![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
European Neuroscience Institute, Göttingen, Germany (S.-B.Y., M.R.); and Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Göttingen, Germany (F.M., L.F.T.)
Received March 18, 2005; accepted July 7, 2005.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
). However, effects of haloperidol other than D2 receptor antagonism have been observed. Up-regulation of A-type potassium channel on chronic haloperidol treatment has been proposed to suppress neuronal activity (Hahn et al., 2003). Conversely, acute application of haloperidol has been reported to block numerous types of ion channels, including ATP-sensitive potassium channel (Yang et al., 2004), G protein-activated inwardly rectifying potassium channel (Kobayashi et al., 2000), and human ether-a-go-go-related gene (HERG) potassium channels (Shuba et al., 2001). Drug-induced torsade de pointes, a lethal type of cardiac arrhythmia, has been correlated with blocking of the HERG channel by certain compounds, including haloperidol (Brown et al., 2004; Testai et al., 2004). Therefore, understanding the basic mechanism of drug-channel interaction may provide useful information for structure-based drug design (Fermini and Fossa, 2003).
Potassium channels have been found in all the known organisms and exhibit a high level of heterogeneity (Jan and Jan, 1997). Aberrant activity of potassium channels has been shown in pathophysiological conditions, such as neurologic disorders, cardiac arrhythmia, and diabetes (Shieh et al., 2000). Therefore, the therapeutic and toxicologic aspects of drug-induced alterations in potassium channel activity are particularly relevant (Fermini and Fossa, 2003; Testai et al., 2004). Slow opening and lack of a fast inactivation process characterize delayed-rectifier potassium channels (KDR). Because of the nature of its kinetics, modification of KDR channel activity affects the shape and duration of action potentials (Bekkers, 2000). Prolonged opening of the channels can lead to elevation of the local extracellular potassium concentration [K+]o. Under pathological conditions, even a moderate increase in [K+]o drastically influences neuronal excitability and synaptic transmission (Moulder et al., 2004). On the other hand, [K+]o also regulates potassium channel kinetics (Kuo, 1997), and interactions between drugs with ion channels can be modified at different [K+]o (Kuo, 1998; Jo et al., 2000; Yang et al., 2004).
In humans, haloperidol is metabolized via three major pathways. One metabolic route is oxidative N-dealkylation by cytochrome P450 and generates two metabolites, 4-chloro-4-hydroxypiperidine (4C4HP) and 3-fluorobenzoyl propionic acid (3FBPA). About 20% of haloperidol is degraded via this pathway. Another 50 to 60% of haloperidol is glucuronidated at the hydroxyl group and excreted in the urine. Alternatively, about 20 to 30% of haloperidol is reduced at the carbonyl group by ketone reductase and converted to reduced haloperidol (R-haloperidol) (Froemming et al., 1989; Kudo and Ishizaki, 1999). R-Haloperidol is believed to have little clinical relevance because the binding affinity to D2 receptors is fairly low compared with haloperidol (Kirch et al., 1985). However, its prolonged half-life and bigger volume of distribution (Vd) than haloperidol produces a substantial buildup of R-haloperidol in certain tissues (Korpi et al., 1984). Because it can be oxidized back to haloperidol through the cytochrome P450 system, R-haloperidol has been proposed as an in vivo haloperidol reservoir (Kudo and Ishizaki, 1999).
In this study, we investigated the effect of R-haloperidol and other chemically related compounds on KDR channels in mouse cortical neurons. We found that R-haloperidol is an open channel blocker for KDR channels. The binding site of R-haloperidol is located at the intracellular side of the channel. Binding of R-haloperidol to the KDR channel is modulated by [K+]o.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Electrophysiology. Potassium currents were recorded from cultured cortical neurons using standard whole-cell patch-clamp configuration by an EPC10 amplifier (HEKA, Lambrecht/Pfalz, Germany). Data were acquired at 20 kHz with PULSE8.6 software (HEKA). Pipettes were pulled from 1.5-mm borosilicate glass capillaries (Harvard Apparatus Inc., Holliston, MA), and their tips were heat-polished using a microforge (MF830; Narishige, Tokyo, Japan). Pipette resistances were 3 to 5 M
in standard intracellular solution. Recordings with series resistance higher than 20 M were excluded from this study. Unless otherwise indicated, the KDR currents were elicited by 400-ms voltage steps from holding potential at -40 mV to +100 mV every 6 s. The capacitive transients were subtracted online by the P/4 method. All the experiments were done at room temperature (20–25°C).
