A5023826878- Adenosine and Purinergic Signaling
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Amino Acid Enzymes and Metabolism
- Neuropeptides and Animal Physiology
- Epigenetics and DNA Methylation
- Pharmacological Receptor Mechanisms and Effects
- Cardiac Ischemia and Reperfusion
- Synthesis and Biological Evaluation
- Photoreceptor and optogenetics research
- RNA modifications and cancer
- Lysosomal Storage Disorders Research
- Tryptophan and brain disorders
- Neuroendocrine regulation and behavior
- Histone Deacetylase Inhibitors Research
- Ion channel regulation and function
- Immune Cell Function and Interaction
- Mast cells and histamine
- Asthma and respiratory diseases
- Vagus Nerve Stimulation Research
- Immunodeficiency and Autoimmune Disorders
- Cardiac electrophysiology and arrhythmias
- Immunotherapy and Immune Responses
- Neurotransmitter Receptor Influence on Behavior
- Sirtuins and Resveratrol in Medicine
Temple University
2013-2021
United States Military Academy
2000-2016
Jacobs (United Kingdom)
2013
Merck & Co., Inc., Rahway, NJ, USA (United States)
1989-2010
Psychiatry Research Trust
2010
Schizophrenia Research Institute
2009
Bayer (Germany)
2007
Merck (Germany)
1998-2007
Université Libre de Bruxelles
2007
Oklahoma Medical Research Foundation
2007
Background— Ecto-5′-nucleotidase (CD73)–dependent adenosine generation has been implicated in tissue protection during acute injury. Once generated, can activate cell-surface receptors (A 1 AR, A 2A 2B 3 AR). In the present study, we define contribution of to cardioprotection by ischemic preconditioning. Methods and Results— On basis observations CD73 induction preconditioning, found that inhibition or targeted gene deletion cd73 abolished infarct size-limiting effects. Moreover,...
The human A3 adenosine receptor was cloned from a striatal cDNA library using probe derived the homologous rat sequence. encodes protein of 318 amino acids and exhibits 72% 85% overall identity with sheep sequences, respectively. Specific saturable binding agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine [125I]ABA measured on stably expressed in Chinese hamster ovary cells Kd = 10 nM. potency order for agonists N-ethylcarboxamidoadenosine (NECA) > or (R)-N6-phenyl-2-propyladenosine...
The forebrain cholinergic system promotes higher brain function in part by signaling through the M(1) muscarinic acetylcholine receptor (mAChR). During Alzheimer's disease (AD), these neurons degenerate, therefore selectively activating receptors could improve cognitive patients while avoiding unwanted peripheral responses associated with non-selective agonists. We describe here benzyl quinolone carboxylic acid (BQCA), a highly selective allosteric potentiator of mAChR. BQCA reduces...
The A<sub>3</sub> adenosine receptor (A3AR) is one of four subtypes for and expressed in a broad spectrum tissues. In order to study the function A3AR, mouse line carrying mutant allele was generated. Mice homozygous targeted disruption <i>A3AR</i> gene,<i>A3AR</i> <sup>−/−</sup>, are fertile visually histologically indistinguishable from wild type mice. lack functional <sup>−/−</sup> mice confirmed by molecular pharmacological analyses. absence A3AR protein expression demonstrated...
We found that 3-cyano-<i>N</i>-(1,3-diphenyl-1<i>H</i>-pyrazol-5-yl)benzamide (CDPPB) is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). In Chinese hamster ovary cells expressing human mGluR5, CDPPB potentiated threshold responses to in fluorometric Ca<sup>2+</sup> assays more than 7-fold with an EC<sub>50</sub> value approximately 27 nM. At 1 μM, shifted mGluR5 agonist concentration response curves glutamate, quisqualate,...
The molecular and neuronal substrates conferring on clozapine its unique superior efficacy in the treatment of schizophrenia remain elusive. interaction with many G protein-coupled receptors is well documented but less known about biologically active metabolite, N -desmethylclozapine. Recent clinical preclinical evidences antipsychotic activity muscarinic agonist xanomeline prompted us to investigate effects -desmethylclozapine cloned human M1-M5 receptors. preferentially bound M1 an IC 50...
We have identified a family of highly selective allosteric modulators the group I metabotropic glutamate receptor subtype 5 (mGluR5). This closely related analogs exerts spectrum effects, ranging from positive to negative modulation, and includes compounds that do not themselves modulate mGluR5 agonist activity but rather prevent other members exerting their modulatory effects. 3,3′-Difluorobenzaldazine (DFB) has no activity, it acts as modulator human rat mGluR5. DFB potentiates threshold...
Abstract Objective Low‐dose weekly methotrexate therapy remains a mainstay in the treatment of inflammatory arthritis. Results previous studies demonstrated that adenosine, acting at one or more its receptors, mediates antiinflammatory effects animal models both acute and chronic inflammation. We therefore sought to establish which receptor(s) is involved modulation inflammation by nonpolyglutamated analog MX‐68 ( N ‐[[4‐[(2,4‐diaminopteridin‐6‐yl)methyl]‐3,4‐dihydro‐2 H...
