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https://www.readbyqxmd.com/read/28676923/biochemical-and-pharmacological-role-of-a1-adenosine-receptors-and-their-modulation-as-novel-therapeutic-strategy
#1
Katia Varani, Fabrizio Vincenzi, Stefania Merighi, Stefania Gessi, Pier Andrea Borea
Adenosine, the purine nucleoside, mediates its effects through activation of four G-protein coupled adenosine receptors (ARs) named as A1, A2A, A2B and A3. In particular, A1ARs are distributed through the body, primarily inhibitory in the regulation of adenylyl cyclase activity and able to reduce the cyclic AMP levels. Considerable advances have been made in the pharmacological and molecular characterization of A1ARs, which had been proposed as targets for the discovery and drug design of antagonists, agonists and allosteric enhancers...
July 5, 2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28652388/optimization-of-thermolytic-response-to-a1-adenosine-receptor-agonists-in-rats
#2
Isaac R Bailey, Bernard Laughlin, Lucille Moore, Lori K Bogren, Zeinab Barati, Kelly L Drew
Cardiac arrest is a leading cause of death in the United States and currently, therapeutic hypothermia, now called targeted temperature management (TTM), is the only recent treatment modality proven to increase survival rates and reduce morbidity for this condition. Shivering and subsequent metabolic stress, however, limits application and benefit of TTM. Stimulating CNS A1 adenosine receptors inhibits shivering and non-shivering thermogenesis in rats and induces a hibernation-like response in hibernating species...
June 26, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28548869/neurotransmitter-receptor-availability-in-the-rat-brain-is-constant-in-a-24-hour-period
#3
A Oskamp, F Wedekind, T Kroll, D Elmenhorst, A Bauer
Wakefulness and sleep are fundamental characteristics of the brain. We, therefore, hypothesized that transmitter systems contribute to their regulation and will exhibit circadian alterations. We assessed the concentration of various neurotransmitter receptors and transporters including adenosinergic (A1AR, A2AAR, and ENT1), dopaminergic (D1R, D2R, and DAT), and serotonergic (5-HT2AR) target proteins. Adult male Sprague Dawley rats were used and maintained in a 12 h light: 12 h dark cycle (lights on from 07:00 h to 19:00 h)...
May 26, 2017: Chronobiology International
https://www.readbyqxmd.com/read/28508339/induction-of-hibernation-like-hypothermia-by-central-activation-of-the-a1-adenosine-receptor-in-a-non-hibernator-the-rat
#4
Hiroki Shimaoka, Takayuki Kawaguchi, Kahori Morikawa, Yuuki Sano, Kiyotada Naitou, Hiroyuki Nakamori, Takahiko Shiina, Yasutake Shimizu
Central adenosine A1-receptor (A1AR)-mediated signals play a role in the induction of hibernation. We determined whether activation of the central A1AR enables rats to maintain normal sinus rhythm even after their body temperature has decreased to less than 20 °C. Intracerebroventricular injection of an adenosine A1 agonist, N6-cyclohexyladenosine (CHA), followed by cooling decreased the body temperature of rats to less than 20 °C. Normal sinus rhythm was fundamentally maintained during the extreme hypothermia...
May 15, 2017: Journal of Physiological Sciences: JPS
https://www.readbyqxmd.com/read/28447789/exploring-the-role-of-n-6-substituents-in-potent-dual-acting-5-c-ethyltetrazolyladenosine-derivatives-synthesis-binding-functional-assays-and-antinociceptive-effects-in-mice-%C3%A2
#5
Riccardo Petrelli, Mirko Scortichini, Sonja Kachler, Serena Boccella, Carmen Cerchia, Ilaria Torquati, Fabio Del Bello, Daniela Salvemini, Ettore Novellino, Livio Luongo, Sabatino Maione, Kenneth A Jacobson, Antonio Lavecchia, Karl-Norbert Klotz, Loredana Cappellacci
Structural determinants of affinity of N(6)-substituted-5'-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N(6)-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28373571/recovery-sleep-after-extended-wakefulness-restores-elevated-a1-adenosine-receptor-availability-in-the-human-brain
#6
David Elmenhorst, Eva-Maria Elmenhorst, Eva Hennecke, Tina Kroll, Andreas Matusch, Daniel Aeschbach, Andreas Bauer
Adenosine and functional A1 adenosine receptor (A1AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A1AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [(18)F]CPFPX positron emission tomography was used to quantify A1AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A1AR values after 8 h of baseline sleep from an earlier dataset...