Solutions and Chemicals. The extracellular solution contained 150 mM NaCl, 10 mM HEPES, 5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, and 5 mM 4-aminopyridine (4-AP) with pH adjusted to 7.2 (by NaOH). In certain experiments, equimolar KCl or RbCl was used to replace NaCl, and pH was adjusted by adding KOH or RbOH, respectively. The intracellular solution contained 150 mM KCl, 10 mM HEPES, 1 mM MgCl2, 5 mM Na2ATP, and 5 mM EGTA, with pH adjusted to 7.2 (by KOH). Na2ATP (5 mM) and EGTA (5 mM) were added to block ATP-sensitive potassium currents (IKATP) and Ca2+-activated potassium currents (IKCa) (Speier et al., 2005). Contamination by voltage-activated sodium and calcium currents at voltage steps to +100 mV was negligible; therefore, no blockers were added to the extracellular solution. KCl (150 mM) in the intracellular solution was substituted with equimolar RbCl in some experiments. In these experiments, a minimum of 2 min was used for dialysis to diminish the contamination with residual intracellular potassium ions. The osmolarity of all the solutions was 300 ± 10 mOsm/l. The recording chamber had a volume of 2 ml, and chemicals were focally applied to the cell through a self-made manifold pipe and driven by gravity with a flow rate of 5 ml/min.
L-741,626, sulpiride, and loperamide were purchased from Tocris Cookson Inc. (Bristol, UK), and 4C4HP was obtained from Alfa Aesar (Ward Hill, MA). All the other chemicals were from Sigma-Aldrich Laborchemikalien (Seelze, Germany). Haloperidol, R-haloperidol, 4C4HP, 3FBPA, sulpiride, and L-741,626 were dissolved in dimethyl sulfoxide. The final concentrations of dimethyl sulfoxide were less than 0.1%, which did not affect the potassium currents tested.
N-Methyl-R-haloperidol (N-Me-R-haloperidol) was synthesized from haloperidol as follows. NaBH4 (50 mg, 1.33 mmol) was added to a stirred solution of haloperidol (500 mg, 1.33 mmol) in MeOH (50 ml) at room temperature for 80 min; water (10 ml) then was added. After 15 min, the solvent was removed in vacuo, and the resulting crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 10:1) to provide R-haloperidol (450 mg, 90%) as a white powder.
A solution of R-haloperidol (100 mg, 265 µmol) in acetone (1 ml) was treated drop-wise with CH3I (18 µl, 291 µmol) and heated under microwave irradiation conditions (Personal Chemistry SmithCreator microwave reactor; Biotage, Charlottesville, VA) at 60°C for 1 h. The solvent was then removed in vacuo, and the resulting crude product was recrystallized from CH2Cl2 to give the desired N-Me-R-haloperidol iodide (85 mg, 62%) as a pale yellow solid, which was subjected to 1H NMR, 13C NMR, and mass spectroscopy. The obtained spectra matched the proposed structure of N-Me-R-haloperidol iodide.
Data Analysis. Curve fitting was done using PulseFit v8.65 (HEKA) and SigmaPlot v8.0 (SPSS Inc., Chicago, IL). Data are given as mean ± S.E.M., and n indicates the number of cells analyzed. Statistical significance of the difference between the samples was determined using Student's t test. The clogP value of each compound was predicted by using OSIRIS software (Actelion, South San Francisco, CA). The pKa value of R-haloperidol was predicted by SciFinder database (Chemical Abstracts Service, Columbus, OH).
