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https://www.readbyqxmd.com/read/29777683/probing-the-binding-site-of-novel-selective-positive-allosteric-modulators-at-the-m-1-machr
#1
Elham Khajehali, Celine Valant, Manuela Jörg, Andrew B Tobin, P Jeffrey Conn, Craig W Lindsley, Patrick M Sexton, Peter J Scammells, Arthur Christopoulos
Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one)...
May 16, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29757524/mosquito-diptera-culicidae-grouping-based-on-larval-habitat-characteristics-in-high-mountain-ecosystems-of-antioquia-colombia
#2
Doris Rosero-García, Guillermo Rúa-Uribe, Margarita M Correa, Jan E Conn, Sandra Uribe-Soto
Information about mosquito ecology in the high mountain ecosystems of the Neotropical region is sparse. In general, few genera and species have been reported in these ecosystems and there is no information available on habitats and the mosquitoes occupying them. In the present study, specimens collected from NW Colombia in HME were grouped using larval habitat data via an Operational Taxonomic Unit (OTU) determination. A total of 719 mosquitoes was analyzed belonging to 44 OTUs. The analysis considered habitat features and clustered the specimens into six groups from A-F...
June 2018: Journal of Vector Ecology: Journal of the Society for Vector Ecology
https://www.readbyqxmd.com/read/29754948/the-discovery-of-vu0486846-steep-sar-from-a-series-of-m-1-pams-based-on-a-novel-benzomorpholine-core
#3
Jeanette L Bertron, Hyekyung P Cho, Pedro M Garcia-Barrantes, Joseph D Panarese, James M Salovich, Kellie D Nance, Darren W Engers, Jerri M Rook, Anna L Blobaum, Colleen M Niswender, Shaun R Stauffer, P Jeffrey Conn, Craig W Lindsley
This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties)...
May 5, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29751152/the-use-of-telemedicine-for-penicillin-allergy-skin-testing
#4
Mary L Staicu, Anne Marie Holly, Kelly M Conn, Allison Ramsey
BACKGROUND: Penicillin skin testing (PST) is increasingly utilized as a tool to evaluate penicillin allergy in patients with a reported history. The limited availability of allergists, however, may be an impeding factor. OBJECTIVE: We sought to assess the clinical utility of telemedicine to facilitate PST. METHODS: Penicillin allergic inpatients receiving systemic antibiotics were prospectively identified between April and August 2017. Qualifying patients underwent PST performed by a trained Allergy/Immunology physician assistant (PA)...
May 8, 2018: Journal of Allergy and Clinical Immunology in Practice
https://www.readbyqxmd.com/read/29750858/a-mof-with-cooperative-phosphines-that-permits-post-synthetic-installation-of-open-metal-sites
#5
Samuel G Dunning, Gianne Nandra, Adam D Conn, Wenrui Chai, R Eric Sikma, Ji-Sung Lee, Pranaw Kunal, Joseph E Reynolds Iii, Jong-San Chang, Alexander Steiner, Graeme Henkelman, Simon Michael Humphrey
PCM-101 is a new phosphine coordination material comprised of tris(p-carboxylato)triphenylphosphine and secondary pillaring groups coordinated to [M3(OH)]5+ nodes (M = Co, Ni). PCM-101 has a unique topology in which R3P: sites are arranged directly trans- to one another, with a P···P separation distance dictated by the pillars. Post-synthetic coordination of soft metals to the P: sites proceeds at room temperature to provide X-ray quality crystals that permit full structural resolution. Addition of AuCl groups forces a large distortion of the parent framework...
May 11, 2018: Angewandte Chemie
https://www.readbyqxmd.com/read/29743331/what-is-the-quality-of-reporting-on-guideline-protocol-or-algorithm-implementation-in-adult-trauma-centres-protocol-for-a-systematic-review
#6
Lesley Gotlib Conn, Avery B Nathens, Laure Perrier, Barbara Haas, Aaron Watamaniuk, Diego Daniel Pereira, Ashley Zwaiman, Luis Teodoro da Luz
INTRODUCTION: Quality improvement (QI) is mandatory in trauma centres but there is no prescription for doing successful QI. Considerable variation in implementation strategies and inconsistent use of evidence-based protocols therefore exist across centres. The quality of reporting on these strategies may limit the transferability of successful initiatives across centres. This systematic review will assess the quality of reporting on guideline, protocol or algorithm implementation within a trauma centre in terms of the Revised Standards for Quality Improvement Reporting Excellence (SQUIRE 2...
