicotine, epibatidine and the azetidinyl ether, (R)-5-(2-azetidinylmethoxy-2-chloropyridine (ABT-594) possesses significant efficacy in preclinical models of pain. A preponderance of evidence suggests that nicotinic acetylcholine receptor agonists produce their analgesic effects predominantly via activation of descending inhibitory pain pathways originating in the key brainstem regions of the nucleus raphe magnus, dorsal raphe, and locus coeruleus, and that alpha4-containing nicotinic acetylcholine receptor subunits mediate these effects. Although these studies may provide a pharmacological target for the development of nicotinic acetylcholine receptor analgesics, the rational design of selective ligands based on the protein structure of the binding site is hampered by insufficient structural information. Using an approach based upon homology to known high-affinity ligands for the alpha4beta2 binding site, a four-point model is proposed which defines distance and directionality parameters common to this set of nicotinic acetylcholine receptor ligands.
ESTHER : Meyer_2000_Eur.J.Pharmacol_393_171
PubMedSearch : Meyer_2000_Eur.J.Pharmacol_393_171
PubMedID: 10771011

Title : Antinociceptive effects of the novel neuronal nicotinic acetylcholine receptor agonist, ABT-594, in mice - Decker_1998_Eur.J.Pharmacol_346_23
Author(s) : Decker MW , Bannon AW , Buckley MJ , Kim DJ , Holladay MW , Ryther KB , Lin NH , Wasicak JT , Williams M , Arneric SP
Ref : European Journal of Pharmacology , 346 :23 , 1998
Abstract : ABT-594 [5-((2R)-azetidinylmethoxy)-2-chloropyridine], a novel neuronal nicotinic acetylcholine receptor agonist, produced significant antinociceptive effects in mice against both acute noxious thermal stimulation--the hot-plate and cold-plate tests--and persistent visceral irritation--the abdominal constriction (writhing) assay (maximally-effective dose in each test 0.62 micromol/kg, i.p.). This effect was not stereoselective since the S-enantiomer, A-98593 [5-((2S)-azetidinylmethoxy)-2-chloropyridine], produced similar antinociceptive effects in this dose range. The effect in the hot-plate test peaked at 30 min after i.p. administration and was still present 60 min, but not 120 min, after injection. ABT-594 was orally active, but 10-fold less potent by this route than after i.p. administration. The antinociceptive effect of ABT-594 was prevented, but not reversed, by the noncompetitive neuronal nicotinic acetylcholine receptor antagonist mecamylamine (5 micromol/kg, i.p.). In contrast, the antinociceptive effect of ABT-594 was not prevented by hexamethonium (10 micromol/kg, i.p.), a neuronal nicotinic acetylcholine receptor antagonist that does not readily enter the central nervous system, nor by naltrexone (0.8 micromol/kg), an opioid receptor antagonist. Thus, initiation of antinociception by ABT-594 involves activation of central nicotinic acetylcholine receptors, but does not require activation of naltrexone-sensitive opioid receptors. The antinociceptive effects of morphine and ABT-594 in the mouse hot-plate test appeared to be additive, but ABT-594 did not potentiate the respiratory depression produced by morphine when the two compounds were coadministered. ABT-594 reduced body temperature and spontaneous exploration in the antinociceptive dose range, but did not reliably impair motor coordination in the rotarod test. Thus, it is unlikely that the antinociceptive effects result simply from impaired motor function. The compound also produced an anxiolytic-like effect in the elevated plus maze (at 0.019 and 0.062 micromol/kg, i.p.). Preliminary safety testing revealed an ED50 for overt seizure production of 1.9 micromol/kg, i.p. and an LD50 of 19.1 micromol/kg i.p. in mice, values 10 and 100 times the minimum effective antinociceptive dose of the compound. ABT-594 increased the duration of ethanol-induced hypnotic effects, tended to increase pentobarbital-induced hypnotic effects (P = 0.0502), and had no effect on pentobarbital-induced lethality. These data indicate that ABT-594 is a centrally acting neuronal nicotinic acetylcholine receptor agonist with potent antinociceptive and anxiolytic-like effects in mice.
ESTHER : Decker_1998_Eur.J.Pharmacol_346_23
PubMedSearch : Decker_1998_Eur.J.Pharmacol_346_23
PubMedID: 9617748