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). We used the standard pharmacological method to isolate KDR currents by including 4-AP into the extracellular solution. Figure 1A shows typical currents recorded from a cortical pyramidal neuron. The fast inactivating potassium currents (A-type K+ currents) were suppressed by holding cells at -40 mV and adding 4-AP to the extracellular solutions further decreased the peak currents (Fig. 1B). The residual currents were insensitive to 4-AP and can be further blocked by tetraethylammonium extracellularly (data not shown), which resembles the typical KDR currents (Bekkers, 2000). To reduce the contaminations of A-type potassium currents with minimum effects on KDR currents, 5 mM 4-AP was added into the extracellular solutions.
|
Block of KDR Currents by Haloperidol and Its Metabolites. We first examined the block of KDR current by haloperidol and its metabolites listed in Fig. 2A. Haloperidol blocked the KDR currents in a reversible manner (Fig. 2B). The concentration-dependence curve was constructed by fitting data to the Hill equation (Fig. 2C):
 | (1) |
|
Sidedness of R-Haloperidol Block. Potassium channels possess multiple drug binding sites, and some are only accessible from one side of the plasma membrane. R-haloperidol is a tertiary amine, and it can either directly bind to its binding site from the extracellular side or diffuse across the plasma membrane and dock to the binding site on the cytoplasmic side (Hille, 1977). To explore the sidedness of R-haloperidol binding, we synthesized N-Me-R-haloperidol, the quaternary amine derivative of R-haloperidol (Fig. 3A). Because it contains a permanent charge, it cannot cross the plasma membrane easily as its tertiary amine form when applied to either side of the membrane. Extracellular N-Me-R-haloperidol only partially blocks the KDR current even at concentrations above 100 µM (Fig. 3, B and D), but 100 µM N-Me-R-haloperidol significantly blocked the KDR currents when included in the intracellular solutions (Fig. 3, C and D). The diffusion of intracellular N-Me-R-haloperidol was so fast that the characteristic blocking kinetics could be observed in the first trace after the establishment of whole-cell configuration (Fig. 3C). Assuming N-Me-R-haloperidol binds to the same binding site as R-haloperidol, these experiments implied that R-haloperidol has to cross the membrane to access its binding site.
|
). To assess the voltage-dependent block of R-haloperidol on KDR currents, we used 400-ms voltage steps from -40 mV to potentials between +20 and +100 mV (Fig. 4A). R-Haloperidol (10 µM) blocked these currents to a similar extent (Fig. 4B). To quantify the voltage dependence of the R-haloperidol block, the normalized currents were plotted against the membrane potential and fitted by the Woodhull equation (Choi et al., 2001):
 | (2) |
is the fractional electrical distance from the external surface of the pore. F is the Faraday constant, V is the membrane potential, T is the absolute temperature, and R is the gas constant. A value of 25 was used for RT/F because the experiments were performed at room temperature (20°C). The calculated fractional electrical distance was 0.07 (Fig. 4C), indicating a weak voltage dependence of R-haloperidol block.
|
Elevation of [K+]o Reduces the Affinity of R-Haloperidol to KDR Channels. Binding of haloperidol and other compounds to the potassium channels is sensitive to the [K+]o (Kuo, 1998; Boccaccio et al., 2004; Yang et al., 2004). The interaction of R-haloperidol and [K+]o was tested by increasing the [K+]o from 5 to 150 mM, and the degree of R-haloperidol block of KDR currents was decreased at high [K+]o (Fig. 5, A and B). The concentration-dependence curve was shifted toward the right, and the IC50 of R-haloperidol was elevated from 4.4 µM at 5 mM [K+]o to 21 µM at 150 mM [K+]o (Fig. 5E). However, when potassium ions on both sides of the membrane were substituted by rubidium, another potassium channel permeant ion, the Rb+ currents were blocked by R-haloperidol to a similar extent, irrespective of [Rb+]o (Fig. 5, C, D, and F).
