Academic literature on the topic 'P2X3 antagonist'
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Journal articles on the topic "P2X3 antagonist"
1
Coutinho-Silva, Robson, Lynn Stahl, Kwok-Kuen Cheung, et al. "P2X and P2Y purinergic receptors on human intestinal epithelial carcinoma cells: effects of extracellular nucleotides on apoptosis and cell proliferation." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 5 (2005): G1024—G1035. http://dx.doi.org/10.1152/ajpgi.00211.2004.
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Extracellular nucleotides interact with purinergic receptors, which regulate ion transport in a variety of epithelia. With the use of two different human epithelial carcinoma cell lines (HCT8 and Caco-2), we have shown by RT-PCR that the cells express mRNA for P2X1, P2X3, P2X4, P2X5, P2X6, P2X7, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, and P2Y12 receptors. Protein expression for P2Y1 and P2Y2 receptors was also demonstrated immunohistochemically, and P2X receptor subtype protein was present in the following decreasing order: P2X4 > P2X7 > P2X1 > P2X3 > P2X6 > P2X5 >> P2X2. The functional presence of P2X7, P2Y1, P2Y2, and P2Y4 receptors was shown based on the effect of extracellular nucleotides on apoptosis or cell proliferation, and measurement of nucleotide-dependent calcium fluxes using a fluorometric imaging plate reader in the presence of different selective agonists and antagonists. ATP, at high concentrations, induced apoptosis through ligation of P2X7 and P2Y1 receptors; conversely, ATP, at lower concentrations, and UTP stimulated proliferation, probably acting via P2Y2 receptors. We therefore propose that stimulation or dysfunction of purinergic receptors may contribute at least partially to modulation of epithelial carcinoma cell proliferation and apoptosis.
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Nakamura, Ei'Ichiro, Yasuhito Uezono, Ken'Ichiro Narusawa, et al. "ATP activates DNA synthesis by acting on P2X receptors in human osteoblast-like MG-63 cells." American Journal of Physiology-Cell Physiology 279, no. 2 (2000): C510—C519. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c510.
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In human osteoblast-like MG-63 cells, extracellular ATP increased [3H]thymidine incorporation and cell proliferation and synergistically enhanced platelet-derived growth factor- or insulin-like growth factor I-induced [3H]thymidine incorporation. ATP-induced [3H]thymidine incorporation was mimicked by the nonhydrolyzable ATP analogs adenosine 5′- O-(3-thiotriphosphate) and adenosine 5′-adenylylimidodiphosphate and was inhibited by the P2 purinoceptor antagonist suramin, suggesting involvement of P2 purinoceptors. The P2Y receptor agonist UTP and UDP and a P2Y receptor antagonist reactive blue 2 did not affect [3H]thymidine incorporation, whereas the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4-disulfonic acid inhibited ATP-induced [3H]thymidine incorporation, suggesting that ATP-induced DNA synthesis was mediated by P2X receptors. RT-PCR analysis revealed that MG-63 cells expressed P2X4, P2X5, P2X6, and P2X7, but not P2X1, P2X2, and P2X3, receptors. In fura 2-loaded cells, not only ATP, but also UTP, increased intracellular Ca2+concentration, and inhibitors for several Ca2+-activated protein kinases had no effect on ATP-induced DNA synthesis, suggesting that an increase in intracellular Ca2+concentration is not indispensable for ATP-induced DNA synthesis. ATP increased mitogen-activated protein kinase activity in a Ca2+-independent manner and synergistically enhanced platelet-derived growth factor- or insulin-like growth factor I-induced kinase activity. Furthermore, the mitogen-activated protein kinase kinase inhibitor PD-98059 totally abolished ATP-induced DNA synthesis. We conclude that ATP increases DNA synthesis and enhances the proliferative effects of growth factors through P2X receptors by activating a mitogen-activated protein kinase pathway.
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Nunes, Ana R., Raul Chavez-Valdez, Tarrah Ezell, David F. Donnelly, Joel C. Glover, and Estelle B. Gauda. "Effect of development on [Ca2+]i transients to ATP in petrosal ganglion neurons: a pharmacological approach using optical recording." Journal of Applied Physiology 112, no. 8 (2012): 1393–402. http://dx.doi.org/10.1152/japplphysiol.00511.2011.
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ATP, acting through P2X2/P2X3 receptor-channel complexes, plays an important role in carotid body chemoexcitation in response to natural stimuli in the rat. Since the channels are permeable to calcium, P2X activation by ATP should induce changes in intracellular calcium ([Ca2+]i). Here, we describe a novel ex vivo approach using fluorescence [Ca2+]i imaging that allows screening of retrogradely labeled chemoafferent neurons in the petrosal ganglion of the rat. ATP-induced [Ca2+]i responses were characterized at postnatal days (P) 5–8 and P19–25. While all labeled cells showed a brisk increase in [Ca2+]i in response to depolarization by high KCl (60 mM), only a subpopulation exhibited [Ca2+]i responses to ATP. ATP (250–1,000 μM) elicited one of three temporal response patterns: fast (R1), slow (R2), and intermediate (R3). At P5–8, R2 predominated and its magnitude was attenuated 44% by the P2X1 antagonist, NF449 (10 μM), and 95% by the P2X1/P2X3/P2X2/3 antagonist, TNP-ATP (10 μM). At P19–25, R1 and R3 predominated and their magnitudes were attenuated 15% by NF449, 66% by TNP-ATP, and 100% by suramin (100 μM), a nonspecific P2 purinergic receptor antagonist. P2X1 and P2X2 protein levels in the petrosal ganglion decreased with development, while P2X3 protein levels did not change significantly. We conclude that the profile of ATP-induced P2X-mediated [Ca2+]i responses changes in the postnatal period, corresponding with changes in receptor isoform expression. We speculate that these changes may participate in the postnatal maturation of chemosensitivity.