Title : Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors - Holladay_1998_J.Med.Chem_41_407
Author(s) : Holladay MW , Wasicak JT , Lin NH , He Y , Ryther KB , Bannon AW , Buckley MJ , Kim DJ , Decker MW , Anderson DJ , Campbell JE , Kuntzweiler TA , Donnelly-Roberts D , Piattoni-Kaplan M , Briggs CA , Williams M , Arneric SP
Ref : Journal of Medicinal Chemistry , 41 :407 , 1998
Abstract : New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.
ESTHER : Holladay_1998_J.Med.Chem_41_407
PubMedSearch : Holladay_1998_J.Med.Chem_41_407
PubMedID: 9484491

Title : Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors - Bannon_1998_Science_279_77
Author(s) : Bannon AW , Decker MW , Holladay MW , Curzon P , Donnelly-Roberts D , Puttfarcken PS , Bitner RS , Diaz A , Dickenson AH , Porsolt RD , Williams M , Arneric SP
Ref : Science , 279 :77 , 1998
Abstract : Development of analgesic agents for the treatment of severe pain requires the identification of compounds that are devoid of opioid receptor liabilities. A potent (inhibition constant = 37 picomolar) neuronal nicotinic acetylcholine receptor (nAChR) ligand called ABT-594 was developed that has antinociceptive properties equal in efficacy to those of morphine across a series of diverse animal models of acute thermal, persistent chemical, and neuropathic pain states. These effects were blocked by the nAChR antagonist mecamylamine. In contrast to morphine, repeated treatment with ABT-594 did not appear to elicit opioid-like withdrawal or physical dependence. Thus, ABT-594 may be an analgesic that lacks the problems associated with opioid analgesia.
ESTHER : Bannon_1998_Science_279_77
PubMedSearch : Bannon_1998_Science_279_77
PubMedID: 9417028

Title : The role of neuronal nicotinic acetylcholine receptors in antinociception: effects of ABT-594 - Decker_1998_J.Physiol.Paris_92_221
Author(s) : Decker MW , Curzon P , Holladay MW , Nikkel AL , Bitner RS , Bannon AW , Donnelly-Roberts D , Puttfarcken PS , Kuntzweiler TA , Briggs CA , Williams M , Arneric SP
Ref : Journal de Physiologie (Paris) , 92 :221 , 1998
Abstract : ABT-594, a nicotinic acetylcholine receptor agonist, has antinociceptive effects in rat models of acute thermal, persistent chemical, and neuropathic pain. Direct injection of ABT-594 into the nucleus raphe magnus (NRM) is antinociceptive in a thermal threshold test and destruction of serotonergic neurons in the NRM attenuates the effect of systemic ABT-594. However, lidocaine-inactivation of the NRM prevents the antinociceptive effect of systemic (-)-nicotine but not that of systemic ABT-594.
ESTHER : Decker_1998_J.Physiol.Paris_92_221
PubMedSearch : Decker_1998_J.Physiol.Paris_92_221
PubMedID: 9789812