|
R-Haloperidol not only decreased the current amplitude but also changed the kinetics by accelerating the current decay (Fig. 2F). This implied that R-haloperidol preferentially binds to an open state of the channels. We further analyzed the kinetics of the R-haloperidol binding and the effect of external ions on the binding kinetics. Current traces at different R-haloperidol concentrations were point-by-point divided by the trace recorded in control conditions, and these normalized traces were fitted by a single exponential function (Fig. 6, A–D):
 | (3) |
-1) is the inverted decay time constant of each normalized current trace and was increased at higher concentration of R-haloperidol (Fig. 6, E and F). This result suggests a bimolecular interaction between R-haloperidol and channels in the open state as shown in the following scheme:
 |
|
The block rate can be expressed as:
 | (4) |
The kon values were comparable at either 5 or 150 mM [K+]o, but the koff values were accelerated at 150 mM [K+]o (Fig. 6E). In contrast, the binding and unbinding kinetics of R-haloperidol were insensitive to [Rb+]o (Fig. 6F); the kon was about twice as fast in rubidium solutions than in potassium solutions, and the koff at both [Rb+]o was comparable with the koff at low [K+]o (Fig. 6A).
The intercept of the normalized current traces on the y-axis represents the fraction of channels blocked before they opened (Fig. 6, A–D). Therefore, the affinity of R-haloperidol to the channels in the closed state can be estimated by plotting the y-intercept versus R-haloperidol concentration. The apparent binding affinities to the channel in the closed state were also decreased in the presence of extracellular potassium ions (Fig. 6G).
Block of KDR Channels by Compounds Functionally or Structurally Related to Haloperidol. The backbone structure of R-haloperidol is similar to haloperidol, although the affinity to D2 receptor is reduced by about two orders of magnitude (Kirch et al., 1985; Froemming et al., 1989). Thus, binding of R-haloperidol to KDR channels does not correlate to the D2 receptor potency. To address the active chemical moiety, several compounds with either functional or structural similarity were tested (Fig. 7A). Sulpiride, another D2 receptor antagonist with similar potency as haloperidol but structurally unrelated, did not inhibit the potassium currents when applied extracellularly (Fig. 7B). In contrast, L-741,626, a D2 receptor antagonist with a similar chlorophenyl piperidine moiety, blocked the potassium currents to a similar extent as R-haloperidol (Fig. 7, C and D). If the chlorophenyl piperidine moiety determines the block ability, other compounds with this fragment should also block the channels. Loperamide, an antidiarrheal drug that activates opioid receptors, also contains this fragment. Therefore, we tested whether loperamide also blocked the KDR currents. To avoid the activation of opioid receptor, 10 µM naloxone was continuously present in the extracellular solution before and during the application of loperamide. KDR currents were not affected in the presence of 10 µM naloxone (data not shown). We found that loperamide was even more potent than other compounds tested, with an IC50 value of 0.75 µM (Fig. 7, E and F).
