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https://www.readbyqxmd.com/read/28646631/synthesis-of-novel-and-functionally-selective-non-competitive-muscarinic-antagonists-as-chemical-probes
#1
John F Boulos, Jan Jakubik, John M Boulos, Jelena Momirov, Alena Randakova
Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site...
June 24, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28641950/cholinergic-signaling-plasticity-maintains-viscerosensory-responses-during-aspiculuris-tetraptera-infection-in-mice-small-intestine
#2
Egina C Villalobos-Hernández, Carlos Barajas-López, Elizabeth A Martínez-Salazar, Roberto C Salgado-Delgado, Marcela Miranda-Morales
Intestinal parasites alter gastrointestinal (GI) functions like the cholinergic function. Aspiculuris tetraptera is a pinworm frequently observed in laboratory facilities, which infests the mice cecum and proximal colon. However, little is known about the impact of this infection on the GI sensitivity. Here, we investigated possible changes in spontaneous mesenteric nerve activity and on the mechanosensitivity function of worm-free regions of naturally infected mice with A. tetraptera. Infection increased the basal firing of mesenteric afferent nerves in jejunum...
June 3, 2017: Autonomic Neuroscience: Basic & Clinical
https://www.readbyqxmd.com/read/28638222/corticotropin-releasing-factor-stimulates-colonic-motility-via-muscarinic-receptors-in-the-rat
#3
Kyung-Jo Kim, Ki Bae Kim, Soon Man Yoon, Joung-Ho Han, Hee Bok Chae, Seon Mee Park, Sei Jin Youn
AIM: To measure exogenous corticotropin-releasing factor (CRF)-induced motility of the isolated rat colon and to demonstrate the effect of pharmacologic inhibition on CRF-induced motility. METHODS: The isolated vascularly-perfused rat colon was used. Luminal pressure was monitored via microtip catheter pressure transducers in the proximal and distal colon. At first, exogenous CRF was administered in a stepwise manner and the concentration of CRF yielding maximal colonic motility was selected...
June 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28635176/genetic-loss-of-the-muscarinic-m3-receptor-m3-r-markedly-alters-bile-formation-and-cholestatic-liver-injury-in-mice
#4
Franziska Durchschein, Elisabeth Krones, Marion J Pollheimer, Gernot Zollner, Martin Wagner, Jean-Pierre Raufman, Peter Fickert
Hepatic innervation represents a potentially underestimated regulator of liver function and regeneration. The muscarinic 3 receptor (M3 -R) is the primary cholangiocyte receptor for the afferent parasympathetic innervation of bile ducts. We aimed to determine the specific role of the M3 -R in bile formation and models for cholestatic liver disease in mice. We compared bile flow and composition in M3 -R knock-out mice (M3 -R(-/-) ) and wild type littermates (WT). M3 -R(-/-) mice showed significantly reduced bile flow compared to WT mice, most likely due to decreased biliary HCO3(-) secretion...
June 21, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/28633897/discovery-and-optimization-of-3-4-aryl-heteroarylsulfonyl-piperazin-1-yl-6-piperidin-1-yl-pyridazines-as-novel-cns-penetrant-pan-muscarinic-antagonists
#5
Aaron M Bender, Rebecca L Weiner, Vincent B Luscombe, Sonia Ajmera, Hyekyung P Cho, Sichen Chang, Xiaoyan Zhan, Alice L Rodriguez, Colleen M Niswender, Darren W Engers, Thomas M Bridges, P Jeffrey Conn, Craig W Lindsley
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2...
May 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28633665/optimizing-bronchodilation-in-the-prevention-of-copd-exacerbations
#6
REVIEW
Marc Miravitlles, Antonio Anzueto, José R Jardim
The natural disease course of chronic obstructive pulmonary disease (COPD) is often punctuated by exacerbations: acute events of symptom worsening associated with significant morbidity and healthcare resource utilization; reduced quality of life; and increased risk of hospitalization and death. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that patients at risk of exacerbations (GOLD Groups C and D) receive a long-acting muscarinic antagonist (LAMA) or a long-acting β2-agonist (LABA)/LAMA combination, respectively, as preferred initial treatments...