Title : ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization - Donnelly-Roberts_1998_J.Pharmacol.Exp.Ther_285_777
Author(s) : Donnelly-Roberts D , Puttfarcken PS , Kuntzweiler TA , Briggs CA , Anderson DJ , Campbell JE , Piattoni-Kaplan M , McKenna DG , Wasicak JT , Holladay MW , Williams M , Arneric SP
Ref : Journal of Pharmacology & Experimental Therapeutics , 285 :777 , 1998
Abstract : The discovery of (+/-)-epibatidine, a naturally occurring neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity 200-fold more potent than that of morphine, has renewed interest in the potential role of nAChRs in pain processing. However, (+/-)-epibatidine has significant side-effect liabilities associated with potent activity at the ganglionic and neuromuscular junction nAChR subtypes which limit its potential as a clinical entity. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine] is a novel, potent cholinergic nAChR ligand with analgesic properties (see accompanying paper by Bannon et al., 1998b) that shows preferential selectivity for neuronal nAChRs and a consequently improved in vivo side-effect profile compared with (+/-)-epibatidine. ABT-594 is a potent inhibitor of the binding of [3H](-)-cytisine to alpha 4 beta 2 neuronal nAChRs (Ki = 37 pM, rat brain; Ki = 55 pM, transfected human receptor). At the alpha 1 beta 1 delta gamma neuromuscular nAChR labeled by [125I] alpha-bungarotoxin (alpha-Btx), ABT-594 has a Ki value of 10,000 nM resulting in a greater than 180,000-fold selectivity of the compound for the neuronal alpha 4 beta 2 nAChR. In contrast, (+/-)-epibatidine has Ki values of 70 pM and 2.7 nM at the alpha 4 beta 2 and alpha 1 beta 1 delta gamma nAChRs, respectively, giving a selectivity of only 38-fold. The S-enantiomer of ABT-594, A-98593 has activity at the neuronal alpha 4 beta 2 nAChR identical with ABT-594 (Ki = 34-39 pM), which demonstrates a lack of stereospecific binding similar to that reported previously for (+/-)-epibatidine. A similar lack of stereoselectivity is seen at the human alpha 7 receptor. However, A-98593 is 3-fold more potent at the neuromuscular nAChR (Ki = 3420 nM) and the brain alpha-Btx-sensitive nAChR (Ki = 4620 nM) than ABT-594. ABT-594 has weak affinity in binding assays for adrenoreceptor subtypes alpha-1B (Ki = 890 nM), alpha-2B (Ki = 597 nM) and alpha-2C (Ki = 342 nM), and it has negligible affinity (Ki > 1000 nM) for approximately 70 other receptors, enzyme and transporter binding sites. Functionally, ABT-594 is an agonist. At the transfected human alpha 4 beta 2 neuronal nAChR (K177 cells), with increased 86Rb+ efflux as a measure of cation efflux, ABT-594 had an EC50 value of 140 nM with an intrinsic activity (IA) compared with (-)-nicotine of 130%; at the nAChR subtype expressed in IMR-32 cells (sympathetic ganglion-like), an EC50 of 340 nM (IA = 126%); at the F11 dorsal root ganglion cell line (sensory ganglion-like), an EC50 of 1220 nM (IA = 71%); and via direct measurement of ion currents, an EC50 value of 56,000 nM (IA = 83%) at the human alpha 7 homooligimeric nAChR produced in oocytes. A-98593 is 2- to 3-fold more potent and displays approximately 50% greater intrinsic activity than ABT-594 in all four functional assays. In terms of potency, ABT-594 is 8- to 64-fold less active than (+/-)-epibatidine and also has less IA in these functional assays. ABT-594 (30 microM) inhibits the release of calcitonin gene-related peptide from C-fibers terminating in the dorsal horn of the spinal cord, an effect mediated via nAChRs. Pharmacologically, ABT-594 has an in vitro profile distinct from that of the prototypic nicotinic analgesic (+/-)-epibatidine, with the potential for substantially reduced side-effect liability and, as such, represents a potentially novel therapeutic approach to pain management.
ESTHER : Donnelly-Roberts_1998_J.Pharmacol.Exp.Ther_285_777
PubMedSearch : Donnelly-Roberts_1998_J.Pharmacol.Exp.Ther_285_777
PubMedID: 9580626