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Binding Site of R-Haloperidol on the KDR Channels. According to the scheme shown in eq. 4, R-haloperidol binds to the KDR channel in the open state. If the binding of R-haloperidol to the KDR channels did not have the preferential state, a proportional reduction of current size should have been expected without altering the channel kinetics. There are two lines of evidence suggesting that R-haloperidol has a higher affinity to open KDR channels. First, the current decayed faster at higher R-haloperidol concentration (Fig. 6). Equation 4 predicts a one-to-one relationship between R-haloperidol and the KDR channel, and the binding rate should be linearly related to the ligand concentration. Second, the IC50 of R-haloperidol to the closed channels was estimated to be 76 µM, which was more than 10 times higher than 4.4 µM, the IC50 of the R-haloperidol block to the open channels (Figs. 2G and 5G). The voltage gate of potassium channels is located at the cytoplasmic end of the channel protein (Jiang et al., 2002). Therefore, we propose that the binding site of R-haloperidol is either formed or accessible when the channel is opened. The quaternary amine binding has been located in the central cavity of the channel (Zhou et al., 2001), and we also have shown that the N-Me-R-haloperidol, the quaternary amine derivative of R-haloperidol, preferentially blocked the KDR currents from the intracellular side (Fig. 3). The fractional electrical distance of 0.07 indicated a weak voltage dependence of R-haloperidol block (Fig. 4). When the channel is in its open configuration, the voltage decreases significantly across the selective filter, and the central cavity is at the same membrane potential as the cytosolic solution (Jiang et al., 2002). If the R-haloperidol binding site is in the central cavity and it is only accessible when the channel is open, it is plausible that the R-haloperidol block is independent of membrane voltage. Nevertheless, we cannot exclude the possibility that R-haloperidol blocks the channel in its neutral form.
Interaction of R-Haloperidol and External Cations on the KDR Channels. Raising of [K+]o reduced the R-haloperidol binding affinity to its binding site, whereas an increase in [Rb+]o, another potassium channel permeant ion, does not produce a similar effect (Figs. 5 and 6). Interactions between permeant ions and blockers have been observed previously (Kuo, 1998; Boccaccio et al., 2004; Yang et al., 2004; Yang and Kuo, 2005). The main effect of external K+ is accelerating the unbinding of R-haloperidol from the KDR channel; therefore, it seems that only K+, but not Rb+, can knock off the R-haloperidol from its binding site. According to the structure of a potassium channel, the selective filter has different conformation when crystallized in solutions with different K+ concentrations, but not Rb+. Based on this scenario, the selective filter has a low energy barrier for K+, and this ion can freely move across the filter, but it functions as a molecular hurdle for other permeant ions, for example, Rb+ or Cs+; even these ions can traverse through the channel as K+ (Morais-Cabral et al., 2001; Zhou and MacKinnon, 2003). Increase of external K+ but not Rb+ boosts the ion flow through the permeant pathway and therefore pushes R-haloperidol out from the binding site. Recently, Lin et al. (2005) reported a similar phenomenon that K+ but not Cs+ regulates the binding of cisapride, a prokinetic compound, to HERG channels. Nevertheless, the possibility of allosteric modulation of a channel by K+ cannot be completely ruled out.
Nature of the Binding Motif on R-Haloperidol. The ability of compounds to block the KDR channels is dependent on the existence of the 4C4HP fragment but is not related to the pharmacological character of the compounds. We found a linear relationship between the logIC50 and calculated the hydrophobicity index (clogP) in compounds containing the 4C4HP fragment (Fig. 8). We proposed that the 4C4HP is the key fragment that binds to the KDR channel, and the affinity of 4C4HP is enhanced by adding a hydrophobic motif at the nitrogen atom on the piperidine ring, which increases the accessibility of 4C4HP to its intracellular binding site. On the other hand, increase of hydrophobicity also facilitates the binding of the active fragment to the receptor, and the hydrophobic motif functioned as a "binder" of the active fragment. The binder concept was recently suggested in a fragment-based lead discovery, in which optimizing the binder part of the molecule augments the binding affinity (Rees et al., 2004). It has been shown that increase of the hydrophobicity of quaternary amines enhances the binding affinity to its binding site (Choi et al., 1993). The chemical nature of the binder can be unspecific because the key fragment determines the main biological effect. Therefore, it is worth checking the channel blocking ability of compounds with the 4C4HP motif at an early stage of drug development to avoid adverse effects caused by ion channel blocking (Fermini and Fossa, 2003).
|
The oxygen atom in the carbonyl group has been proposed to involve the binding of haloperidol to the central cavity of HERG channels in an in silico study (Testai et al., 2004). Most compounds listed in that study have already been reported as blockers for other potassium channels, including KDR channels. R-Haloperidol, in contrast, has a hydroxyl group at this position. Nevertheless, the binding affinities to the KDR channel of both R-haloperidol and haloperidol were comparable. It is likely the role of carbonyl oxygen was over-estimated in the above-mentioned in silico study (Testai et al., 2004).
