Classic D1 Dopamine Receptor Antagonist<i>R</i>-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1<i>H</i>-3-benzazepine hydrochloride (SCH23390) Directly Inhibits G Protein-Coupled Inwardly Rectifying Potassium Channels

Kuzhikandathil, Eldo V.; Oxford, Gerry S.

doi:10.1124/mol.62.1.119

Cited by 95 publications

(80 citation statements)

References 28 publications

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“…As opposed to these drugs, citalopram, which only slightly inhibits GIRK channels even at toxic concentrations, has a lower seizure risk (Barbey and Roose, 1998). The inhibition of GIRK channels leads to depolarize the membrane potential, resulting in an increase in neuronal excitability (Kuzhikandathil and Oxford, 2002). In addition, GIRK2-deficient mice show spontaneous seizures (Signorini et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Kobayashi

Washiyama

Ikeda

2004

Neuropsychopharmacol

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G protein-activated inwardly rectifying K þ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage-and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A 1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

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Section: Discussionmentioning

confidence: 99%

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Kobayashi

Washiyama

Ikeda

2004

Neuropsychopharmacol

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“…For U50488H, the inhibitory concentration (IC 50 ) for inhibition of the GIRK1/2 heteromultimeric channel was 70.28 Ϯ 3.68 M. 45 However, lack of complete inhibition of the platelet functional responses by 200 M SCH23390 and 100 M U50488H in our experiments argues against a homogeneous population of GIRK1/GIRK2 heteromultimeric channels and could be due to the presence of multiple combinations of the different GIRK subunits on platelets, differing potency of GIRK inhibitors with the varying subunit assembly, or tissue-specific GIRK channel splice variants in platelets. 64 Previous studies have implicated Rap 1b and PI3-kinase ␥ as possible signaling molecules downstream of the P2Y 12 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

“…60 As there is no dopamine source present in our experiments, we conclude that SCH23390 is not mediating its effects through the dopamine D1 receptor. Toward ascertaining the specificity of SCH23390, we used SKF38393, a structurally similar compound that lacks the GIRK channel-blocking ability, 45 in our study. SKF38393 did not have any effect on agonist-induced platelet aggregation, implying that effects seen with SCH23390 are mainly due to GIRK channel blockade.…”

Section: Discussionmentioning

confidence: 99%

“…5,57 To investigate the specificity of SCH23390 toward blocking GIRK channels we used SKF38393, which is structurally related to SCH23390 but inactive at blocking GIRK channels. 45 We evaluated the effect of SKF38393 (200 M) on ADP-, 2-MeSADP-, U46619-, and low-dose thrombin-induced aggregation. We noticed that SKF38393 did not affect platelet aggregation induced by any of the above agonists ( Figure 2F).…”

Section: Effect Of Girk Inhibitors On Agonist-induced Platelet Aggregmentioning

confidence: 99%

“…35,[41][42][43][44] Recently, 2 structurally unrelated compounds, SCH23390 (R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(Ϯ)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), were shown to directly block GIRK channels with different potencies. 45,46 In this study, we used a pharmacologic approach to investigate whether GIRK channels mediate any of the downstream effects of P2Y 12 receptor activation in platelets, culminating in fibrinogen receptor activation. We demonstrate that 2 structurally distinct GIRK channel blockers inhibit P2Y 12 receptor-mediated functional responses in platelets, while sparing functional responses associated with G q signaling.…”

Section: Introductionmentioning

confidence: 99%

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Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