Title : ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective antinociceptive agent acting via neuronal nicotinic acetylcholine receptors: II. In vivo characterization - Bannon_1998_J.Pharmacol.Exp.Ther_285_787
Author(s) : Bannon AW , Decker MW , Curzon P , Buckley MJ , Kim DJ , Radek RJ , Lynch JK , Wasicak JT , Lin NH , Arnold WH , Holladay MW , Williams M , Arneric SP
Ref : Journal of Pharmacology & Experimental Therapeutics , 285 :787 , 1998
Abstract : The antinociceptive effects of ABT-594, a novel nicotinic acetylcholine receptor (nAChR) ligand, were examined in rats in models of acute thermal (hot box) and persistent chemical (formalin test) pain. Also, the effects of ABT-594 treatment on motor function and electroencephalogram (EEG) were determined. In the hot box and formalin test (i.e., phase 1 and 2), acute treatment with ABT-594 (0.03, 0.1 and 0.3 mumol/kg i.p.) produced significant dose-dependent antinociceptive effects. In the hot box, the efficacy of ABT-594 was maintained after a repeated dosing paradigm (5 days b.i.d.i.p.). ABT-594 was fully efficacious in the formalin test when administered before formalin, and also retained significant efficacy (0.3 mumol/kg i.p.) when administered after formalin injection. The antinociceptive effects of ABT-594 in the hot box and formalin tests were attenuated by pretreatment with the nAChR antagonist, mecamylamine, and in animals treated with the nAChR antagonist chlorisondamine, given centrally (10 micrograms/rat i.c.v. 5 days before), but not in animals pretreated with the opioid receptor antagonist, naltrexone. Acute treatment with ABT-594 produced an initial decrease in open-field locomotor activity, which was absent in animals dosed repeatedly (5 days b.i.d.) with ABT-594. Also, acute treatment with ABT-594 decreased body temperature and decreased the amount of time the animals could maintain balance in an edge-balance test. These effects were no longer present in animals dosed repeatedly with ABT-594. At antinociceptive doses, ABT-594 produced activation of free running EEG in contrast to the sedative-like effects of morphine. Full antinociceptive efficacy was maintained in both the hot box and formalin tests after oral administration, whereas the effects on motoric performance were attenuated. In conclusion, these data demonstrate that ABT-594 is a potent antinociceptive agent with full efficacy in models of acute and persistent pain and that these effects are mediated predominately by an action at central neuronal nAChRs. In addition, antinociceptive effects were maintained after repeated dosing, whereas effects of ABT-594 on motor and temperature measures were attenuated in animals treated repeatedly with ABT-594. Thus, compounds acting at nAChRs may represent a novel approach for the treatment of a variety of pain states.
ESTHER : Bannon_1998_J.Pharmacol.Exp.Ther_285_787
PubMedSearch : Bannon_1998_J.Pharmacol.Exp.Ther_285_787
PubMedID: 9580627

Title : ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties - Sullivan_1997_J.Pharmacol.Exp.Ther_283_235
Author(s) : Sullivan JP , Donnelly-Roberts D , Briggs CA , Anderson DJ , Gopalakrishnan M , Xue IC , Piattoni-Kaplan M , Molinari E , Campbell JE , McKenna DG , Gunn DE , Lin NH , Ryther KB , He Y , Holladay MW , Wonnacott S , Williams M , Arneric SP
Ref : Journal of Pharmacology & Experimental Therapeutics , 283 :235 , 1997
Abstract : Accumulating preclinical and clinical evidence data suggests that compounds that selectively activate neuronal nicotinic acetylcholine receptor (nAChR) subtypes may have therapeutic utility for the treatment of several neurological disorders. In the present study, the in vitro pharmacological properties of the novel cholinergic channel modulator ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine], are described. In radioligand binding studies, ABT-089 was shown to display selectivity toward the high-affinity (-)-cytisine binding site present on the alpha4beta2 nAChR subtype (Ki = 16 nM) relative to the [125I]alpha-bungarotoxin binding site present on the alpha7 (Ki > or = 10,000 nM) and alpha1beta1deltagamma (Ki > 1000 nM) nAChR subtypes. In cation flux and channel current studies, ABT-089 displayed a more complex profile than (-)-nicotine having agonist, partial agonist and inhibitory activities depending on the nAChR subtype with which it interacts. ABT-089 differentially stimulated neurotransmitter release. The compound displayed a similar potency and efficacy to (-)-nicotine to facilitate ACh release (ABT-089, EC50 = 3 microM; (-)-nicotine, EC50 = 1 microM), but was markedly less potent and less efficacious than (-)-nicotine to stimulate dopamine release (ABT-089, EC50 = 1.1 microM; (-)-nicotine, EC50 = 0.04 microM). Additionally, ABT-089 was neuroprotective against the excitotoxic insults elicited by exposure to glutamate in both rat cortical cell cultures (EC50 = 10 +/- 3 microM) and differentiated human IMR32 cells (EC50 = 3 +/- 2 microM). The differential full agonist/partial agonist profile of ABT-089, as compared with (-)-nicotine and ABT-418, illustrates the complexity of nAChR activation and the potential to target responses at subclasses of the neuronal and peripheral receptors.
ESTHER : Sullivan_1997_J.Pharmacol.Exp.Ther_283_235
PubMedSearch : Sullivan_1997_J.Pharmacol.Exp.Ther_283_235
PubMedID: 9336329