Therapeutic and Toxicological Relevance of R-Haloperidol Block on KDR Channels. The plasma concentration of haloperidol and R-haloperidol is between 10 and 100 nM (Chang et al., 1989; Kudo and Ishizaki, 1999; Roh et al., 2001), which is about two orders of magnitude below the IC50 to block KDR channels. Our results indicated the block of KDR currents by haloperidol and/or R-haloperidol does not produce clinically relevant symptoms. However, in occasional cases, micromolar haloperidol and R-haloperidol have been detected in human cortex (Korpi et al., 1984; Kornhuber et al., 1999). A portion of potassium channels could be blocked under at these concentrations. The local concentration of haloperidol and R-haloperidol cannot be predicted from the plasma haloperidol concentration, and haloperidol metabolism is variable among different individuals (Chang et al., 1989; Lam et al., 1995; Roh et al., 2001). Adverse effects related to the R-haloperidol block of KDR channels can be expected, particularly when other drugs capable of modifying metabolic enzymes are coprescribed (Kudo and Ishizaki, 1999).
The loperamide block of KDR channel in cortical neurons should not be relevant because of the poor bioavailability and restricted blood-brain barrier penetration. The antidiarrheal effect of loperamide is suggested to result from a decrease in the local ganglia activity in the enteric nervous system (Awouters et al., 1983). Although the plasma concentration of loperamide is fairly low, in the nanomolar range, the local concentration in the gut may be much higher because of the low solubility and enterohepatic shunt (Awouters et al., 1983). Loperamide has been shown to decrease potassium efflux from epithelial cells, and direct block of potassium channels may be one explanation for this phenomenon (Epple et al., 2001). Interestingly, haloperidol has already been shown to reduce the fluid secretion in rabbit and human small intestine mucosa, a property that is necessary for antidiarrheal treatment (Smith and Field, 1980).
In conclusion, we have found that R-haloperidol, a main metabolite of haloperidol, is an open channel blocker for neuronal KDR channels. The binding site is intracellular, as N-Me-R-haloperidol, a quaternary amine form of R-haloperidol, preferentially blocked the channel from intracellular side. Our findings also suggest the 4C4HP motif is the main fragment blocking the channel because increasing the hydrophobicity of compounds containing 4C4HP enhances the binding to the KDR channels. Although the concentration of R-haloperidol needed to block the KDR channels is above the clinical relevant range, it may produce some pharmacological or toxic effects because of the polymorphism of enzymes metabolizing haloperidol.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: HERG, human ether-a-go-go-related gene; KDR, delayed-rectifier potassium channel(s); 4C4HP, 4-chlorophenyl-4-hydroxypiperidine; 3FBPA, 3-fluorobenzoyl propionic acid; R-haloperidol, reduced haloperidol; 4-AP, 4-aminopyridine; L-741,626, 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-L-yl]methyl-1H-indole; N-Me-R-haloperidol, N-methyl-reduced haloperidol.
Address correspondence to: Shi-Bing Yang, Waldweg 33, 37073 Göttingen, Germany. E-mail: syang1{at}gwdg.de
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Awouters F, Niemegeers CJ, and Janssen PA (1983) Pharmacology of antidiarrheal drugs. Annu Rev Pharmacol Toxicol 23: 279-301.[CrossRef][Medline]
Bekkers JM (2000) Properties of voltage-gated potassium currents in nucleated patches from large layer 5 cortical pyramidal neurons of the rat. J Physiol 525: 593-609.
Boccaccio A, Conti F, Olivera BM, and Terlau H (2004) Binding of kappa-conotoxin PVIIA to Shaker K+ channels reveals different K+ and Rb+ occupancies within the ion channel pore. J Gen Physiol 124: 71-81.