June 20, 2017: Respiratory Research
https://www.readbyqxmd.com/read/28632409/l-satropane-prevents-retinal-neuron-damage-by-attenuating-cell-apoptosis-and-a%C3%AE-production-via-activation-of-m1-muscarinic-acetylcholine-receptor
#7
Ping Yu, Wei Zhou, Lu Liu, Ya-Bin Tang, Yun Song, Juan-Juan Lu, Li-Na Hou, Hong-Zhuan Chen, Yong-Yao Cui
Muscarinic acetylcholine receptor (mAChR) agonists have been used to treat glaucoma due to their intraocular pressure-lowering effects. Recently, it has been reported that retinal mAChRs activation can also stimulate neuroprotective pathways. PURPOSE: In our study, we evaluated the potential neuroprotective effect of L-satropane, a novel mAChR agonist, on retinal neuronal injury induced by cobalt chloride (CoCl2) and ischemia/reperfusion (I/R). METHODS: CoCl2-induced hypoxia injury in cultured cell models and I/R-induced retinal neuronal damage in rats in vivo were used to evaluate the abilities of L-satropane...
June 20, 2017: Current Eye Research
https://www.readbyqxmd.com/read/28631387/umeclidinium-bromide-versus-placebo-for-people-with-chronic-obstructive-pulmonary-disease-copd
#8
REVIEW
Han Ni, Aung Htet, Soe Moe
BACKGROUND: People with chronic obstructive pulmonary disease (COPD) have poor quality of life, reduced survival, and accelerated decline in lung function, especially associated with acute exacerbations, leading to high healthcare costs. Long-acting bronchodilators are the mainstay of treatment for symptomatic improvement, and umeclidinium is one of the new long-acting muscarinic antagonists approved for treatment of patients with stable COPD. OBJECTIVES: To assess the efficacy and safety of umeclidinium bromide versus placebo for people with stable COPD...
June 20, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28629847/evidence-for-m2-muscarinic-receptor-modulation-of-axon-terminals-and-dendrites-in-the-rodent-basolateral-amygdala-an-ultrastructural-and-electrophysiological-analysis
#9
Ana Fajardo-Serrano, Lei Liu, David D Mott, Alexander J McDonald
The basolateral amygdala receives a very dense cholinergic innervation from the basal forebrain that is important for memory consolidation. Although behavioral studies have shown that both M1 and M2 muscarinic receptors are critical for these mnemonic functions, there have been very few neuroanatomical and electrophysiological investigations of the localization and function of different types of muscarinic receptors in the amygdala. In the present study we investigated the subcellular localization of M2 muscarinic receptors (M2Rs) in the anterior basolateral nucleus (BLa) of the mouse, including the localization of M2Rs in parvalbumin (PV) immunoreactive interneurons, using double-labeling immunoelectron microscopy...
June 16, 2017: Neuroscience
https://www.readbyqxmd.com/read/28628945/precise-spike-timing-dynamics-of-hippocampal-place-cell-activity-sensitive-to-cholinergic-disruption
#10
Ehren L Newman, Sarah Jo C Venditto, Jason R Climer, Elijah A Petter, Shea N Gillet, Sam Levy
New memory formation depends upon both the hippocampus and modulatory effects of acetylcholine. The mechanism by which acetylcholine levels in the hippocampus enable new encoding remains poorly understood. Here, we tested the hypothesis that cholinergic modulation supports memory formation by leading to structured spike timing in the hippocampus. Specifically, we tested if phase precession in dorsal CA1 was reduced under the influence of a systemic cholinergic antagonist. Unit and field potential was recorded from the dorsal CA1 of rats as they completed laps on a circular track for food rewards before and during the influence of the systemically administered acetylcholine muscarinic receptor antagonist scopolamine...
