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Article: P2X7 receptor antagonists for the treatment of systemic inflammatory disorders.

Gelin, Christine F / Bhattacharya, Anindya / Letavic, Michael A

2020 Volume 59, Page(s) 63–99

Abstract: P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been ... ...

Abstract	P2X7 has continued to be a target of immense interest since it is implicated in several peripheral and central nervous system disorders that result from inflammation. This review primarily describes new P2X7 receptor antagonists that have been investigated and disclosed in patent applications or primary literature since 2015. While a crystal structure of the receptor to aid in the design of novel chemical structures remains elusive, many of the chemotypes that have been disclosed contain similarities, with an amide motif present in all series that have been explored to date. Several of the recent antagonists described are brain penetrant, and two compounds are currently in clinical trials for CNS indications. Additionally, brain penetrant PET ligands have been developed that aid in measuring target engagement and these ligands can potentially be used as biomarkers.
MeSH term(s)	Humans ; Ligands ; Molecular Structure ; Mood Disorders/drug therapy ; Mood Disorders/metabolism ; Non-alcoholic Fatty Liver Disease/drug therapy ; Non-alcoholic Fatty Liver Disease/metabolism ; Purinergic P2X Receptor Antagonists/chemistry ; Purinergic P2X Receptor Antagonists/pharmacology ; Receptors, Purinergic P2X7/metabolism
Chemical Substances	Ligands ; P2RX7 protein, human ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7
Language	English
Publishing date	2020-01-31
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	209306-6
ISSN	1875-7863 ; 0079-6468
ISSN (online)	1875-7863
ISSN	0079-6468
DOI	10.1016/bs.pmch.2019.11.002
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Article ; Online: Molecular determinants of ASIC1 modulation by divalent cations.

Liu, Yi / Ma, Jichun / DesJarlais, Renee L / Hagan, Rebecca / Rech, Jason / Liu, Changlu / Miller, Robyn / Schoellerman, Jeffrey / Luo, Jinquan / Letavic, Michael / Grasberger, Bruce / Maher, Michael P

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2320

Abstract: Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent ... ...

Abstract	Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent cations are not well understood. Previously, we identified two small molecules that bind to ASIC1a at a novel site in the acidic pocket and modulate ASIC1 gating in a manner broadly resembling divalent cations, raising the possibility that these small molecules may help to illuminate the molecular determinants of gating modulation by divalent cations. Here, we examined how these two groups of modulators might interact as well as mutational effects on ASIC1a gating and its modulation by divalent cations. Our results indicate that binding of divalent cations to an acidic pocket site plays a key role in gating modulation of the channel.
MeSH term(s)	Cations, Divalent/metabolism ; Acid Sensing Ion Channels/metabolism ; Protons ; Mutation
Chemical Substances	Cations, Divalent ; Acid Sensing Ion Channels ; Protons
Language	English
Publishing date	2024-01-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-52845-3
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Article ; Online: Discovery of a Series of Substituted 1

Gelin, Christine F / Stenne, Brice / Coate, Heather / Hiscox, Afton / Soyode-Johnson, Akinola / Wall, Jessica L / Lord, Brian / Schoellerman, Jeffrey / Coe, Kevin J / Wang, Kai / Alcázar, Jesus / Chrovian, Christa C / Dvorak, Curt A / Carruthers, Nicholas I / Koudriakova, Tatiana / Balana, Bartosz / Letavic, Michael A

Journal of medicinal chemistry

2023 Volume 66, Issue 4, Page(s) 2877–2892

Abstract: Herein, we describe a series of substituted ... ...

Abstract	Herein, we describe a series of substituted 1
MeSH term(s)	Animals ; Rats ; Brain/metabolism ; Pyrimidines ; Receptors, N-Methyl-D-Aspartate/metabolism ; Structure-Activity Relationship
Chemical Substances	NR2B NMDA receptor ; Pyrimidines ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2023-02-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01916
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Article ; Online: The evolution of P2X7 antagonists with a focus on CNS indications.

Rech, Jason C / Bhattacharya, Anindya / Letavic, Michael A / Savall, Brad M

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 16, Page(s) 3838–3845

Abstract: The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of ... ...

Abstract	The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists.
MeSH term(s)	Animals ; Central Nervous System Diseases/drug therapy ; Central Nervous System Diseases/metabolism ; Clinical Trials as Topic ; Cytokines/metabolism ; Half-Life ; Humans ; Inflammation/prevention & control ; Protein Binding ; Purinergic P2X Receptor Antagonists/chemistry ; Purinergic P2X Receptor Antagonists/pharmacokinetics ; Purinergic P2X Receptor Antagonists/therapeutic use ; Receptors, Purinergic P2X7/chemistry ; Receptors, Purinergic P2X7/metabolism
Chemical Substances	Cytokines ; Purinergic P2X Receptor Antagonists ; Receptors, Purinergic P2X7
Language	English
Publishing date	2016--15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.06.048
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Article: P2X7 antagonists as potential therapeutic agents for the treatment of CNS disorders.