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Gui, Yu, ZengYong Wang, XiaoRui Sun, et al. "Uridine adenosine tetraphosphate induces contraction of airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 5 (2011): L789—L794. http://dx.doi.org/10.1152/ajplung.00203.2011.
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Contraction of airway smooth muscle (ASM) plays an important role in the regulation of air flow and is potentially involved in the pathophysiology of certain respiratory diseases. Extracellular nucleotides regulate ASM contraction via purinergic receptors, but the signaling mechanisms involved are not fully understood. Uridine adenosine tetraphosphate (Up4A) contains both pyrimidine and purine moieties, which are known to potentially activate P2X and P2Y receptors. Both P2X and P2Y receptors have been identified in the lung, including airway epithelial cells and ASM. We report here a study of purinergic signaling in the respiratory system, with a focus on the effect of Up4A on ASM contraction. Up4A induced contraction of rat isolated trachea and extrapulmonary bronchi as well as human intrapulmonary bronchioles. Up4A-induced contraction was blocked by di-inosine pentaphosphate, a P2X antagonist, but not by suramin, a nonselective P2 antagonist. Up4A-induced contraction was also attenuated by α,β-methylene-ATP-mediated P2X receptor desensitization. Several P2X receptors were detected at the mRNA level: P2X1, P2X4, P2X6, and P2X7, and to a lesser extent P2X3. Furthermore, the Up4A response was inhibited by removal of extracellular Ca2+ and by the presence of the L-type Ca2+ channel blocker, nifedipine, or the Rho-associated kinase inhibitor, H1152. We conclude that Up4A stimulates ASM contraction, and the underlying signaling mechanism appears to involve P2X (most likely P2X1) receptors, extracellular Ca2+ entry via L-type Ca2+ channels, and Ca2+ sensitization through the RhoA/Rho-associated kinase pathway. This study will add to our understanding of the pathophysiological roles of extracellular nucleotides in the lung.
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Hu, Bo, Chen Yu Chiang, James W. Hu, Jonathan O. Dostrovsky, and Barry J. Sessle. "P2X Receptors in Trigeminal Subnucleus Caudalis Modulate Central Sensitization in Trigeminal Subnucleus Oralis." Journal of Neurophysiology 88, no. 4 (2002): 1614–24. http://dx.doi.org/10.1152/jn.2002.88.4.1614.
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This study investigated the role of trigeminal subnucleus caudalis (Vc) P2X receptors in the mediation of central sensitization induced in nociceptive neurons in subnucleus oralis (Vo) by mustard oil (MO) application to the tooth pulp in anesthetized rats. MO application produced a long-lasting central sensitization reflected in neuroplastic changes (i.e., increases in neuronal mechanoreceptive field size and responses to innocuous and noxious mechanical stimuli) in Vo nociceptive neurons. Twenty minutes after MO application, the intrathecal (i.t.) administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor antagonist, 2′-(or 3′-) O-trinitrophenyl-ATP (TNP-ATP), significantly and reversibly attenuated the MO-induced central sensitization for more than 15 min; saline administration had no effect. Administration to the rostral Vc of the selective P2X1, P2X3, and P2X2/3 receptor agonist, α,β-methylene ATP (α,β-meATP, i.t.) produced abrupt and significant neuroplastic changes in Vo nociceptive neurons, followed by neuronal desensitization as evidenced by the ineffectiveness of a second i.t. application of α,β-meATP and subsequent MO application to the pulp. Administration to the rostral Vc of the selective P2X1 receptor agonist β,γ-methylene ATP (β,γ-meATP, i.t.) produced no significant neuroplastic changes per se and did not affect the subsequent MO-induced neuroplastic changes in Vo nociceptive neurons. These results suggest that P2X3 and possibly also the P2X2/3 receptor subtypes in Vc may play a role in the initiation and maintenance of central sensitization in Vo nociceptive neurons induced by MO application to the pulp.
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Gomes, Dayane A., Zhilin Song, Wanida Stevens, and Celia D. Sladek. "Sustained stimulation of vasopressin and oxytocin release by ATP and phenylephrine requires recruitment of desensitization-resistant P2X purinergic receptors." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 297, no. 4 (2009): R940—R949. http://dx.doi.org/10.1152/ajpregu.00358.2009.
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Coexposure of hypothalamo-neurohypophyseal system explants to ATP and phenylephrine [PE; an α1-adrenergic receptor (α1-AR) agonist] induces an extended elevation in vasopressin and oxytocin (VP/OT) release. New evidence is presented that this extended response is mediated by recruitment of desensitization-resistant ionotropic purinergic receptor subtypes (P2X-Rs): 1) Antagonists of the P2X2/3 and P2X7-Rs truncated the sustained VP/OT release induced by ATP+PE but did not alter the transient response to ATP alone. 2) The P2X2/3 and P2X7-R antagonists did not alter either ATP or ATP+PE-induced increases in [Ca2+]i. 3) P2X2/3 and P2X7-R agonists failed to elevate [Ca2+]i, while ATP-γ-S, an agonist for P2X2-Rs increased [Ca2+]iand induced a transient increase in VP/OT release. 4) A P2Y1-R antagonist did not prevent initiation of the synergistic, sustained stimulation of VP/OT release by ATP+PE but did reduce its duration. Thus, the desensitization-resistant P2X2/3 and P2X7-R subtypes are required for the sustained, synergistic hormone response to ATP+PE, while P2X2-Rs are responsible for the initial activation of Ca2+-influx by ATP and ATP stimulation of VP/OT release. Immunohistochemistry, coimmunoprecipitation, and Western blot analysis confirmed the presence of P2X2 and P2X3, P2X2/3, and P2X7-R protein, respectively in SON. These findings support the hypothesis that concurrent activation of P2X2-R and α1-AR induces calcium-driven recruitment of P2X2/3 and 7-Rs, allowing sustained activation of a homeostatic circuit. Recruitment of these receptors may provide sustained release of VP during dehydration and may be important for preventing hemorrhagic and septic shock.