June 19, 2017: Hippocampus
https://www.readbyqxmd.com/read/28625546/the-lateral-parabrachial-nucleus-and-central-angiotensinergic-mechanisms-in-the-control-of-sodium-intake-induced-by-different-stimuli
#11
Camila F Roncari, Richard B David, Patrícia M De Paula, Débora S A Colombari, Laurival A De Luca, Eduardo Colombari, José V Menani
Angiotensin II (ANG II) is a typical facilitatory stimulus for sodium appetite. Surprisingly, hyperosmolarity and central cholinergic stimulation, two classical antinatriorexigenic stimuli, also facilitate NaCl intake when they are combined with injections of the α2-adrenoceptor/imidazoline agonist moxonidine into the lateral parabrachial nucleus (LPBN). In the present study, we tested the relative importance of central angiotensinergic and cholinergic mechanisms for the control of water and NaCl intake by combining different dipsogenic or natriorexigenic stimuli with moxonidine injection into the LPBN...
June 15, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28625139/targeting-cholinergic-system-to-modulate-liver-injury
#12
Ravirajsinh N Jadeja, Vikrant P Rachakonda, Sandeep Khurana
Over the past few decades, evidence accumulated to indicate that parasympathetic innervation regulates liver injury and regeneration. Liver derives its parasympathetic input via vagus nerve. In animal models, vagus nerve stimulation and transection are frequently used to determine the impact of parasympathetic input on liver injury responses. Such strategies provide limited understanding of post-neuronal mechanisms involved in regulation of liver injury. The hepatic branch of vagus nerve releases acetylcholine (ACh), which activates muscarinic and nicotinic receptors in hepatocytes as well as non-parenchymal cells to modulate cellular functions...
June 18, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28623171/broad-analgesic-activity-of-a-novel-selective-m1-agonist
#13
Michael W Wood, Giovanni Martino, Martin Coupal, Mattias Lindberg, Patricia Schroeder, S Santhakumar, Manon Valiquette, Johan Sandin, Daniel Widzowski, Jennifer Laird
Although the muscarinic receptor family has long been a source of potentially compelling targets for small molecule drug discovery, it was difficult to achieve agonist selectivity within the family. A new class of M1 muscarinic agonists has emerged, and these compounds have been characterized as agonists that activate the receptor at an allosteric site. Members of this class of M1 agonists have been shown to be selective across the muscarinic receptors. However, upon introduction of a novel pharmacologic mechanism, it is prudent to ensure that no new off-target activities have arisen, particularly within the context of in vivo experiments...
June 13, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28619712/targeting-acetylcholine-receptor-m3-prevents-the-progression-of-airway-hyperreactivity-in-a-mouse-model-of-childhood-asthma
#14
Kruti R Patel, Yan Bai, Kenneth G Trieu, Juliana Barrios, Xingbin Ai
Asthma often progresses into adulthood from early-life episodes of adverse environmental exposures. However, how the injury to developing lungs contributes to the pathophysiology of persistent asthma remains poorly understood. In this study, we identified an age-related mechanism along the cholinergic nerve-airway smooth muscle (ASM) axis that underlies prolonged airway hyperreactivity (AHR) in mice. We showed that ASM continued to mature until ∼3 wk after birth. Coinciding with postnatal ASM maturation, there was a critical time window for the development of ASM hypercontractility after cholinergic stimulation...
June 15, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28618875/implementation-of-guideline-based-therapy-for-chronic-obstructive-pulmonary-disease-differences-between-men-and-women-veterans
#15
Seppo T Rinne, A Rani Elwy, Chuan-Fen Liu, Renda Soylemez Wiener, Lisa Thayer, Alexandra Gerity, Lori A Bastian
Chronic obstructive pulmonary disease (COPD) is common among both men and women, and guidelines recommend the same therapy for both sexes. While previous studies have identified gender differences in other chronic disease management, few studies have examined how implementation of COPD guidelines differs between men and women. We performed a cross-sectional study of veterans admitted to Veterans Affairs (VA) hospitals for COPD during October 1, 2008, to September 30, 2011. We collected information on baseline COPD medications during the 6 months prior to hospitalization and categorized therapies as "appropriate" or "inappropriate" based on current guidelines...