April 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28344125/capadenoson-a-clinically-trialed-partial-adenosine-a1-receptor-agonist-can-stimulate-adenosine-a2b-receptor-biased-agonism
#7
Jo-Anne Baltos, Elizabeth A Vecchio, Matthew A Harris, Cheng Xue Qin, Rebecca H Ritchie, Arthur Christopoulos, Paul J White, Lauren T May
The adenosine A2B receptor (A2BAR) has been identified as an important therapeutic target in cardiovascular disease, however in vitro and in vivo targeting has been limited by the paucity of pharmacological tools, particularly potent agonists. Interestingly, 2-((6-amino-3,5-dicyano-4-(4-(cyclopropylmethoxy)phenyl)-2-pyridinyl)thio)acetamide (BAY60-6583), a potent and subtype-selective A2BAR agonist, has the same core structure as 2-amino-6-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methylsulfanyl]-4-[4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitril (capadenoson)...
July 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28242442/genetic-biomarkers-of-posttraumatic-epilepsy-a-systematic-review
#8
REVIEW
Devyn Cotter, Andrew Kelso, Aidan Neligan
INTRODUCTION: Posttraumatic epilepsy (PTE) is caused by traumatic brain injury (TBI) and is an important contributor to the overall social and economic burden of epilepsy. Epidemiological studies suggest that there is a genetic contribution to the development of PTE. Identification of clinically useful genetic biomarkers is important for advancements in diagnosis and treatment of PTE. METHODS: A systematic review was performed on the existing literature of genetic biomarkers of posttraumatic epilepsy (PTE)...
March 2017: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/28217962/synthesis-and-pharmacological-evaluation-of-identified-and-putative-metabolites-of-the-a1-adenosine-receptor-antagonist-8-cyclopentyl-3-3-fluoropropyl-1-propylxanthine-cpfpx
#9
Marcus H Holschbach, Dirk Bier, Wiebke Sihver, Annette Schulze, Bernd Neumaier
The A1 adenosine receptor (A1 AR) antagonist [(18) F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([(18) F]CPFPX), used in imaging human brain A1 ARs by positron emission tomography (PET), is stable in the brain, but rapidly undergoes transformation into one major (3-(3-fluoropropyl)-8-(3-oxocyclopenten-1-yl)-1-propylxanthine, M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with no-carrier-added (n...
May 22, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28202385/long-term-consequences-of-disrupting-adenosine-signaling-during-embryonic-development
#10
REVIEW
Scott A Rivkees, Christopher C Wendler
There is growing evidence that disruption in the prenatal environment can have long-lasting effects on an individual's health in adulthood. Research on the fetal programming of adult diseases, including cardiovascular disease, focuses on epi-mutations, which alter the normal pattern of epigenetic factors such as DNA methylation, miRNA expression, or chromatin modification, rather than traditional genetic alteration. Thus, understanding how in utero chemical exposures alter epigenetics and lead to adult disease is of considerable public health concern...
June 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28034618/adenosine-receptors-regulate-susceptibility-to-noise-induced-neural-injury-in-the-mouse-cochlea-and-hearing-loss
#11
Srdjan M Vlajkovic, Kaushi Ambepitiya, Meagan Barclay, Detlev Boison, Gary D Housley, Peter R Thorne
Our previous studies have shown that the stimulation of A1 adenosine receptors in the inner ear can mitigate the loss of sensory hair cells and hearing loss caused by exposure to traumatic noise. Here, we focus on the role of adenosine receptors (AR) in the development of noise-induced neural injury in the cochlea using A1AR and A2AAR null mice (A1AR(-/-) and A2AAR(-/-)). Wildtype (WT) and AR deficient mice were exposed to octave band noise (8-16 kHz, 100 dB SPL) for 2 h to induce cochlear injury and hearing loss...