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Burgard, Edward C., Wende Niforatos, Tim van Biesen, et al. "P2X Receptor–Mediated Ionic Currents in Dorsal Root Ganglion Neurons." Journal of Neurophysiology 82, no. 3 (1999): 1590–98. http://dx.doi.org/10.1152/jn.1999.82.3.1590.
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Nociceptive neurons in the dorsal root ganglia (DRG) are activated by extracellular ATP, implicating P2X receptors as potential mediators of painful stimuli. However, the P2X receptor subtype(s) underlying this activity remain in question. Using electrophysiological techniques, the effects of P2X receptor agonists and antagonists were examined on acutely dissociated adult rat lumbar DRG neurons. Putative P2X-expressing nociceptors were identified by labeling neurons with the lectin IB4. These neurons could be grouped into three categories based on response kinetics to extracellularly applied ATP. Some DRG responses (slow DRG) were relatively slowly activating, nondesensitizing, and activated by the ATP analogue α,β-meATP. These responses resembled those recorded from 1321N1 cells expressing recombinant heteromultimeric rat P2X2/3 receptors. Other responses (fast DRG) were rapidly activating and desensitized almost completely during agonist application. These responses had properties similar to those recorded from 1321N1 cells expressing recombinant rat P2X3 receptors. A third group (mixed DRG) activated and desensitized rapidly (P2X3-like), but also had a slow, nondesensitizing component that functionally prolonged the current. Like the fast component, the slow component was activated by both ATP and α,β-meATP and was blocked by the P2X antagonist TNP-ATP. But unlike the fast component, the slow component could follow high-frequency activation by agonist, and its amplitude was potentiated under acidic conditions. These characteristics most closely resemble those of rat P2X2/3 receptors. These data suggest that there are at least two populations of P2X receptors present on adult DRG nociceptive neurons, P2X3 and P2X2/3. These receptors are expressed either separately or together on individual neurons and may play a role in the processing of nociceptive information from the periphery to the spinal cord.
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Kiyatkin, Michael E., Bin Feng, Erica S. Schwartz, and G. F. Gebhart. "Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 9 (2013): G638—G648. http://dx.doi.org/10.1152/ajpgi.00180.2013.
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The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity.
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Niane, Lalah M., David F. Donnelly, Vincent Joseph, and Aida Bairam. "Ventilatory and carotid body chemoreceptor responses to purinergic P2X receptor antagonists in newborn rats." Journal of Applied Physiology 110, no. 1 (2011): 83–94. http://dx.doi.org/10.1152/japplphysiol.00871.2010.
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Adenosine triphosphate, acting through purinergic P2X receptors, has been shown to stimulate ventilation and increase carotid body chemoreceptor activity in adult rats. However, its role during postnatal development of the ventilatory response to hypoxia is yet unknown. Using whole body plethysmography, we measured ventilation in normoxia and in moderate hypoxia (12% fraction of inspired O2, 20 min) before and after intraperitoneal injection of suramin (P2X2 and P2X3 receptor antagonist, 40 mg/kg) in 4-, 7-, 12-, and 21-day-old rats. Suramin reduced baseline breathing (∼20%) and the response to hypoxia (∼30%) in all rats, with a relatively constant effect across ages. We then tested the effect of the specific P2X3 antagonist, A-317491 (150 mg/kg), in rats aged 4, 7, and 21 days. As with suramin, A-317491 reduced baseline ventilation (∼55%) and the hypoxic response (∼40%) at all ages studied. Single-unit carotid body chemoreceptor activity was recorded in vitro in 4-, 7-, and 21-day-old rats. Suramin (100 μM) and A-317491 (10 μM) significantly depressed the sinus nerve chemosensory discharge rate (∼80%) in normoxia (Po2 ∼150 Torr) and hypoxia (Po2 ∼60 Torr), and this decrease was constant across ages. We conclude that, in newborn rats, P2X purinergic receptors are involved in the regulation of breathing under basal and hypoxic condition, and P2X3-containing receptors play a major role in carotid body function. However, these effects are not age dependent within the age range studied.
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LIGHT, ALAN R., YING WU, RONALD W. HUGHEN, and PETER B. GUTHRIE. "Purinergic receptors activating rapid intracellular Ca2+ increases in microglia." Neuron Glia Biology 2, no. 2 (2005): 125–38. http://dx.doi.org/10.1017/s1740925x05000323.
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We provide both molecular and pharmacological evidence that the metabotropic, purinergic, P2Y6, P2Y12 and P2Y13 receptors and the ionotropic P2X4 receptor contribute strongly to the rapid calcium response caused by ATP and its analogues in mouse microglia. Real-time PCR demonstrates that the most prevalent P2 receptor in microglia is P2Y6 followed, in order, by P2X4, P2Y12, and P2X7 = P2Y13. Only very small quantities of mRNA for P2Y1, P2Y2, P2Y4, P2Y14, P2X3 and P2X5 were found. Dose-response curves of the rapid calcium response gave a potency order of: 2MeSADP>ADP=UDP=IDP=UTP>ATP>BzATP, whereas A2P4 had little effect. Pertussis toxin partially blocked responses to 2MeSADP, ADP and UDP. The P2X4 antagonist suramin, but not PPADS, significantly blocked responses to ATP. These data indicate that P2Y6, P2Y12, P2Y13 and P2X receptors mediate much of the rapid calcium responses and shape changes in microglia to low concentrations of ATP, presumably at least partly because ATP is rapidly hydrolyzed to ADP. Expression of P2Y6, P2Y12 and P2Y13 receptors appears to be largely glial in the brain, so that peripheral immune cells and CNS microglia share these receptors. Thus, purinergic, metabotropic, P2Y6, P2Y12, P2Y13 and P2X4 receptors might share a role in the activation and recruitment of microglia in the brain and spinal cord by widely varying stimuli that cause the release of ATP, including infection, injury and degeneration in the CNS, and peripheral tissue injury and inflammation which is signaled via nerve signaling to the spinal cord.
