Inverse agonism at G protein‐coupled receptors: (patho)physiological relevance and implications for drug discovery

Ligt, Rianne A.F. de; Kourounakis, Angeliki P.; IJzerman, Adriaan P.

doi:10.1038/sj.bjp.0703311

Cited by 174 publications

(110 citation statements)

References 72 publications

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“…messenger systems [6]. Pharmacological differences in terms of neutral antagonists and inverse agonists, however, have been determined [7]. In the AR research field, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, an agent with a xanthinic scaffold) is widely used as a reference A 1 R antagonist in preclinical studies.…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Lu¹,

Wang²,

Zhang³

et al. 2014

Purinergic Signalling

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Potent and selective adenosine A 1 receptor (A 1 AR) antagonists with favourable pharmacokinetic properties used as novel diuretics and antihypertensives are desirable. Thus, we designed and synthesized a series of novel 4-alkylamino substitution-2-arylpyrazolo[4,3-c]quinolin-3-one derivatives. The aim of the present study is to characterize the biological profiles of the optimized compound, PQ-69. In vitro binding assay revealed a K i value of 0.96 nM for PQ-69 in cloned hA 1 receptor, which was 217-fold more selective compared with hA 2A receptors and >1,000-fold selectivity for hA 1 over hA 3 receptor. The results obtained from [ 35 S]-GTPγS binding and cAMP concentration assays indicated that PQ-69 might be an A 1 AR antagonist with inverse agonist activity. In addition, PQ-69 displayed highly inhibitory activities on isolated guinea pig contraction (pA2 value of 8.99) induced by an A 1 AR agonist, 2-chloro-N6-cyclopentyl adenosine. Systemic administration of PQ-69 (0.03, 0.3, 3 mg/kg) increased urine flow and sodium excretion in normal rats. Furthermore, PQ-69 displayed better metabolic stability in vitro and longer terminal elimination half-life (t 1/2 ) in vivo compared with 1,3-dipropyl-8-cyclopentylxanthine. These findings suggest that PQ-69 exhibits potent antagonist effects on A 1 AR in vitro, ex vivo and in vivo, it might be a useful research tool for investigating A 1 AR function, and it could be developed as a potential therapeutic agent.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Lu¹,

Wang²,

Zhang³

et al. 2014

Purinergic Signalling

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“…This is an increase from only 12.9% of control astrocytes exhibiting spontaneous activity in the soma to 42.1% in the TTX incubated astrocytes ( Figure 3E). Because it is known that GPCRs exhibit "intrinsic" or constitutive activity in the absence of agonist 21,26,28 , and that the level of this intrinsic activity increases with increasing receptor expression levels, these data suggest that the density of astrocytic Gq GPCRs increases following long-term reduction in neuronal action potential firing. Similar to agonist-evoked responses, the rise times of the spontaneous Ca 2+ elevations are also increased ( Figure 3E).…”

Section: Representative Resultsmentioning

confidence: 90%

Inducing Plasticity of Astrocytic Receptors by Manipulation of Neuronal Firing Rates

Xie

Lauderdale

Murphy

et al. 2014

JoVE

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Close to two decades of research has established that astrocytes in situ and in vivo express numerous G protein-coupled receptors (GPCRs) that can be stimulated by neuronally-released transmitter. However, the ability of astrocytic receptors to exhibit plasticity in response to changes in neuronal activity has received little attention. Here we describe a model system that can be used to globally scale up or down astrocytic group I metabotropic glutamate receptors (mGluRs) in acute brain slices. Included are methods on how to prepare parasagittal hippocampal slices, construct chambers suitable for long-term slice incubation, bidirectionally manipulate neuronal action potential frequency, load astrocytes and astrocyte processes with fluorescent Ca 2+ indicator, and measure changes in astrocytic Gq GPCR activity by recording spontaneous and evoked astrocyte Ca 2+ events using confocal microscopy. In essence, a "calcium roadmap" is provided for how to measure plasticity of astrocytic GqGPCRs. Applications of the technique for study of astrocytes are discussed. Having an understanding of how astrocytic receptor signaling is affected by changes in neuronal activity has important implications for both normal synaptic function as well as processes underlying neurological disorders and neurodegenerative disease. Video LinkThe video component of this article can be found at

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“…This equilibrium is not shifted by the antagonists because they present equivalent affinity for the inactive R and the active R* functional states of the receptor. Several reviews of the inverse agonism have appeared [19,31,41,128,176].…”

Section: Molecular Mechanism Of Receptor-g Protein Couplingmentioning

confidence: 99%

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

González-Maeso

Meana²

2006

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Mood disorders such as major depression and bipolar disorder are common, severe, chronic and often lifethreatening illnesses. Suicide is estimated to be the cause of death in up to approximately 10-15% of individuals with mood disorders. Alterations in the signal transduction through G protein-coupled receptor (GPCR) pathways have been reported in the etiopathology of mood disorders and the suicidal behavior. In this regard, the implication of certain GPCR subtypes such as 2A -adrenoceptor has been repeatedly described using different approaches. However, several discrepancies have been recently reported in density and functional status of the heterotrimeric G proteins both in major depression and bipolar disorder. A compilation of the most relevant research topics about the implication of heterotrimeric G proteins in the etiology of mood disorders (i.e., animal models of mood disorders, studies in peripheral tissue of depressive patients, and studies in postmortem human brain of suicide victims with mood disorders) will provide a broad perspective of this potential therapeutic target field. Proposed causes of the discrepancies reported at the level of G proteins in postmortem human brain of suicide victims will be discussed.

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Inverse agonism at G protein‐coupled receptors: (patho)physiological relevance and implications for drug discovery

Cited by 174 publications

References 72 publications

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

Inducing Plasticity of Astrocytic Receptors by Manipulation of Neuronal Firing Rates

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

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