December 26, 2016: Hearing Research
https://www.readbyqxmd.com/read/27975140/profound-hypothermia-after-adenosine-kinase-inhibition-in-a1ar-deficient-mice-suggests-a-receptor-independent-effect-of-intracellular-adenosine
#12
Christoph Eisner, SooMi Kim, Alexandra Grill, Yan Qin, Marion Hoerl, Josephine Briggs, Hayo Castrop, Manfred Thiel, Jurgen Schnermann
Administration of the nucleoside adenosine has been shown to induce hypothermia in a number of species, an effect mediated predominantly by the adenosine 1 receptor (A1AR) subtype. The present experiments were performed to explore the possibility that the rise of intracellular adenosine levels expected to accompany adenosine administration may contribute to the hypothermic effect of adenosine independent of A1AR activation. Since phosphorylation of adenosine by adenosine kinase (ADK) is causal in the maintenance of low intracellular adenosine, we have examined the effect of ADK inhibition on core body temperature (CBT)...
December 14, 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27958734/novel-irreversible-agonists-acting-at-the-a1-adenosine-receptor
#13
Manuela Jörg, Alisa Glukhova, Alaa Abdul-Ridha, Elizabeth A Vecchio, Anh T N Nguyen, Patrick M Sexton, Paul J White, Lauren T May, Arthur Christopoulos, Peter J Scammells
The A1 adenosine receptor (A1AR) is an important G protein-coupled receptor that regulates a range of physiological functions. Herein we report the discovery of novel irreversible agonists acting at the A1AR, which have the potential to serve as useful research tools for studying receptor structure and function. A series of novel adenosine derivatives bearing electrophilic substituents was synthesized, and four compounds, 8b, 15a, 15b, and 15d, were shown to possess similar potency and efficacy to the reference high efficacy agonist, NECA, in an assay of ERK1/2 phosphorylation assay...
December 22, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27914963/hypothermia-in-mouse-is-caused-by-adenosine-a1-and-a3-receptor-agonists-and-amp-via-three-distinct-mechanisms
#14
Jesse Lea Carlin, Shalini Jain, Elizabeth Gizewski, Tina C Wan, Dilip K Tosh, Cuiying Xiao, John A Auchampach, Kenneth A Jacobson, Oksana Gavrilova, Marc L Reitman
Small mammals have the ability to enter torpor, a hypothermic, hypometabolic state, allowing impressive energy conservation. Administration of adenosine or adenosine 5'-monophosphate (AMP) can trigger a hypothermic, torpor-like state. We investigated the mechanisms for hypothermia using telemetric monitoring of body temperature in wild type and receptor knock out (Adora1(-/-), Adora3(-/-)) mice. Confirming prior data, stimulation of the A3 adenosine receptor (AR) induced hypothermia via peripheral mast cell degranulation, histamine release, and activation of central histamine H1 receptors...
March 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27889899/a1-adenosine-receptor-activation-modulates-central-nervous-system-development-and-repair
#15
REVIEW
Shirin Kashfi, Kamran Ghaedi, Hossein Baharvand, Mohammad Hossein Nasr-Esfahani, Mohammad Javan
Adenosine is an endogenous, autacoid purine nucleoside which performs many important biological roles, particularly during stressful events. Adenosine can signal through four adenosine receptor (AR) subtypes: A1, A2A, A2B, and A3. Of these, adenosine A1 receptor (A1AR) has a broad, wide distribution throughout different vertebrate cell types and the highest affinity to adenosine. The A1AR-dependent action of adenosine is well documented in reports from numerous studies that have used different selective A1AR agonists and antagonists as well as in animals that have a genetically manipulated A1AR gene...
November 26, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27871900/insulin-adenosine-axis-linked-signalling
#16
REVIEW
Luis Silva, Mario Subiabre, Joaquín Araos, Tamara Sáez, Rocío Salsoso, Fabián Pardo, Andrea Leiva, Rody San Martín, Fernando Toledo, Luis Sobrevia
Regulation of blood flow depends on systemic and local release of vasoactive molecules such as insulin and adenosine. These molecules cause vasodilation by activation of plasma membrane receptors at the vascular endothelium. Adenosine activates at least four subtypes of adenosine receptors (A1AR, A2AAR, A2BAR, A3AR), of which A2AAR and A2BAR activation leads to increased cAMP level, generation of nitric oxide, and relaxation of the underlying smooth muscle cell layer. Vasodilation caused by adenosine also depends on plasma membrane hyperpolarization due to either activation of intermediate-conductance Ca(2+)-activated K(+) channels in vascular smooth muscle or activation of ATP-activated K(+) channels in the endothelium...