Dissertations / Theses on the topic "P2X3 antagonist"
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Helms, Nick. "Wechselwirkungen von Agonisten und kompetitiven Antagonisten mit der Ligandenbindungsstelle des schnell desensitisierenden P2X3-Rezeptors." Doctoral thesis, Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-197364.
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Purinerge P2X3-Rezeptoren spielen eine bedeutende Rolle in der Vermittlung chronischer Schmerzen, welche ein führendes Problem des Gesundheitswesens mit vielen sozioökonomischen Konsequenzen darstellen. Die Tatsache, dass P2X3-Rezeptoren fast ausschließlich von
nozizeptiven Neuronen exprimiert werden, macht sie trotz ihres besonderen Desensitisierungsverhaltens zu vielversprechenden Angriffspunkten zukünftiger Schmerztherapien, beispielsweise mithilfe kompetitiver Antagonisten an diesen Rezeptoren. Zur Analyse der Wechselwirkungen zwischen Agonist und kompetitivem Antagonist wird meist der Schild-Plot benutzt. Jedoch ist dieser im Falle der sehr schnell desensitisierenden P2X3-Rezeptoren ungeeignet, da die Vorbedingung
eines stabilen Gleichgewichts zwischen Agonist und Antagonist aufgrund der Desensitisierung nicht erfüllt ist.
Ziel der vorliegenden Arbeit war es, eine neue Methode zur Analyse der Interaktion kompetitiver Antagonisten mit ihrer Bindungsstelle am Beispiel des P2X3-Rezeptors zu entwickeln und so für die Antagonistenbindung bedeutende Aminosäuren der Bindungsstelle zu identifizieren.
Mittels der Patch-Clamp-Technik wurden die Effekte der Antagonisten A-317491, TNP-ATP und PPADS auf die vom P2X1,3-Rezeptor-selektiven Agonisten α,β-MeATP induzierten Ströme am P2X3-Wildtyp-Rezeptor und an fünf Rezeptormutanten mit veränderter Ligandenbindungsstelle
untersucht. Alle Rezeptoren wurden in HEK293-Zellen exprimiert. Anhand der gemessenen Daten wurde ein Hidden Markov Model (HMM) erstellt, welches die sequentiellen Übergänge des Rezeptors von geschlossen zu offen und desensitisiert in An- und Abwesenheit des Antagonisten miteinander kombiniert. Die am P2X3-Rezeptor induzierten Ströme konnten mithilfe dieses Modells korrekt gefittet und die für die Antagonistenbindung wichtigen Aminosäuren innerhalb der Bindungsstelle bestimmt werden. Als Resultat dieser Arbeit konnte außerdem gezeigt werden, dass das HMM eine geeignete Methode zur Analyse der Wirkung kompetitiver Antagonisten an schnell desensitisierenden Rezeptoren darstellt. Die untersuchten Antagonisten A-317491 und TNP-ATP haben einen kompetitiven Wirkmechanismus, während PPADS eine pseudoirreversible Blockade verursacht.
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Farmer, Louise Katie. "The molecular basis of antagonism at cardiovascular P2X1 and P2X4 receptors." Thesis, University of Leicester, 2014. http://hdl.handle.net/2381/40322.
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Structural information for the zebrafish P2X4 receptor in both an agonist bound and unbound resting state provided a major advance in understanding agonist action and has given insight into movement that occurs in the receptor upon ATP binding. Despite agonist action now being well characterised, the molecular basis of antagonism is poorly understood. In this thesis the mechanism of antagonist action at the hP2X1 receptor has been investigated through determining properties of chimeras and mutant receptors based on differences between antagonist sensitive and insensitive P2X receptors. The antagonists suramin, NF449 and PPADS potently inhibit the human P2X1 receptor but have little or no action at the rat P2X4 receptor. The extracellular loop of the hP2X1 receptor was shown to determine antagonist sensitivity and was therefore split into four sections, residues of which were swapped with corresponding residues of the antagonist insensitive rP2X4 receptor and vice versa. Sub-chimeras and point mutations were then made to identify particular residues and regions which contribute to antagonist action. These experiments identified two regions important for NF449 binding at the receptor. These are a cluster of four positively charged residues at the base of the cysteine rich head region (136-140) and three residues located just below them (T216, H224 and Q231). An NF449 bound model of the hP2X1 receptor has been generated. The introduction of the four positively charged residues at the base of the cysteine rich head region to the rP2X4 receptor introduced suramin and PPADS sensitivity to this previously insensitive receptor. This mutation is thought to cause a conformational change which allows the antagonist to bind at residues which are already present in the wildtype receptor. In summary this thesis has advanced the understanding of antagonist action at the hP2X1 receptor and the antagonist insensitivity of the rP2X4 receptor.
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Jackson, Alexander Rodney. "Pharmacological Evaluation of Cyanoguanidine P2X7 Receptor Antagonists." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17186.