Shankar

Murugappan²,

Kim³

et al. 2004

Blood

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The role of the G i -coupled platelet P2Y 12 receptor in platelet function has been well established. However, the functional effector or effectors contributing directly to ␣IIb␤3 activation in human platelets has not been delineated. As the P2Y 12 receptor has been shown to activate G protein-gated, inwardly rectifying potassium (GIRK) channels, we investigated whether GIRK channels mediate any of the functional responses of the platelet P2Y 12 receptor. Western blot analysis revealed that platelets express GIRK1, GIRK2, and GIRK4. In aspirin-treated and washed human platelets, 2 structurally distinct GIRK inhibitors, SCH23390 (R(؉)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride) and U50488H (trans-(؎)-3,4-dichloro-N-methyl-N-[2-(pyrrolidinyl)cyclohexyl] benzeneacetamide methanesulfonate), inhibited adenosine diphosphate (ADP)-, 2-methylthioADP (2-MeSADP)-, U46619-, and low-dose thrombin-mediated platelet aggregation. However, the GIRK channel inhibitors did not affect platelet aggregation induced by high concentrations of thrombin, AYPGKF, or convulxin. Furthermore, the GIRK channel inhibitors reversed SFLLRN-induced platelet aggregation, inhibited the P2Y 12 -mediated potentiation of dense granule secretion and Akt phosphorylation, and did not affect the agonist-induced G qmediated platelet shape change and intracellular calcium mobilization. Unlike AR-C 69931MX, a P2Y 12 receptor-selective antagonist, the GIRK channel blockers did not affect the ADP-induced adenlylyl cyclase inhibition, indicating that they do not directly antagonize the P2Y 12 receptor. We conclude that GIRK channels are important functional effectors of the P2Y 12 receptor in human platelets. IntroductionPlatelets play an important role in normal hemostasis and abnormal activation of platelets leads to thrombosis. During vascular injury or conditions of high shear, exposure of the collagen-rich subendothelium activates the platelets and results in the formation of a stable thrombus due to the combined action of adenosine diphosphate (ADP) secreted from platelet-dense granules and generated thrombin. 1 Any perturbations in this system can have pathologic cardiovascular implications such as intravascular thrombus formation and vascular occlusion.ADP is an important component of the platelet-dense granules and also an important platelet agonist that stimulates platelets by acting on the G q -coupled P2Y 1 receptor and G i -coupled P2Y 12 receptor. 2,3 Once released, it amplifies the primary responses of other agonists such as collagen and thrombin, leading to enhanced platelet aggregation and stability of the thrombus. 4,5 It is now well established that concomitant signaling through G q -coupled P2Y 1 and G i -coupled P2Y 12 is necessary and sufficient for the integrin GPIIb/IIIa activation. 3 Furthermore, selective G i activation, when coupled with selective G 12/13 stimulation, also results in platelet aggregation. 6,7 Notably, the P2Y 12 -coupled G i signaling is also crucial for potentiating dense...

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A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects

Spiros

Roberts

Geerts

2012

Drug Development Research

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Despite tremendous advances in understanding the neurobiology of schizophrenia, no real therapeutic breakthrough in terms of novel antipsychotics has been made since the serendipitous discovery of chlorpromazine. We describe a computer-based mechanistic disease simulation model of biophysically realistic neurons that captures most of the subcortical neuromodulatory processes important in the pathophysiology of schizophrenia and calibrate this with a large retrospective clinical database for Positive and Negative Symptoms Scale in Schizophrenia (PANSS total) and extrapyramidal symptoms (EPS) liability. Additionally we make this platform more actionable for practical use in central nervous system drug discovery by introducing a synaptic receptor competition model that accurately captures clinical target exposures. The model accounts for threefold more variance than the simple dopamine D2 receptor occupancy rule and is also superior in a number of independent clinical data sets. As such, the model is a first step in a better understanding of the human neurobiology of schizophrenia. Using human pharmacology and a positron emission tomography target engagement study as input, the model can estimate a value for the clinical efficacy on PANSS total and EPS side effect liability for the clinical doses of a new investigative compound. This Quantitative Systems Pharmacology platform, by simulating the effect of co-medications and genotypes in a clinical setting, represents a useful addition to psychiatric drug discovery efforts. Drug Dev Res 73 : 196-213, 2012.

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Classic D1 Dopamine Receptor AntagonistR-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) Directly Inhibits G Protein-Coupled Inwardly Rectifying Potassium Channels

Cited by 95 publications

References 28 publications

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Various Antidepressant Drugs

Role of G protein–gated inwardly rectifying potassium channels in P2Y12 receptor–mediated platelet functional responses

A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects

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