May 9, 2018: BMJ Open
https://www.readbyqxmd.com/read/29737955/comparison-of-two-neutral-oral-contrast-agents-in-pediatric-patients-a-prospective-randomized-study
#7
Jonathan R Dillman, Alexander J Towbin, Rebecca Imbus, Julie Young, Erica Gates, Andrew T Trout
Purpose To prospectively compare small bowel distention provided by, as well as patient acceptance of, two different neutral (negative) oral contrast materials used for cross-sectional enterography in a pediatric population. Materials and Methods In this noninferiority study, 66 pediatric patients undergoing clinical computed tomographic (CT) or magnetic resonance (MR) enterography were randomized to receive either a flavored beverage for neutral abdominal and pelvic imaging (Breeza; Beekley Medical, Bristol, Conn) or a low-density barium sulfate suspension...
May 8, 2018: Radiology
https://www.readbyqxmd.com/read/29735612/signal-detection-for-bleeding-associated-with-the-use-of-direct-oral-anticoagulants
#8
Kobi T Nathan, Kelly M Conn, Robbert P van Manen, Jack E Brown
PURPOSE: The potential link between serious or life-threatening bleeding and the use of direct oral anticoagulants (DOACs) was evaluated. METHODS: Qualitative and quantitative reviews of case reports of bleeding events involving dabigatran, rivaroxaban, apixaban, edoxaban, and warfarin through March 31, 2017, were performed. A disproportionality analysis was conducted for each DOAC using an empirical Bayesian approach based on the relative reporting rate. Subanalyses were performed to assess (1) bleeding events (including mortality and life-threatening events) associated with DOACs among all adverse-event reports and (2) warfarin-related bleeding events...
May 7, 2018: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/29735571/don-t-go-in-circles-confounding-factors-in-gene-expression-profiling
#9
John Toubia, Vanessa M Conn, Simon J Conn
No abstract text is available yet for this article.
May 7, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29728637/abundance-of-impacted-forest-patches-less-than-5-km-2-is-a-key-driver-of-the-incidence-of-malaria-in-amazonian-brazil
#10
Leonardo Suveges Moreira Chaves, Jan E Conn, Rossana Verónica Mendoza López, Maria Anice Mureb Sallum
The precise role that deforestation for agricultural settlements and commercial forest products plays in promoting or inhibiting malaria incidence in Amazonian Brazil is controversial. Using publically available databases, we analyzed temporal malaria incidence (2009-2015) in municipalities of nine Amazonian states in relation to ecologically defined variables: (i) deforestation (rate of forest clearing over time); (ii) degraded forest (degree of human disturbance and openness of forest canopy for logging) and (iii) impacted forest (sum of deforested and degraded forest patches)...
May 4, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29725854/metastasising-pleomorphic-salivary-adenoma-a-rare-case-report-of-a-massive-untreated-minor-salivary-gland-pleomorphic-adenoma-with-concurrent-ipsilateral-cervical-node-metastases
#11
Melanie Watson, Peter McAllister, Brendan Conn, Morna MacNeill, Thomas P B Handley
Salivary gland tumours constitute approximately 1-5% of all human neoplasms. Pleomorphic adenoma (PA) is the commonest benign neoplasm affecting the parotid gland most often (> 75%), followed by the submandibular gland (13%), then the palate (9%). Metastasising pleomorphic adenoma (MPA) is extremely rare. The effects can be severe and a reported 40% of MPA patients die with disease. This case represents the first known case in English literature of an untreated minor salivary gland PSA of the palate metastasising to an ipsilateral cervical node...
May 3, 2018: Head and Neck Pathology
https://www.readbyqxmd.com/read/29720449/development-of-a-stress-response-therapy-targeting-aggressive-prostate-cancer
#12
Hao G Nguyen, Crystal S Conn, Yae Kye, Lingru Xue, Craig M Forester, Janet E Cowan, Andrew C Hsieh, John T Cunningham, Charles Truillet, Feven Tameire, Michael J Evans, Christopher P Evans, Joy C Yang, Byron Hann, Constantinos Koumenis, Peter Walter, Peter R Carroll, Davide Ruggero
Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown...
May 2, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29705142/discovery-of-6-pyrimidin-5-ylmethyl-quinoline-8-carboxamide-negative-allosteric-modulators-of-metabotropic-glutamate-receptor-subtype-5
#13
Andrew S Felts, Alice L Rodriguez, Ryan D Morrison, Anna L Blobaum, Frank W Byers, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Kyle A Emmitte
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors...
April 22, 2018: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29701957/a-novel-m1-pam-vu0486846-exerts-efficacy-in-cognition-models-without-displaying-agonist-activity-or-cholinergic-toxicity
#14
Jerri M Rook, Jeanette L Bertron, Hyekyung P Cho, Pedro M Garcia-Barrantes, Sean P Moran, James T Maksymetz, Kellie D Nance, Jonathan W Dickerson, Daniel H Remke, Sichen Chang, Joel Harp, Anna L Blobaum, Colleen M Niswender, Carrie K Jones, Shaun R Stauffer, P Jeffrey Conn, Craig W Lindsley
Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impairs cognitive function, induces behavioral convulsions, and results in other classic cholinergic adverse events (AEs)...