January 1, 2017: Chronic Respiratory Disease
https://www.readbyqxmd.com/read/28610667/why-choose-tiotropium-for-my-patient-a-comprehensive-review-of-actions-and-outcomes-versus-other-bronchodilators
#16
REVIEW
David M Halpin, Alan G Kaplan, Richard K Russell
PURPOSE: Chronic obstructive pulmonary disease (COPD) and asthma are leading causes of morbidity and mortality. This narrative review provides an appraisal of the pharmacological and clinical characteristics of tiotropium in COPD and asthma, and examines how these compare with other long-acting bronchodilators. The evidence base is placed into context by relating it to factors affecting clinicians' choice of therapy. MAIN FINDINGS: Desirable attributes of a long-acting muscarinic antagonist (LAMA) maintenance therapy include effective pharmacological bronchodilation, improved lung function, exacerbation efficacy, and positive effects on symptom control, exercise capacity and quality of life across a broad patient population...
July 2017: Respiratory Medicine
https://www.readbyqxmd.com/read/28609709/novel-muscarinic-acetylcholine-receptor-hybrid-ligands-embedding-quinuclidine-and-1-4-dioxane-fragments
#17
Fabio Del Bello, Alessandro Bonifazi, Gianfabio Giorgioni, Riccardo Petrelli, Wilma Quaglia, Angela Altomare, Aurelia Falcicchio, Rosanna Matucci, Giulio Vistoli, Alessandro Piergentili
To obtain novel muscarinic acetylcholine receptor (mAChR) antagonists, the enantiomers of the hybrid compounds 3-5, in which the quinuclidin-3-yloxy fragment of solifenacin and the 6,6-diphenyl-1,4-dioxane-2-yl moiety of 2 linked by an ester or ether spacer were embedded in the same chemical entity, were prepared and evaluated for their affinity at the five mAChR subtypes (M1-M5). Stereochemistry and the nature of the linker between the quinuclidine moiety and the 1,4-dioxane nucleus play an important role on the affinities of the compounds...
June 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28609582/mild-heating-and-reduction-of-bladder-spontaneous-contractions
#18
Darryl G Kitney, Rita I Jabr, Bahareh Vahabi, Christopher H Fry
OBJECTIVES: To measure the effect of external heating on bladder wall contractile function, histological structure and expression of proteins related to tissue protection and apoptosis. MATERIAL AND METHODS: In vitro preparations of bladder wall and ex vivo perfused pig bladders were heated from 37°C to 42, 46 and 50°C for 15 minutes. Isolated preparations were heated by radiant energy and perfused bladders by altering perfusate temperature. Spontaneous contractions or pressure variations were recorded, as well as responses to the muscarinic agonist carbachol or motor nerve excitation in vitro during heating...
June 13, 2017: BJU International
https://www.readbyqxmd.com/read/28609577/cerebrolysin-prevents-deficits-in-social-behavior-repetitive-conduct-and-synaptic-inhibition-in-a-rat-model-of-autism
#19
Roberto Cuevas-Olguin, Swagata Roychowdhury, Anwesha Banerjee, Francisco Garcia-Oscos, Eric Esquivel-Rendon, María Elena Bringas, Michael P Kilgard, Gonzalo Flores, Marco Atzori
Autism spectrum disorder (ASD) is a syndrome of diverse neuropsychiatric diseases of growing incidence characterized by repetitive conduct and impaired social behavior and communication for which effective pharmacological treatment is still unavailable. While the mechanisms and etiology of ASD are still unknown, a consensus is emerging about the synaptic nature of the syndrome, suggesting a possible avenue for pharmacological treatment with synaptogenic compounds. The peptidic mixture cerebrolysin (CBL) has been successfully used during the last three decades in the treatment of stroke and neurodegenerative disease...
June 13, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28608746/new-insights-in-the-metabolism-of-oxybutynin-evidence-of-n-oxidation-of-propargylamine-moiety-and-rearrangement-to-enaminoketone
#20
Silvio Aprile, Rossana Canavesi, Rosanna Matucci, Cristina Bellucci, Erika Del Grosso, Giorgio Grosa
1. Oxybutynin hydrochloride is an antimuscarinic agent prescribed to patients with an overactive bladder and symptoms of urinary urge incontinence. Oxybutynin undergoes pre-systemic metabolism, and the N-desethyloxybutynin (Oxy-DE), is reported to have similar anticholinergic effects. 2. We revisited the oxidative metabolic fate of oxybutynin by liquid chromatography tandem mass spectrometry analysis of incubations with rat and human liver fractions, and by measuring plasma and urine samples collected after oral administration of oxybutynin in rats...
June 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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