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ABSTRACT BACKGROUND AND AIMS: The P2X7 receptor (P2X7R) is an ATP-gated, non-selective cation channel highly expressed on monocytes, macrophages and microglia. Prolonged activation of the P2X7R by ATP leads to cytolytic pore formation and the release of inflammatory mediators including interleukin-1β and prostaglandin E2. Accumulating evidence suggests a role for the P2X7R in neuroinflammation and thus P2X7R antagonists might be useful in diseases including chronic pain, depression and Alzheimer’s disease. Both negative allosteric modulators of the P2X7R, such as the adamantyl benzamides, and orthosteric antagonists, such as the aryl cyanoguanidines, inhibit the ATP-induced release of IL-1β from immune cells. This shared ability to inhibit IL-1β release may explain why no attempts have been made to determine the features which promote binding to the allosteric or orthosteric site. An advantage of targeting the allosteric or orthosteric site might emerge however, if a different agonist of the P2X7R is used. An antimicrobial peptide produced within the human body, LL-37, is also able to activate the P2X7R and yet LL-37 is never used in the characterisation of new series of P2X7R antagonists. The aims of this project were to characterise a novel series of P2X7R antagonists, the adamantyl cyanoguanidines, which have a hybrid structure derived from the adamantyl benzamides and aryl cyanoguanidines. Characterisation of the adamantyl cyanoguanidines should allow determination of the features which promote binding to the orthosteric or allosteric site of the P2X7R, which was one of the primary aims of this project. A second aim was to evaluate the potential of the hybrid series for further development as P2X7R antagonists by considering their potency and physicochemical P a g e | 13 properties. The final aim was to determine if there was any advantage of targeting the orthosteric or allosteric site of the P2X7R particularly with regard to inhibiting LL-37-mediated activation of the P2X7R. METHODS: The potency of adamantyl cyanoguanidines and reference P2X7R antagonists were determined in YO-PRO-1 dye uptake assays and interleukin-1β release assays to develop structure-activity relationships. A potent member of the adamantyl cyanoguanidines and several reference P2X7R antagonists were pharmacologically characterised in Schild assays, washout studies and receptor protection studies. The ability of several negative allosteric modulators and an orthosteric antagonist to inhibit LL-37-induced dye uptake was also examined. RESULTS: More compact adamantyl cyanoguanidines including those with a methylene linker between the adamantyl and cyanoguanidine groups and no linker between the cyanoguanidine group and phenyl ring were more potent than analogues with longer linkers. Ortho-substitution of the phenyl ring or substitution of the ring with 5-quinoline led to increased potency. The potency seen in the dye uptake assay was also seen in the interleukin-1β release assay. A potent member of the series 3-19 was determined to be a slowly reversible negative allosteric modulator as was 1-17 an adamantyl benzamide. The parent aryl cyanoguanidine, A-804598, was confirmed to be an orthosteric antagonist. None of the compounds were able to inhibit LL-37-induced dye uptake. DISCUSSION AND CONCLUSIONS: The determined structure-activity relationships for the adamantyl cyanoguanidines confirm their potential for further development since the series was highly amenable to modification and several potent analogues have favourable physicochemical properties including lower molecular weight. Since 3-19 P a g e | 14 was a negative allosteric modulator despite its structural similarity to A-804598 this suggests the adamantyl group promotes binding to the allosteric site and that cyanoguanidine is a tolerated bioisostere for the acetamide group at the allosteric site. The 5-quinolinyl group, in the appropriate position, facilitates binding to either site. The failure of multiple P2X7R antagonists to inhibit LL-37-induced dye uptake is concerning since LL-37 alone has been shown to induce the release of interleukin-1β from human monocytes. Future research must determine if LL-37 is responsible for cytokine release in vivo and develop small molecule antagonists of the action of LL-37.
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El-Ajouz, Sam. "Molecular basis of antagonist action at the P2X1 receptor." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10260.
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P2X receptors are ATP-gated cation channels. P2X1 receptors are widely expressed throughout the body and have a range of functional roles, e.g. contraction of mesenteric arteries and regulation of blood clotting. The recent crystallisation of the zebra fish P2X4 receptor has provided a major advance in understanding the molecular basis of receptor properties. However, how agonists or antagonists are co-ordinated and the extent of the proposed ligand binding site have not been addressed at a structural level. A mutagenesis based approach was used to propose a model of the ATP binding site and has highlighted some residues involved in antagonist action at P2X receptors. The aim of this thesis was to investigate the molecular basis of antagonist action at the P2X1 receptor using site-directed mutagenesis and P2X receptor chimeras. The wild-type, mutant and chimaeric P2X receptors were expressed in Xenopus laevis oocytes and the currents were characterised using two electrode voltage clamp. Initially, suramin was shown to act as a competitive antagonist and PPADS as a non-competitive antagonist at the P2X1 receptor. The contribution of residues V74 to G96 to human P2X1 receptor properties were determined using cysteine scanning mutagenesis. This region contains a residue that has been shown to be important in suramin action at the P2X4 receptor (K78) but cysteine mutation of the residues V74 to G96 had either no effect or slightly increased antagonism by suramin or PPADS. Also, a further residue was found to be important in ATP potency (F92) and the use of partial agonists and modification with cysteine reactive methanethiosulfonate (MTS) reagents identified additional residues important in channel activation. Mapping these residues onto a homology model of the P2X1 receptor showed the depth of the agonist binding site and highlighted the importance of the rear/inner cavity of the binding pocket in the gating of the channel subsequent to agonist binding. The cysteine rich head region of the P2X receptor, which is adjacent to the proposed ATP binding pocket, is absent in the antagonist insensitive Dictyostelium receptors. P2X1 and P2X2 receptors have ~1400-fold difference in sensitivity to a suramin analogue NF449. Chimeras and point mutations in the cysteine rich head region were made between the P2X1 and P2X2 receptors and they identified the region between the third and fourth conserved cysteine residues of the P2X1 receptor as being important in conferring the difference in sensitivity. In particular, the positively charged residues at the base of the cysteine rich head region of the P2X1 receptor accounted for the highly selective antagonism of NF449 at the P2X1 receptor. Additionally, these residues were shown to play a role in the molecular basis of suramin and PPADS action at the P2X1 receptor. Reciprocal chimeras and mutations in the P2X2 receptor produced modest increases in antagonist sensitivity. In silico docking models highlighted possible sites of action for NF449 and suramin on the P2X1 receptor showing that the base of the cysteine rich head region may be important in the binding of antagonists. In summary, this research furthered understanding of ligand action at the P2X1 receptor.