April 27, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29694676/prediction-of-fractures-in-men-using-bone-microarchitectural-parameters-assessed-by-high-resolution-peripheral-quantitative-computed-tomography-the-prospective-strambo-study
#15
Pawel Szulc, Stéphanie Boutroy, Roland Chapurlat
Areal bone mineral density (aBMD) poorly identifies men at high fracture risk. Our aim was to assess prediction of fractures in men by bone microarchitectural measures. At baseline, 825 men aged 60-87 had the assessment of bone microarchitecture at distal radius and distal tibia by high resolution peripheral QCT (HR-pQCT, XtremeCT-I SCANCO). Bone strength was estimated by micro-finite element analysis. During the prospective 8-year follow-up, 105 men sustained fractures (59 vertebral fractures in 49 men, 70 non-vertebral ones in 68 men)...
April 25, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29689319/experiences-of-young-adults-with-type-1-diabetes-while-using-alcohol-and-recreational-drugs-an-interpretative-phenomenological-analysis-ipa-of-semi-structured-interviews
#16
Adam Pastor, Casey L O'Brien, Jessie Teng, Jennifer Conn, Margaret Loh, Lisa Collins, Richard MacIsaac, Yvonne Bonomo
AIMS: Alcohol and recreational drug use is common in young adults with type 1 diabetes (T1DM) and may account for increased morbidity and mortality. This study explores the motivations and experiences unique to this population while using alcohol and recreational drugs. METHODS: Semi-structured interviews focusing on substance use were performed with 16 young adults aged 18-35 with T1DM who drink alcohol (at least 50 grams, 5 Australian standard drinks, in a single session) and/or used recreational drugs...
April 21, 2018: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/29683647/structure-activity-relationships-of-pan-g%C3%AE-q-11-coupled-muscarinic-acetylcholine-receptor-positive-allosteric-modulators
#17
Alice Berizzi, Aaron M Bender, Craig W Lindsley, P Jeffrey Conn, Patrick M Sexton, Christopher Langmead, Arthur Christopoulos
Recent years have seen a large increase in the discovery of allosteric ligands targeting muscarinic acetylcholine receptors (mAChRs). One of the challenges in screening such compounds is to understand their mechanisms of action and define appropriate parameter estimates for affinity, cooperativity and efficacy. Herein we describe the mechanisms of action and structure-activity relationships for a series of "pan-Gq-coupled" muscarinic acetylcholine (ACh) receptor (mAChR) positive allosteric modulators (PAMs)...
April 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29683646/pf-06827443-displays-robust-allosteric-agonist-and-positive-allosteric-modulator-activity-in-high-receptor-reserve-and-native-systems
#18
Sean P Moran, Hyekyung P Cho, James Maksymetz, Daniel H Remke, Ryan M Hanson, Colleen M Niswender, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects...
April 23, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29678111/discovery-and-optimization-of-potent-and-cns-penetrant-m5-preferring-pams-derived-from-a-novel-chiral-n-indanyl-piperidine-amide-scaffold
#19
Aaron M Bender, Hyekyung P Cho, Kellie D Nance, Kaelyn S Lingenfelter, Vincent B Luscombe, Patrick R Gentry, Karl Voigtritter, Alice E Berizzi, Patrick M Sexton, Christopher Langmead, Arthur Christopoulos, Charles W Locuson, Thomas M Bridges, Sichen Chang, Jordan C O'Neil, Xiaoyan Zhan, Colleen M Niswender, Carrie K Jones, P Jeffrey Conn, Craig W Lindsley
The pharmacology of the M5 muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M5 PAM, ML380, and have discovered and optimized a new series of M5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M5 PAM EC50s < 100 nM and rat brain:plasma Kps of ~0.40. Interestingly, unlike M1 and M4 PAMs with unprecedented mAChR subtype selectivity, this series of M5 PAMs displayed varying degrees of PAM activity at the other two natively Gq-coupled mAChRs, M1 and M3, yet were inactive at M2 and M4...
April 20, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29677098/update-treatment-for-hbv-infection-and-persistent-risk-for-hepatocellular-carcinoma-prospect-for-an-hbv-cure
#20
REVIEW
Joseph Yoo, Hie-Won Hann, Robert Coben, Mitchell Conn, Anthony J DiMarino
Since the discovery of the hepatitis B virus (HBV) by Blumberg et al. in 1965, its genome, sequence, epidemiology, and hepatocarcinogenesis have been elucidated. Globally, hepatitis B virus (HBV) is still responsible for the majority of hepatocellular carcinoma (HCC). HCC is the sixth-most common cancer in the world and the second-most common cancer death. The ultimate goal of treating HBV infection is the prevention of HCC. Fortunately, anti-HBV treatment with nucleos(t)ide analogues (NAs), which began with lamivudine in 1998, has resulted in remarkable improvements in the survival of patients with chronic hepatitis B and a reduced incidence of HCC...
April 20, 2018: Diseases (Basel)
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