November 19, 2016: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/27821347/new-potent-a1-adenosine-receptor-radioligands-for-positron-emission-tomography
#17
Sabrina Kreft, Dirk Bier, Marcus H Holschbach, Annette Schulze, Heinz H Coenen
8-Cyclopentyl-3-(3-[(18)F]fluoropropyl)-1-propylxanthine ([(18)F]CPFPX) is meanwhile an accepted receptor ligand to examine the A1 adenosine receptor (A1AR) in humans by positron emission tomography (PET). A major drawback of this compound is its rather fast metabolic degradation in vivo. Therefore two new xanthine derivatives, namely 8-cyclobutyl-1-cyclopropymethyl-3-(3-fluoropropyl)xanthine (CBCPM; 5) and 1-cyclopropylmethyl-3-(3-fluoropropyl)-8-(1-methylcyclobutyl)xanthine (CPMMCB; 6) were designed and synthesized as potential alternatives to CPFPX...
January 2017: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/27702592/alpha-naphthylisothiocyanate-impairs-bile-acid-homeostasis-through-ampk-fxr-pathways-in-rat-primary-hepatocytes
#18
Xiaojiaoyang Li, Runping Liu, Linxi Yu, Zihang Yuan, Rong Sun, Hang Yang, Luyong Zhang, Zhenzhou Jiang
Alpha-naphthylisothiocyanate (ANIT) is widely used to induce cholestasis in basic researches. Although direct damage induced by ANIT to bile duct epithelial cells has been documented in previous studies, few works investigated ANIT-induced effects on hepatocytes. Our previous study indicated that activated AMP-activated protein kinase (AMPK) inhibited farnesoid X receptor (FXR) expression and further participated in the pathogenesis of estrogen-induced cholestasis. However, whether ANIT has effects on bile acid homeostasis in hepatocytes, and the role of AMPK-FXR pathway played in these effects remain unclear...
August 31, 2016: Toxicology
https://www.readbyqxmd.com/read/27683014/extracellular-loop-2-of-the-adenosine-a1-receptor-has-a-key-role-in-orthosteric-ligand-affinity-and-agonist-efficacy
#19
Anh T N Nguyen, Jo-Anne Baltos, Trayder Thomas, Toan D Nguyen, Laura López Muñoz, Karen J Gregory, Paul J White, Patrick M Sexton, Arthur Christopoulos, Lauren T May
The adenosine A1 G protein-coupled receptor (A1AR) is an important therapeutic target implicated in a wide range of cardiovascular and neuronal disorders. Although it is well established that the A1AR orthosteric site is located within the receptor's transmembrane (TM) bundle, prior studies have implicated extracellular loop 2 (ECL2) as having a significant role in contributing to orthosteric ligand affinity and signaling for various G protein-coupled receptors (GPCRs). We thus performed extensive alanine scanning mutagenesis of A1AR-ECL2 to explore the role of this domain on A1AR orthosteric ligand pharmacology...
December 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27683013/role-of-the-second-extracellular-loop-of-the-adenosine-a1-receptor-on-allosteric-modulator-binding-signaling-and-cooperativity
#20
Anh T N Nguyen, Elizabeth A Vecchio, Trayder Thomas, Toan D Nguyen, Luigi Aurelio, Peter J Scammells, Paul J White, Patrick M Sexton, Karen J Gregory, Lauren T May, Arthur Christopoulos
Allosteric modulation of adenosine A1 receptors (A1ARs) offers a novel therapeutic approach for the treatment of numerous central and peripheral disorders; however, despite decades of research, there is a relative paucity of structural information regarding the A1AR allosteric site and mechanisms governing cooperativity with orthosteric ligands. We combined alanine-scanning mutagenesis of the A1AR second extracellular loop (ECL2) with radioligand binding and functional interaction assays to quantify effects on allosteric ligand affinity, cooperativity, and efficacy...
December 2016: Molecular Pharmacology
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