Brown CS, Farmer RG, Soberman JE, and Eichner SF (2004) Pharmacokinetic factors in the adverse cardiovascular effects of antipsychotic drugs. Clin Pharmacokinet 43: 33-56.[Medline]
Chang WH, Lin SK, Jann MW, Lam YW, Chen TY, Chen CT, Hu WH, and Yeh EK (1989) Pharmacodynamics and pharmacokinetics of haloperidol and reduced haloperidol in schizophrenic patients. Biol Psychiatry 26: 239-249.[Medline]
Choi BH, Choi JS, Yoon SH, Rhie DJ, Min DS, Jo YH, Kim MS, and Hahn SJ (2001) Effects of norfluoxetine, the major metabolite of fluoxetine, on the cloned neuronal potassium channel Kv3.1. Neuropharmacology 41: 443-453.[CrossRef][Medline]
Choi KL, Mossman C, Aube J, and Yellen G (1993) The internal quaternary ammonium receptor site of Shaker potassium channels. Neuron 10: 533-541.[CrossRef][Medline]
Epple HJ, Fromm M, Riecken EO, and Schulzke JD (2001) Antisecretory effect of loperamide in colon epithelial cells by inhibition of basolateral K+ conductance. Scand J Gastroenterol 36: 731-737.[Medline]
Fermini B and Fossa AA (2003) The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov 2: 439-447.[CrossRef][Medline]
Froemming JS, Lam YW, Jann MW, and Davis CM (1989) Pharmacokinetics of haloperidol. Clin Pharmacokinet 17: 396-423.[Medline]
Garcia-Ferreiro RE, Kerschensteiner D, Major F, Monje F, Stuhmer W, and Pardo LA (2004) Mechanism of block of hEag1 K+ channels by imipramine and astemizole. J Gen Physiol 124: 301-317.
Hahn J, Tse TE, and Levitan ES (2003) Long-term K+ channel-mediated dampening of dopamine neuron excitability by the antipsychotic drug haloperidol. J Neurosci 23: 10859-10866.
Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69: 497-515.
Jan LY and Jan YN (1997) Cloned potassium channels from eukaryotes and prokaryotes. Annu Rev Neurosci 20: 91-123.[CrossRef][Medline]
Jiang Y, Lee A, Chen J, Cadene M, Chait BT, and MacKinnon R (2002) The open pore conformation of potassium channels. Nature (Lond) 417: 523-526.[CrossRef][Medline]
Jo SH, Youm JB, Lee CO, Earm YE, and Ho WK (2000) Blockade of the HERG human cardiac K(+) channel by the antidepressant drug amitriptyline. Br J Pharmacol 129: 1474-1480.[CrossRef][Medline]
Kirch DG, Palmer MR, Egan M, and Freedman R (1985) Electrophysiological interactions between haloperidol and reduced haloperidol and dopamine, norepinephrine and phencyclidine in rat brain. Neuropharmacology 24: 375-379.[Medline]
Kobayashi T, Ikeda K, and Kumanishi T (2000) Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes. Br J Pharmacol 129: 1716-1722.[CrossRef][Medline]
Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter CH, Zochling R, Boissl KW, Leblhuber F, and Riederer P (1999) Persistence of haloperidol in human brain tissue. Am J Psychiatry 156: 885-890.
Korpi ER, Kleinman JE, Costakos DT, Linnoila M, and Wyatt RJ (1984) Reduced haloperidol in the post-mortem brains of haloperidol-treated patients. Psychiatry Res 11: 259-269.[CrossRef][Medline]
Kudo S and Ishizaki T (1999) Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet 37: 435-456.[CrossRef][Medline]
Kuo CC (1997) Deactivation retards recovery from inactivation in Shaker K+ channels. J Neurosci 17: 3436-3444.
Kuo CC (1998) Imipramine inhibition of transient K+ current: an external open channel blocker preventing fast inactivation. Biophys J 75: 2845-2857.