Chrovian, Christa C / Rech, Jason C / Bhattacharya, Anindya / Letavic, Michael A

Progress in medicinal chemistry

2014 Volume 53, Page(s) 65–100

Abstract: The use of P2X7 antagonists to treat inflammatory disorders has garnered considerable interest in recent years. An increasing number of literature reports support the role of P2X7 in inflammatory pathways of the peripheral and central nervous systems ( ... ...

Abstract	The use of P2X7 antagonists to treat inflammatory disorders has garnered considerable interest in recent years. An increasing number of literature reports support the role of P2X7 in inflammatory pathways of the peripheral and central nervous systems (CNSs). A number of CNS indications such as neuropsychiatric and neurodegenerative disorders and neuropathic pain have been linked to a neuroinflammatory response, and clinical studies have shown that inflammatory biomarkers can be mitigated by modulating P2X7. Recent scientific and patent literature describing novel P2X7 antagonists has indicated their use in CNS disorders. In addition, several reports have disclosed the results of administering P2X7 antagonists in pre-clinical models of CNS disease or investigating brain uptake. This review describes small molecule P2X7 antagonists that have first appeared in the literature since 2009 and have potential therapeutic utility in the CNS, or for which new data have emerged implicating their use in CNS indications.
MeSH term(s)	Animals ; Central Nervous System Diseases/drug therapy ; Clinical Trials as Topic ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases/drug therapy ; Purinergic P2X Receptor Antagonists/therapeutic use
Chemical Substances	Purinergic P2X Receptor Antagonists
Language	English
Publishing date	2014
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	209306-6
ISSN	1875-7863 ; 0079-6468
ISSN (online)	1875-7863
ISSN	0079-6468
DOI	10.1016/B978-0-444-63380-4.00002-0
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Article ; Online: Histamine H3 antagonists as wake-promoting and pro-cognitive agents.

Stocking, Emily M / Letavic, Michael A

Current topics in medicinal chemistry

2008 Volume 8, Issue 11, Page(s) 988–1002

Abstract: The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control ... ...

Abstract	The histamine H3 receptor is a pre-synaptic auto- and hetero-receptor that controls the release of histamine and a variety of other neurotransmitters in the brain. As such, modulation of the histamine H(3) receptor is expected to affect wake via control of the release of histamine and to affect cognition via regulation of several other neurotransmitters including acetylcholine and norepinephrine. Over the last several years numerous pre-clinical studies have shown that histamine H3 antagonists promote wakefulness, improve cognition, and in some cases affect food intake. Based on the interest level generated from these early pharmacology studies, and following the cloning and expression of the human histamine H3 receptor, many pharmaceutical companies began drug discovery programs aimed at the identification of histamine H3 antagonists suitable for human clinical trials. These efforts have led to many new chemotypes, and several promising compounds have recently entered the clinic for a variety of conditions, including ADHD, Narcolepsy, EDS associated with Narcolepsy, Cognitive disorders and Schizophrenia. Recent efforts towards the identification and pharmacological characterization of novel histamine H3 antagonists will be discussed.
MeSH term(s)	Arousal/drug effects ; Central Nervous System Stimulants/chemistry ; Central Nervous System Stimulants/pharmacology ; Cognition/drug effects ; Histamine H3 Antagonists/chemistry ; Histamine H3 Antagonists/pharmacology ; Humans ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Central Nervous System Stimulants ; Histamine H3 Antagonists
Language	English
Publishing date	2008-07-24
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/156802608784936728
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Article: 1

Chrovian, Christa C / Soyode-Johnson, Akinola / Wall, Jessica L / Rech, Jason C / Schoellerman, Jeff / Lord, Brian / Coe, Kevin J / Carruthers, Nicholas I / Nguyen, Leslie / Jiang, Xiaohui / Koudriakova, Tatiana / Balana, Bartosz / Letavic, Michael A

ACS medicinal chemistry letters

2019 Volume 10, Issue 3, Page(s) 261–266

Abstract: Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a ... ...

Abstract	Herein, we disclose a series of selective GluN2B negative allosteric modulators containing a 1
Language	English
Publishing date	2019-01-10
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.8b00542
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Article ; Online: Molecular mechanism and structural basis of small-molecule modulation of the gating of acid-sensing ion channel 1.

Liu, Yi / Ma, Jichun / DesJarlais, Renee L / Hagan, Rebecca / Rech, Jason / Lin, David / Liu, Changlu / Miller, Robyn / Schoellerman, Jeffrey / Luo, Jinquan / Letavic, Michael / Grasberger, Bruce / Maher, Michael

Communications biology

2021 Volume 4, Issue 1, Page(s) 174

Abstract: Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key ... ...