Title : Structure-activity studies on 2-methyl-3-(2(S)-pyrrolidinylmethoxy) pyridine (ABT-089): an orally bioavailable 3-pyridyl ether nicotinic acetylcholine receptor ligand with cognition-enhancing properties - Lin_1997_J.Med.Chem_40_385
Author(s) : Lin NH , Gunn DE , Ryther KB , Garvey DS , Donnelly-Roberts D , Decker MW , Brioni JD , Buckley MJ , Rodrigues AD , Marsh KG , Anderson DJ , Buccafusco JJ , Prendergast MA , Sullivan JP , Williams M , Arneric SP , Holladay MW
Ref : Journal of Medicinal Chemistry , 40 :385 , 1997
Abstract : 2-Methyl-3-(2(S)-pyrrolidinylmethoxy)pyridine, ABT-089 (S-4), a member of the 3-pyridyl ether class of nicotinic acetylcholine receptor (nAChR) ligands, shows positive effects in rodent and primate models of cognitive enhancement and a rodent model of anxiolytic activity and possesses a reduced propensity to activate peripheral ganglionic type receptors. The profiles of S-4, its N-methyl analogue, and the corresponding enantiomers across several measures of cholinergic channel function in vitro and in vivo are presented, together with in vitro metabolism and in vivo bioavailability data. On the basis of its biological activities and favorable oral bioavailability, S-4 is an attractive candidate for further evaluation as a treatment for cognitive disorders.
ESTHER : Lin_1997_J.Med.Chem_40_385
PubMedSearch : Lin_1997_J.Med.Chem_40_385
PubMedID: 9022806

Title : Novel 3-Pyridyl ethers with subnanomolar affinity for central neuronal nicotinic acetylcholine receptors - Abreo_1996_J.Med.Chem_39_817
Author(s) : Abreo MA , Lin NH , Garvey DS , Gunn DE , Hettinger AM , Wasicak JT , Pavlik PA , Martin YC , Donnelly-Roberts D , Anderson DJ , Sullivan JP , Williams M , Arneric SP , Holladay MW
Ref : Journal of Medicinal Chemistry , 39 :817 , 1996
Abstract : Recent evidence indicating the therapeutic potential of cholinergic channel modulators for the treatment of central nervous system (CNS) disorders as well as the diversity of brain neuronal nicotine acetylcholine receptors (nAChRs) have suggested an opportunity to develop subtype-selective nAChR ligands for the treatment of specific CNS disorders with reduced side effect liabilities. We report a novel series of 3-pyridyl ether compounds which possess subnanomolar affinity for brain nAChRs and differentially activate subtypes of neuronal nAChRs. The synthesis and structure-activity relationships for the leading members of the series are described, including A-85380 (4a), which possesses ca.50 pM affinity for rat brain [(3)H]-(-)-cytisine binding sites and 163% efficacy compared to nicotine to stimulate ion flux at human alpha4beta2 nAChR subtype, and A-84543 (2a), which exhibits 84-fold selectivity to stimulate ion flux at human alpha4beta2 nAchR subtype compared to human ganglionic type nAChRs. Computational studies indicate that a reasonable superposition of a low energy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.
ESTHER : Abreo_1996_J.Med.Chem_39_817
PubMedSearch : Abreo_1996_J.Med.Chem_39_817
PubMedID: 8632405