Lam YW, Jann MW, Chang WH, Yu HS, Lin SK, Chen H, and Davis CM (1995) Intra- and interethnic variability in reduced haloperidol to haloperidol ratios. J Clin Pharmacol 35: 128-136.[Abstract]
Lin J, Guo J, Gang H, Wojciechowski P, Wigle JT, and Zhang S (2005) Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels. Mol Pharmacol 68: 855-865.
Morais-Cabral JH, Zhou Y, and MacKinnon R (2001) Energetic optimization of ion conduction rate by the K+ selectivity filter. Nature (Lond) 414: 37-42.[CrossRef][Medline]
Moulder KL, Meeks JP, Shute AA, Hamilton CK, de Erausquin G, and Mennerick S (2004) Plastic elimination of functional glutamate release sites by depolarization. Neuron 42: 423-435.[CrossRef][Medline]
Rees DC, Congreve M, Murray CW, and Carr R (2004) Fragment-based lead discovery. Nat Rev Drug Discov 3: 660-672.[CrossRef][Medline]
Roh HK, Chung JY, Oh DY, Park CS, Svensson JO, Dahl ML, and Bertilsson L (2001) Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients. Br J Clin Pharmacol 52: 265-271.[CrossRef][Medline]
Seeman P and Van Tol HH (1994) Dopamine receptor pharmacology. Trends Pharmacol Sci 15: 264-270.[CrossRef][Medline]
Shieh CC, Coghlan M, Sullivan JP, and Gopalakrishnan M (2000) Potassium channels: molecular defects, diseases and therapeutic opportunities. Pharmacol Rev 52: 557-594.
Shuba YM, Degtiar VE, Osipenko VN, Naidenov VG, and Woosley RL (2001) Testosterone-mediated modulation of HERG blockade by proarrhythmic agents. Biochem Pharmacol 62: 41-49.[CrossRef][Medline]
Smith PL and Field M (1980) In vitro antisecretory effects of trifluoperazine and other neuroleptics in rabbit and human small intestine. Gastroenterology 78: 1545-1553.[Medline]
Speier S, Yang SB, Sroka K, Rose T, and Rupnik M (2005) KATP-channels in beta-cells in tissue slices are directly modulated by millimolar ATP. Mol Cell Endocrinol 230: 51-58.[CrossRef][Medline]
Testai L, Bianucci AM, Massarelli I, Breschi MC, Martinotti E, and Calderone V (2004) Torsadogenic cardiotoxicity of antipsychotic drugs: a structural feature, potentially involved in the interaction with cardiac HERG potassium channels. Curr Med Chem 11: 2691-2706.[Medline]
Trimmer JS and Rhodes KJ (2004) Localization of voltage-gated ion channels in mammalian brain. Annu Rev Physiol 66: 477-519.[CrossRef][Medline]
Yang SB, Proks P, Ashcroft FM, and Rupnik M (2004) Inhibition of ATP-sensitive potassium channels by haloperidol. Br J Pharmacol 143: 960-967.[CrossRef][Medline]
Yang YC and Kuo CC (2005) An inactivation stabilizer of the Na+ channel acts as an opportunistic pore blocker modulated by external Na+. J Gen Physiol 125: 465-481.
Zhou M, Morais-Cabral JH, Mann S, and MacKinnon R (2001) Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors. Nature (Lond) 411: 657-661.[CrossRef][Medline]
Zhou Y and MacKinnon R (2003) The occupancy of ions in the K+ selectivity filter: charge balance and coupling of ion binding to a protein conformational change underlie high conduction rates. J Mol Biol 333: 965-975.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  D. V. Vasilyev, Q. Shan, Y. Lee, S. C. Mayer, M. R. Bowlby, B. W. Strassle, E. J. Kaftan, K. E. Rogers, and J. Dunlop Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons J Neurophysiol, May 1, 2007; 97(5): 3713 - 3721. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