5
Rashed, Mahmoud [Verfasser]. "Syntheses and structure-activity relationships of novel P2X3 receptor antagonists / Mahmoud Rashed." Bonn : Universitäts- und Landesbibliothek Bonn, 2018. http://d-nb.info/1160594392/34.
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Palaskali, Sascha [Verfasser]. "Charakterisierung von Cyclothiazid als Antagonist von humanen P2X7-Rezeptoren / Sascha Palaskali." Ulm : Universität Ulm. Medizinische Fakultät, 2011. http://d-nb.info/1018024883/34.
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Fischer, Wolfgang, Heike Franke, Ute Krügel, et al. "Critical evaluation of P2X7 receptor antagonists in selected seizure models." Universitätsbibliothek Leipzig, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-206115.
Full textAbstract:
The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders.
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Huo, Hong. "The molecular basis of antagonism by PPADS at the human P2X1 receptor." Thesis, University of Leicester, 2018. http://hdl.handle.net/2381/42934.
Full textAbstract:
P2X receptors (P2XRs) activated by ATP are widely expressed throughout the human body and mediate various physiological and pathophysiological roles. Crystal structures have provided a major advance in understanding agonist and subtype selective antagonist actions. However, the molecular basis of antagonism of general antagonists is poorly understood. PPADS is an effective antagonist at most mammalian P2XRs. Previous studies suggested lysine residue 249 (K249) (numbering for P2X1R) was involved in PPADS action. The aim of this study was to determine the PPADS binding site in a molecular model of the human P2X1R based on the zebra fish P2X4R (zfP2X4R) crystal structure. Contributions of individual residues in a ring centred on K249 with a radius of the length of PPADS were investigated by cysteine mutagenesis. The effect of their cysteine substitutions on accessibility following PPADS binding and on PPADS sensitivity were tested. A cluster of positively charged residues (K70, K190 and K249) at the orthosteric pocket showed decreases in both accessibility and sensitivity to PPADS, suggesting they are directly involved in binding of the antagonist. These data allow validation of molecular docking to provide the first model of PPADS binding. Some residues outside the orthosteric area showed decreased accessibility following PPADS binding but on change in antagonist sensitivity, indicating PPADS binding induced significant conformational changes from the apo state. In addition, the charge and conformational changes at the cysteine rich head (CRH) region also contributed to antagonist action by showing a mutation at a positively charged residue (K138C) increased accessibility following PPADS binding and decreased PPADS sensitivity. In summary, this thesis has advanced the understanding of antagonist PPADS action and provided a template to develop subtype selectivity based on the differences between subunits around the orthosteric P2XR binding site and the CRH region.
9
Ahmad, Izzuddin. "Identification and structure activity relationship of small molecule antagonists of the human P2X4 receptor." Thesis, University of East Anglia, 2018. https://ueaeprints.uea.ac.uk/68205/.
Full textAbstract:
P2X4 is a purinergic receptor distributed all over the body with various roles. Among them, it was reportedly overexpressed in several neuronal and immune cell types following peripheral nerve injury and its activation leads to neuropathic pain. Several compounds were found to block P2X4 but none has gone into a clinical stage, probably due to insufficient information about the compound itself and P2X4 in general. One of such compounds, 5-(3-Bromophenyl)-1,3-dihydro-2H-Benzofuro[3,2-e]-1,4-diazepin-2-one (5-BDBD) is known to be widely used in P2X4-related studies despite its limited information. Therefore, this study aimed to (i) find a novel compound that can block the activation of P2X4 through high throughput screening and characterise it, and (ii) study structural-activity relationship between 5-BDBD and P2X4. Human P2X4 receptor was stably expressed in human 1321N1 astrocytoma cells and 1710 compounds from National Cancer Institute were screened for their activity at P2X4. Extensive tests led to identifying a natural product (thaspine) as the most potent inhibitor at reducing P2X4 activation. Further characterisation experiments revealed that thaspine had an IC50 value of 3.8 ± 0.2 μM and showed an allosteric mode, time-dependent and irreversible inhibition. Thaspine was similarly potent at mouse P2X4, but not effective at human P2X2, P2X2/3 and P2X7. It was also inactive at human P2Y2 and P2Y6 at concentrations below 10 μM and 30 μM respectively. In primary microglial cell model (BV2), it inhibited ivermectin-potentiated responses but not normal ATP-evoked responses. Meanwhile, 5-BDBD was found to be inhibiting P2X4 receptor competitively and diazepinone was a pivotal group of the structure to cause inhibition. The binding pocket of 5-BDBD at P2X4 was also predicted using molecular docking. In this study, a novel compound thaspine, has been shown to be effective at inhibiting human P2X4 and thus may have potential therapeutic applications while novel information about 5-BDBD was also acquired.
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Bezerra, Rômulo José Soares. "Triagem de extratos vegetais e fúngicos de diferentes biomas para identificação de antagonistas do receptor P2X7." reponame:Repositório Institucional da FIOCRUZ, 2012. https://www.arca.fiocruz.br/handle/icict/13174.