Title : A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand - Sullivan_1996_Neuropharmacol_35_725
Author(s) : Sullivan JP , Donnelly-Roberts D , Briggs CA , Anderson DJ , Gopalakrishnan M , Piattoni-Kaplan M , Campbell JE , McKenna DG , Molinari E , Hettinger AM , Garvey DS , Wasicak JT , Holladay MW , Williams M , Arneric SP
Ref : Neuropharmacology , 35 :725 , 1996
Abstract : The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2(S)-azetidinylmethoxy)pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM). The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM). (+)- and(-)-Epibatidine display similar potencies at the human human alpha 4 beta 2 (Ki = 0.04 +/- 0.02 nM and 0.07 +/- 0.02 nM, respectively), human alpha 7 (Ki = 16 +/- 2 nM and 22 +/- 3 nM, respectively) and muscle alpha 1 beta 1 delta gamma g (Ki = 2.5 +/- 0.9 nM and 5.7 +/- 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human alpha 4 beta 2 (EC50 = 0.7 +/- 0.1 microM) and ganglionic (EC50 = 0.8 +/- 0.09 microM) subtypes, effects that are attenuated by pretreatment with mecamylamine (10 microM). Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (-)-nicotine but less potent than (+/-)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine with an EC 50 value of 0.003 +/- 0.001 microM which is equipotent to (+/-)-epibatidine, and 20-fold more potent than (-)-nicotine (EC50 = 0.04 +/- 0.009 microM). Thus, A-85380 displays a profile of robust activation of a number of nAChR subtypes with substantially less affinity for [125I] alpha-BgT sites than [3H](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the alpha 4 beta 2 subtype relative to the alpha 7 and alpha 1 beta 1 delta g nAChRs than (+/-)-epibatidine.
ESTHER : Sullivan_1996_Neuropharmacol_35_725
PubMedSearch : Sullivan_1996_Neuropharmacol_35_725
PubMedID: 8887981

Title : Cholinergic channel activators: novel opportunities for the treatment of CNS disorders - Sullivan_1995_Proc.West.Pharmacol.Soc_38_127
Author(s) : Sullivan JP , Decker MW , Donnelly-Roberts D , Brioni JD , Bannon AW , Holladay MW , Anderson DJ , Briggs CA , Williams M , Arneric SP
Ref : Proc West Pharmacol Soc , 38 :127 , 1995
Abstract : Negative connotations associated with the use of (-)-nicotine has limited medicinal chemistry research in the area of nAChRs [5]. However, recent evidence suggests that a diversity of nAChR subunits exist, that each subtype may be involved in mediating specific neurochemical/behaviors, and that these subtypes have a defined pharmacology that may be selectively targeted [1]. (+/-)-Epibatidine, GTS-21 and ABT-418 differentially interact with nAChR subtypes to elicit a diversity of behavioral effects including analgesia, neuroprotection and cognitive enhancement. These agents therefore represent important new pharmacological probes to dissect the nAChR subtype(s) mediating specific pharmacological responses to nAChR activation.
ESTHER : Sullivan_1995_Proc.West.Pharmacol.Soc_38_127
PubMedSearch : Sullivan_1995_Proc.West.Pharmacol.Soc_38_127
PubMedID: 7480004

Title : Potential treatment of Alzheimer disease using cholinergic channel activators (ChCAs) with cognitive enhancement, anxiolytic-like, and cytoprotective properties - Arneric_1995_Alzheimer.Dis.Assoc.Disord_9 Suppl 2_50
Author(s) : Arneric SP , Sullivan JP , Decker MW , Brioni JD , Bannon AW , Briggs CA , Donnelly-Roberts D , Radek RJ , Marsh KC , Kyncl J , Williams M , Buccafusco JJ
Ref : Alzheimer Disease & Associated Disorders , 9 Suppl 2 :50 , 1995
Abstract : Compounds that activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer disease (AD). This article summarizes the preclinical pharmacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole], a novel analog of (-)-nicotine that is being clinically evaluated for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine [Arneric SP, Sullivan JP, Briggs CA, et al. (S)-3-Methyl-5-(1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition enhancing and anxiolytic activity. I. In vitro activity. J Pharmacol Exp Ther 1994 ;270:310-318; Decker MW, Brioni JD, Sullivan JP, et al. (S)-3-Methyl-5-( 1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 1994a;270:319-328; Decker MW, Curzon P, B rioni JD, Arne ric SP. Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats. Eur J Pharmacol 1994;261:217-222; Garvey DS, Wasicak JT, Decker MW, et al. Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 1994;37:1055-1059]. ABT-418 may be the first agonist of nAChRs to be developed and evaluated specifically for the treatment of AD. Some brief speculation will be given on the potential benefits that this or other ChCAs may have in treating neurodegenerative disorders as compared with (-)-nicotine, and how this differs from other potential treatment approaches.
ESTHER : Arneric_1995_Alzheimer.Dis.Assoc.Disord_9 Suppl 2_50
PubMedSearch : Arneric_1995_Alzheimer.Dis.Assoc.Disord_9 Suppl 2_50
PubMedID: 8534424