Abstract	Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.
MeSH term(s)	Acid Sensing Ion Channels/chemistry ; Acid Sensing Ion Channels/drug effects ; Acid Sensing Ion Channels/genetics ; Acid Sensing Ion Channels/metabolism ; Animals ; Binding Sites ; CHO Cells ; Cricetulus ; Ion Channel Gating/drug effects ; Kinetics ; Membrane Potentials ; Membrane Transport Modulators/chemistry ; Membrane Transport Modulators/pharmacology ; Mutation ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; Tachyphylaxis
Chemical Substances	Acid Sensing Ion Channels ; Asic1 protein, rat ; Membrane Transport Modulators
Language	English
Publishing date	2021-02-09
Publishing country	England
Document type	Journal Article
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-021-01678-1
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Article: Selective Inhibition of Orexin-2 Receptors Prevents Stress-Induced ACTH Release in Mice.

Yun, Sujin / Wennerholm, Michelle / Shelton, Jonathan E / Bonaventure, Pascal / Letavic, Michael A / Shireman, Brock T / Lovenberg, Timothy W / Dugovic, Christine

Frontiers in behavioral neuroscience

2017 Volume 11, Page(s) 83

Abstract: Orexins peptides exert a prominent role in arousal-related processes including stress responding, by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptors located widely throughout the brain. Stress or orexin administration stimulates hyperarousal, ... ...

Abstract	Orexins peptides exert a prominent role in arousal-related processes including stress responding, by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptors located widely throughout the brain. Stress or orexin administration stimulates hyperarousal, adrenocorticotropic hormone (ACTH) and corticosterone release, and selective OX1R blockade can attenuate several stress-induced behavioral and cardiovascular responses but not the hypothalamic-pituitary-adrenal (HPA) axis activation. As opposed to OX1R, OX2R are preferentially expressed in the paraventricular hypothalamic nucleus which is involved in the HPA axis regulation. In the present study, we investigated the effects of a psychological stress elicited by cage exchange (CE) on ACTH release in two murine models (genetic and pharmacological) of selective OX2R inhibition. CE-induced stress produced a significant increase in ACTH serum levels. Mice lacking the OX2R exhibited a blunted stress response. Stress-induced ACTH release was absent in mice pre-treated with the selective OX2R antagonist JNJ-42847922 (30 mg/kg po), whereas pre-treatment with the dual OX1/2R antagonist SB-649868 (30 mg/kg po) only partially attenuated the increase of ACTH. To assess whether the intrinsic and distinct sleep-promoting properties of each antagonist could account for the differential stress response, a separate group of mice implanted with electrodes for standard sleep recording were orally dosed with JNJ-42847922 or SB-649868 during the light phase. While both compounds reduced the latency to non-rapid eye movement (NREM) sleep without affecting its duration, a prevalent REM-sleep promoting effect was observed only in mice treated with the dual OX1/2R antagonist. These data indicate that in a psychological stress model, genetic or pharmacological inhibition of OX2R markedly attenuated stress-induced ACTH secretion, as a separately mediated effect from the NREM sleep induction of OX2R antagonism.
Language	English
Publishing date	2017-05-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2017.00083
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Article ; Online: Preclinical Evaluation and Nonhuman Primate Receptor Occupancy Study of

Kolb, Hartmuth C / Barret, Olivier / Bhattacharya, Anindya / Chen, Gang / Constantinescu, Cristian / Huang, Chaofeng / Letavic, Michael / Tamagnan, Gilles / Xia, Chunfang A / Zhang, Wei / Szardenings, Anna Katrin

Journal of nuclear medicine : official publication, Society of Nuclear Medicine

2019 Volume 60, Issue 8, Page(s) 1154–1159

Abstract: The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in ... ...

Abstract	The P2X7 receptor is an adenosine triphosphate-gated ion channel, which is abundantly expressed in glial cells within the central nervous system and in the periphery. P2X7 receptor activation leads to the release of the proinflammatory cytokine IL-1β in the brain, and antagonism of the P2X7 receptor is a novel therapeutic strategy to dampen adenosine triphosphate-dependent IL-1β signaling. PET ligands for the P2X7 receptor will not only be valuable to assess central target engagement of drug candidates but also hold promise as surrogate markers of central neuroinflammation. Herein we describe the in vitro and in vivo evaluation of
MeSH term(s)	Animals ; Blood-Brain Barrier/drug effects ; Brain/drug effects ; Female ; Humans ; In Vitro Techniques ; Inflammation/diagnostic imaging ; Kinetics ; Ligands ; Macaca mulatta ; Male ; Mice, Knockout ; Peptides/pharmacology ; Permeability/drug effects ; Positron-Emission Tomography ; Protein Binding ; Pyrimidines/pharmacology ; Radiochemistry ; Radiopharmaceuticals/pharmacology ; Rats ; Receptors, Purinergic P2X7/metabolism ; Tissue Distribution ; Treatment Outcome
Chemical Substances	(18)F-JNJ-64413739 ; Ligands ; P2RX7 protein, human ; Peptides ; Pyrimidines ; Radiopharmaceuticals ; Receptors, Purinergic P2X7
Language	English
Publishing date	2019-02-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80272-4
ISSN	1535-5667 ; 0097-9058 ; 0161-5505 ; 0022-3123
ISSN (online)	1535-5667
ISSN	0097-9058 ; 0161-5505 ; 0022-3123
DOI	10.2967/jnumed.118.212696
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