Full textAbstract:
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Previous issue date: 2016-02-23<br>O P2X7 é um receptor purinérgico que está envolvido em importantes funções fisiológicas e metabólicas, mas também tem participação em diversas patologias, principalmente aquelas de caráter inflamatório. Apesar de sua relevância, ainda não se têm disponíveis antagonistas específicos que possam ser utilizados na clínica para o tratamento de doenças relacionadas à ativação deste receptor. Muitos fármacos comercializados nos dias de hoje apresentam estruturas químicas relacionadas a um produto natural extraído de alguma espécie botânica de uso consagrado na medicina popular. Baseia-se nisso a relevância do estudo de produtos naturais para obtenção de uma atividade específica sobre alvos celulares. Logo, esse trabalho teve como interesse o estudo de extratos vegetais e fúngicos obtidos de espécies dos diferentes biomas, cedidos pelo LQPN do Centro de Pesquisas René Rachou \2013 Fiocruz-MG, visando á identificação de antagonistas para o receptor P2X7. Nosso primeiro passo foi à padronização de uma metodologia que permitiu a triagem de cerca de 60 extratos ao mesmo tempo, através da utilização de um espectrofotômetro de placas. Depois de padronizada, promovemos a aplicação dessa metodologia na triagem de 1800 extratos, dos quais apenas três extratos (8067,8549 e 8568) apresentaram atividade antagonista na faixa de corte pré-estabelecida [100 \03BCg/mL], com perfis de inibição de 65 %, 62 % e 61 % respectivamente, sobre o P2X7R. Destes extratos foram determinados os IC´s50 tanto em células de linhagem murina (2,1 \03BCg/mL; 2.6 \03BCg/mL e 3.8 \03BCg/mL) quanto em células de linhagem humana (0.69, 0.92 e 1.5 \03BCg/mL), sendo possível verificar maior atividade quando testados em células de linhagem humana
Posteriormente avaliamos a ação destes sobre funções fisiológicas relacionadas à ativação do P2X7R, nessa etapa, observamos o efeito inibitório destes extratos sobre a liberação de IL-1beta, ROS e NO, onde os três compostos foram capazes de inibir estas funções numa faixa entre 50 % a 60 %. Para obtermos uma caracterização do efeito farmacológico destes extratos sobre o receptor P2X7, realizamos experimentos de eletrofisiologia, caracterizando assim uma ação inibitória dose-dependente destes, sendo que nos respectivos IC´s50 os perfis de inibição da corrente foram de: 76 %, 47 % e 75 %. Também avaliamos a citotoxicidade in vitro utilizando as células de ambas às linhagens e verificamos que não apresentaram significativa toxicidade quando tratadas por 24 h. em doses até quatro vezes maiores que o IC50, visto que os resultados foram semelhantes ao controle não tratado. Depois de avaliarmos a atividade antagonista destes extratos in vitro, partimos para os experimentos in vivo utilizando os modelos de úlcera induzida por etanol e de dor neuropática e inflamatória, pois existem trabalhos previamente descritos na literatura que correlacionam a atividade do P2X7R com a evolução dessas patologias. No ensaio de dor neuropática, apenas dois extratos mostraram atividade analgésica (8067 e 8549) inibindo o estímulo de dor em 68 % e 66 %, porém no contexto da dor inflamatória os três extratos mostraram efeito analgésico, inibindo o estímulo em: 8067 = 48%, 8549 = 50% e 8568 = 44 %
Os resultados obtidos do experimento de úlcera induzida por etanol demonstraram o efeito inibitório sobre a formação de úlceras desses extratos em: 88 %, 84 % e 51 %, inclusive foram mais efetivos que o BBG (antagonista reversível deste receptor) e que o medicamento utilizado na clínica (Lansoprazol), os quais inibiram a formação de úlceras em 43 % e 46% respectivamente. Nosso conjunto de resultados apontam extratos com significativa atividade antagonista sobre o P2X7R, com potencial para o desenvolvimento de novos fármacos com grande interesse para a indústria farmacêutica, além de contribuir para o conhecimento acerca de propriedades medicinais presentes na biodiversidade<br>The purinergic receptor P2X7 is involved in important physiological and metabolic
functions, but it also participates in pathology, especially when inflammatory in character. Despite
the importance of P2X7, it has no specifi
c antagonists yet available for use in clinical treatment of
diseases related to the receptor's activation. Today, many drugs on the market have chemical
structures related to natural products obtained from botanical species with traditional use in
indigen
ous medicine, forming the basis for studying natural products to obtain specific activity on
cellular targets. This work focused primarily on the study of plant and fungal species extracts
obtained from different biomes provided by LQPN of the Research Cen
ter René Rachou
-
Fiocruz
-
MG, aiming to identify antagonists for the P2X7 receptor. The first step was to standardize a
method that allowed the screening of approximately 60 extracts at the same time through the use of
a plate spectrophotometer. Once stand
ardized, the application of this methodology was promoted in
the screening of 1800 extracts. Of these, only three extracts (8067, 8549 and 8568) showed
antagonistic activity in the pre
-
established cut range [100 mg/mL], with inhibition profiles of 65%,
62%
, and 61% respectively, on the P2X7R. Th
e
IC's50
of them were determinate
in murine (2.1,
2.6, and 3.8 mg/mL) and human (0.69, 0.92, and 1.5 mg/mL) cell lines.