Title : Characterization of [3H]ABT-418: a novel cholinergic channel ligand - Anderson_1995_J.Pharmacol.Exp.Ther_273_1434
Author(s) : Anderson DJ , Williams M , Pauly JR , Raszkiewicz JL , Campbell JE , Rotert G , Surber B , Thomas SB , Wasicak J , Arneric SP
Ref : Journal of Pharmacology & Experimental Therapeutics , 273 :1434 , 1995
Abstract : ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent and selective agonist at neuronal nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing and anxiolytic activities. [3H]ABT-418 was found to bind with high affinity (KD = 2.85 +/- 0.14 nM) to membranes prepared from rat brain. Binding of [3H]ABT-418 was characterized by rapid association (T1/2 = 1.4 +/- 0.3 min) and dissociation (T1/2 = 2.9 +/- 0.4 min) half-times. The pharmacology of [3H]ABT-418 binding was consistent with an interaction with the putative alpha 4 beta 2 nAChR subtype. The nAChR agonists, (-)-nicotine, (-)-cytisine and (+/-)-epibatidine, displayed a high affinity (Ki = 0.8 +/- 0.1, 0.2 +/- 0.1 and 0.05 +/- 0.01 nM, respectively) for [3H]ABT-418 binding sites, whereas among nAChR antagonists examined, only dihydro-beta-erythroidine competed with high affinity (Ki = 32 +/- 1.5 nM). Although autoradiography studies indicate that the binding distribution of [3H]ABT-418 and (-)-[3H]cytisine are largely identical, there are some brain regions including the striatum, olivary pretectal nucleus and the superior colliculus, in which [3H]ABT-418 demonstrates significantly (P < .05) less binding. The data in the present study demonstrate that [3H]ABT-418 binds with high affinity to a population of binding sites in the rat brain that have the pharmacological characteristics of neuronal nAChRs. [3H]ABT-418 may, therefore, serve as a useful radioligand to further probe the observed differences in pharmacological properties between ABT-418 and other nicotinic agonists in vivo.
ESTHER : Anderson_1995_J.Pharmacol.Exp.Ther_273_1434
PubMedSearch : Anderson_1995_J.Pharmacol.Exp.Ther_273_1434
PubMedID: 7791118

Title : Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities -
Author(s) : Garvey DS , Wasicak JT , Decker MW , Brioni JD , Buckley MJ , Sullivan JP , Carrera GM , Holladay MW , Arneric SP , Williams M
Ref : Journal of Medicinal Chemistry , 37 :1055 , 1994
PubMedID: 7909335

Title : Muscarinic, benzodiazepine, GABA, chloride channel and other binding sites in frontal cortex in hepatic coma in man - Lal_1987_Prog.Neuropsychopharmacol.Biol.Psychiatry_11_243
Author(s) : Lal S , Quirion R , Lafaille F , Nair NP , Loo P , Braunwalder A , Wood P , Williams M
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 11 :243 , 1987
Abstract : Alterations in several neurotransmitter systems in brain have been implicated in the pathophysiology of hepatic coma (HC). Studies on human autopsy material are few. We investigated 3H-quinuclidinylbenzilate (QNB), 3H-spiperone, 3H-imipramine, 3H-PN-200-110, 3naloxone, 3H-flunitrazepam, 3H-muscimol, 35S-t-butylbicyclophosphothionate and 3H-cyclohexyladenosine binding sites in frontal cortex from seven patients with HC and five controls. The density of 3H-QNB binding sites was significantly decreased and the affinity slightly increased in HC. The functional significance of these selective changes in muscarinic receptor binding sites is unclear. Further studies evaluating cholinergic function in HC are indicated. Acute studies in animals point to an increase in GABA and BZ binding sites in HC. The present results show that the BZ/GABA-receptor-chloride-ionophore complex is unchanged in HC in man. Serotonergic (5HT-2), adenosine (A-1), imipramine (5HT uptake sites), opiate (naloxone) and calcium channel antagonist binding sites are unchanged in HC.
ESTHER : Lal_1987_Prog.Neuropsychopharmacol.Biol.Psychiatry_11_243
PubMedSearch : Lal_1987_Prog.Neuropsychopharmacol.Biol.Psychiatry_11_243
PubMedID: 2442800