Adenosine has potent effects on both the cardiovascular and immune systems. Exposure of tissues to adenosine results in increased vascular permeability extravasation serum proteins. The mechanism by which brings about these physiological changes is poorly defined. Using mice deficient A3 receptor (A3AR), we show that increases cutaneous observed after treatment with or its principal metabolite inosine are mediated through A3AR. fails increase mast cell–deficient mice, suggesting this tissue...
We found that N-[4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl]-2-hydroxybenzamide (CPPHA), is a potent and selective positive allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). CPPHA alone had no agonist activity acted as human rat mGluR5. potentiated threshold responses to in fluorometric Ca(2+) assays 7- 8-fold with EC(50) values 400 800 nM range, at 10 microM shifted mGluR5 concentration-response curves glutamate, quisqualate,...
The A3 adenosine receptor is widely expressed in human tissues with the most abundant expression lung and liver, but predominant cellular localization functions of this humans are unknown. Since influences activation circulating resident inflammatory cells within leads to exaggerated airway narrowing individuals disorders, we hypothesized that gene localized upregulated inflammation. Lung tissue were obtained at thoracotomy from nonsmoking subjects disorders associated tobacco smoke or...
Abstract Adenosine has been implicated to play a role in asthma part through its ability influence mediator release from mast cells. Most physiological roles of adenosine are mediated receptors; however, the mechanisms by which influences lung cells not understood. We established primary murine cell cultures and used real-time RT-PCR immunofluorescence demonstrate that A2A, A2B, A3 receptors expressed on Studies using selective receptor agonists antagonists suggested activation could induce...
Mice deficient in the neurotensin (NT)-1 receptor (NTR1) were developed to characterize NT subtypes that mediate various vivo responses NT. F2 generation (C57BL6/Sv129J) NTR1 knockout (-/-) mice viable, and showed normal growth overt behavior. The -/- lacked detectable radioligand binding brain, whereas NTR2 density appeared compared with wild-type (+/+) mice. gene deletion also resulted loss of expression as determined by reverse transcription-polymerase chain reaction situ hybridization....
Abstract Adenosine signaling has been implicated in chronic lung diseases such as asthma and obstructive pulmonary disease; however, the specific roles of various adenosine receptors processes central to these disorders are not well understood. In this study, we have investigated role(s) A3 receptor adenosine-dependent inflammation observed deaminase (ADA)-deficient mice. The (A3R) was found be expressed eosinophils mucus-producing cells airways ADA-deficient Treatment mice with MRS 1523, a...
Over half of all antibiotics target the bacterial ribosome-nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind 50S subunit with nM affinity inhibit protein synthesis blocking passage nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered combinatorial copper-catalyzed click chemistry, was synthesized in situ incubating either E. coli 70S ribosomes or...
Bi-allelic GBA1 mutations cause Gaucher's disease (GD), the most common lysosomal storage disorder. Neuronopathic manifestations in GD include neurodegeneration, which can be severe and rapidly progressive. are also frequent genetic risk factors for Parkinson's disease. Dysfunction of autophagy-lysosomal pathway represents a key pathogenic event GBA1-associated neurodegeneration. Using an induced pluripotent stem cell (iPSC) model GD, we previously demonstrated that alterations neurons...
Calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), amylin and calcitonin (CT) are structurally functionally related neuropeptides. It has recently been shown that the molecular pharmacology of CGRP ADM is determined by coexpression one three receptor activity-modifying proteins (RAMPs) with receptor-like (CRLR). Furthermore, RAMP have also to govern receptor, which in association RAMP1 or RAMP3, binds high affinity. In this study, we cloned rat family characterized receptors. Rat...
We used pharmacological agents and genetic methods to determine whether the potent A<sub>3</sub> adenosine receptor (AR) agonist 2-chloro-<i>N</i><sup>6</sup>-(3-iodobenzyl)adenosine-5′-<i>N</i>-methylcarboxamide (Cl-IB-MECA) protects against myocardial ischemia/reperfusion injury in mice via A<sub>3</sub>AR or interactions with other AR subtypes. Pretreating wild-type (WT) Cl-IB-MECA reduced infarct size induced by 30 min of coronary occlusion 24 h reperfusion at doses (30 100 μg/kg) that...
Multiple studies indicate that <i>N</i>-methyl-d-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA function is to enhance occupancy glycine modulatory site on by increasing availability endogenous coagonists d-serine. Here, we characterized a novel d-amino acid oxidase (DAAO) inhibitor, compound 8 [4<i>H</i>-thieno [3,2-<i>b</i>]pyrrole-5-carboxylic acid] and compared it Compound moderately potent inhibitor...
Abstract Activation of adenosine A3 receptors (A3-R) produced a dose-dependent reduction in the chemotaxis human eosinophils to platelet-activating factor (PAF), RANTES, and leukotriene B4 (LTB4) maximum 58,48, 52%, respectively (P &lt; 0.02). This effect was completely reversed by selective A3-R antagonists. In contrast, activation A1 or A2a-R did not affect PAF-induced eosinophil chemotaxis. PAF upregulated expression CD11b/CD18, down-regulated L-selectin, also increased F-actin...