Which an increased activity
was possible to verify when they were tested
in human cells. Consequ
ent evaluation of action on
physiological functions related to the activation of P2X7R revealed an inhibitory effect of these
extracts on the release of IL
-
1beta, NO, and ROS. The three tested compounds were able to inhibit
these functions in a range betwe
en 50% and 60%. To obtain a pharmacological characterization of
these extracts on the P2X7 receptor, electrophysiological experiments were conducted, which
characterized the dose
-
dependent inhibitory effects, exhibiting inhibitory current profiles of 76%,
47%, and 75%, respectively. In vitro cytotoxicity was also evaluated, using both cell strains,
showing no significant toxicity after 24 hours of treatment at doses of up to four times that of the
IC50; the results were similar to the untreated control. Aft
er evaluating the antagonistic activity of
these extracts in vitro, experiments using the in vivo models of ethanol
-
induced ulcers and
inflammatory and neuropathic pain were performed. Previous studies correlate the activity of the
P2X7R with the evolution
of these pathologies. In the neuropathic pain protocol experiment, only
two extracts showed analgesic activity (8067 and 8549) by inhibiting the pain stimulation by 68%
and 66%, but in the context of inflammatory pain, the three tested extracts showed ana
lgesic effects
by inhibiting the stimulus by the following percentages: 8067 = 48 %, 8549 = 50%, and 8568 =
44%. The results of the ethanol
-
induced ulcer demonstrated an inhibitory effect on the ulcer’s
development of 88%, 84%, and 51% by these extracts, a
nd found that the extracts were more
effective than BBG (reversible antagonist of this receptor) and the medicine used clinically
(Lansoprazole), which inhibited the formation of ulcers by 43% and 46%, respect
ively. The data set
links to extracts
with significant antagonist activity on the P2X7R,
and potential to the development xix
of new
medicines of
great interest to the pharmaceutical industry and important contributions to the
knowledge of medicinal properties present in biodiversity
Book chapters on the topic "P2X3 antagonist"
1
Gelin, Christine F., Anindya Bhattacharya, and Michael A. Letavic. "P2X7 receptor antagonists for the treatment of systemic inflammatory disorders." In Progress in Medicinal Chemistry. Elsevier, 2020. http://dx.doi.org/10.1016/bs.pmch.2019.11.002.
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Souza, Roberta Figueiroa, Mariá Munhoz Evangelinellis, Cristina Eusébio Mendes, Marta Righetti, Múcio Cevulla Silva Lourenço, and Patricia Castelucci. "P2X7 RECEPTOR ANTAGONIST RECOVERS ILEUM MYENTERIC NEURONS AFTER EXPERIMENTAL ULCERATIVE COLITIS." In Novas tecnologias e as competências técnico-científicas nas ciências biológicas. Atena Editora, 2022. http://dx.doi.org/10.22533/at.ed.9682223084.
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Chrovian, Christa C., Jason C. Rech, Anindya Bhattacharya, and Michael A. Letavic. "P2X7 Antagonists as Potential Therapeutic Agents for the Treatment of CNS Disorders." In Progress in Medicinal Chemistry. Elsevier, 2014. http://dx.doi.org/10.1016/b978-0-444-63380-4.00002-0.
Full textConference papers on the topic "P2X3 antagonist"
1
Smith, Jaclyn, and Rachel Giles. "Novel P2X3 antagonist can SOOTHE chronic cough." In ATS 2022 International Conference, edited by Richard Dekhuijzen. Medicom Medical Publishers, 2022. http://dx.doi.org/10.55788/7e412546.
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Friedrich, Christian, Klaus Francke, Surinder S. Birring, et al. "Safety and efficacy of P2X3 antagonist BAY 1902607 in refractory chronic cough." In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.4566.
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3
Martinez, F. J., A. Afzal, M. M. Kitt, et al. "The Treatment of Chronic Cough in Idiopathic Pulmonary Fibrosis Patients with Gefapixant, a P2x3 Receptor Antagonist." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a2638.
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Garceau, D., N. Chauret, and L. Harvey. "BLU-5937 a Highly Selective P2X3 Homotrimeric Receptor Antagonist with Improved Taste Safety Profile in Healthy Subjects." In American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a7396.
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Morice, A. H., J. Smith, L. McGarvey, et al. "Safety and Efficacy of BAY 1817080, a P2X3 Receptor Antagonist, in Patients with Refractory Chronic Cough (RCC)." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a7648.
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Ishihara, Hiroyuki, Hideaki Hida, Mitsuaki Machida, Yoshiyuki Tsuda, and Sayaka Miyazaki. "Design of phase 2b randomised controlled trial of S-600918, P2X3 receptor antagonist for refractory chronic cough." In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.2271.
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Smith, Jaclyn, Lorcan P. Mcgarvey, Alyn H. Morice, et al. "The effect of baseline factors on treatment response with MK-7264, a P2X3 antagonist, in refractory chronic cough." In ERS International Congress 2018 abstracts. European Respiratory Society, 2018. http://dx.doi.org/10.1183/13993003.congress-2018.pa811.
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McGarvey, Lorcan, Jaclyn Smith, Surinder Birring, et al. "Characterization of chronic cough patients participating in a phase 2b clinical trial of gefapixant, a P2X3 receptor antagonist." In ERS International Congress 2019 abstracts. European Respiratory Society, 2019. http://dx.doi.org/10.1183/13993003.congress-2019.pa612.
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Birring, Surinder S., Lorcan Mcgarvey, Jaclyn Smith, et al. "Baseline patient burden in chronic cough from a Phase 2b clinical trial of gefapixant, a P2X3 receptor antagonist." In ERS International Congress 2019 abstracts. European Respiratory Society, 2019. http://dx.doi.org/10.1183/13993003.congress-2019.pa613.
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Bonuccelli, C. M., J. Smith, S. S. Birring, et al. "Design of SOOTHE, a Phase 2b Dose Finding Study with BLU-5937, a Selective P2X3 Antagonist, in Refractory Chronic Cough." In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a2356.
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