Title : Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue - Williams_1984_J.Neurosci_4_2906
Author(s) : Williams M , Robinson JL
Ref : Journal of Neuroscience , 4 :2906 , 1984
Abstract : The nicotinic cholinergic antagonist, dihydro-beta-erythroidine, binds to two sites in rat cortical membranes with dissociation constants of 4 and 22 nM and respective apparent Bmax values of 52 and 164 fmol/mg of protein. Binding to the higher affinity site, defined by the use of 2 nM [3H]dihydro-beta-erythroidine, was saturable, reversible, and susceptible to protein denaturation. Binding was highest in the thalamus and lowest in the spinal cord and showed preferential enrichment in a synaptosomal subfraction of rat brain. Nicotine displaced [3H]dihydro-beta-erythroidine in a stereospecific manner, the (-)-isomer being approximately 6 times more potent than the (+)-isomer. The alkaloid nicotinic agonists, cytisine and lobeline, were potent inhibitors of binding, while acetylcholine in the presence of the cholinesterase inhibitor di-isopropylfluorophosphate was equipotent with (+)-nicotine. Binding was also inhibited by the muscarinic ligands, arecoline, atropine, and oxotremorine. The nicotinic antagonists mecamylamine, hexamethonium, and pempidine were essentially inactive in displacing [3H]dihydro-beta-erythroidine. These findings indicate that dihydro-beta-erythroidine binds to a nicotinic recognition site in rat brain which is neuromuscular, rather than ganglionic, in nature and that such binding is similar in several respects to that seen with nicotinic agonists. Whether such binding is to a nicotinic, as opposed to nicotinic cholinergic, recognition site or to a "common" nicotinic/muscarinic site is an issue that requires further study.
ESTHER : Williams_1984_J.Neurosci_4_2906
PubMedSearch : Williams_1984_J.Neurosci_4_2906
PubMedID: 6502210

Title : Nicotinic receptors in mammalian brain - Williams_1984_Prog.Neuropsychopharmacol.Biol.Psychiatry_8_769
Author(s) : Williams M , Robinson JL
Ref : Prog Neuropsychopharmacol Biological Psychiatry , 8 :769 , 1984
Abstract : Nicotine has marked effects on CNS function increasing brain excitability and spontaneous activity and also has antinociceptive actions. Agonist radioligands for the nicotinic cholinergic receptor bind with high affinity in a saturable manner. Binding is however, insensitive to the ganglionic blockers, hexamethonium and mecamylamine. This suggests that agonists and antagonists bind to different sites on the receptor or that the nicotinic receptor in brain is different from that found in peripheral tissues. The nicotinic antagonist, dihydro-beta-erythroidine binds with high affinity (Kd = 4 nM) to rat brain membranes in a stereospecific, saturable, manner with a regional distribution similar to that seen with radiolabeled acetylcholine. Binding is insensitive to hexamethonium and mecamylamine. It is concluded that the nicotinic recognition sites to which dihydro-beta-erythroidine binds are neuromuscular rather than ganglionic in nature.
ESTHER : Williams_1984_Prog.Neuropsychopharmacol.Biol.Psychiatry_8_769
PubMedSearch : Williams_1984_Prog.Neuropsychopharmacol.Biol.Psychiatry_8_769
PubMedID: 6531449

Title : 2-chloroadenosine inhibits brain acetylcholine turnover in vivo -
Author(s) : Haubrich DR , Williams M , Yarbrough GG , Wood PL
Ref : Canadian Journal of Physiology & Pharmacology , 59 :1196 , 1981
PubMedID: 7317844

Title : Enhancement of the binding of 3H-diazepam to rat brain membranes in vitro by SQ 20009, A novel anxiolytic, gamma-aminobutyric acid (GABA) and muscimol -
Author(s) : Williams M , Risley EA
Ref : Life Sciences , 24 :833 , 1979
PubMedID: 449623