The Experts below are selected from a list of 261 Experts worldwide ranked by ideXlab platform
Nicholas M Barnes - One of the best experts on this subject based on the ideXlab platform.
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3h Zacopride ligand for the identification of 5 ht3 recognition sites
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Nicholas M Barnes, B Costall, R J NaylorAbstract:[3H]Zacopride displayed saturable binding to homogenates of the rat entorhinal cortex as measured by the inclusion of the 5-HT3 receptor antagonist BRL43694 in the incubation media. Scatchard analysis indicated a single high affinity binding site (KD 0.76 +/- 0.08 nM, Bmax 77.5 +/- 6.5 fmol (mg protein)-1) with a Hill slope close to unity. Other 5-HT3 receptor antagonists (Zacopride, ICS 205-930, GR38032F, GR65630, metoclopramide and cocaine) also competed for the binding site displacing 60% of the total [3H]Zacopride binding. 5-HT and 2-methyl-5-HT also were competitive antagonists for [3H]Zacopride binding whereas 5-HT1/5-HT2 agonists and antagonists, and agents acting on other neurotransmitter receptors had Ki values greater than 10(-5) M. It is concluded that [3H]Zacopride may prove a useful ligand for the study of 5-HT3 recognition sites.
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autoradiographic localization of the 3h s Zacopride labelled 5 ht3 receptor in porcine brain
Neuroscience Letters, 1999Co-Authors: Stephanie Fletcher, Nicholas M BarnesAbstract:Using the technique of in vitro receptor autoradiography, we have determined the distribution of the [3H]-(S)-Zacopride labelled 5-HT3 receptor in porcine brain. Highest densities of 5-HT3 receptor-associated [3H]-(S)-Zacopride binding were detected in areas of porcine spinal cord, nodose ganglion, trigeminal nerve nucleus, area postrema and cerebral cortex, with relatively lower levels in other brain regions (e.g. hippocampus, caudate-putamen). The distribution of [3H]-(S)-Zacopride binding in porcine forebrain provides further evidence for inter-species differences with respect to the differential expression of the 5-HT3 receptor in the forebrain.
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distribution of s Zacopride insensitive 125i r Zacopride binding sites in the rat brain and peripheral tissues
European Journal of Pharmacology, 1997Co-Authors: Janine M Barnes, Patrick Towers, Nicholas M BarnesAbstract:Increasing evidence indicates that the 5-HT3 receptor antagonist R(+)-Zacopride labels an additional site in brain tissue that is not sensitive to 5-HT (non-5-HT R(+)-Zacopride site, R(+)-site). Since the levels of R(+)-sites in the brain are relatively low, the present studies explored the use of [125I]R(+)-Zacopride to label the R(+)-site; the incorporation of an [125I] atom considerably increasing the specific activity of the radioligand relative to [3H]R(+)-Zacopride that has been utilised previously. Competition experiments with [125I]R(+)-Zacopride (1.0 nM) binding to rat whole brain homogenates, in the presence of the 5-HT3 receptor antagonist granisetron (1.0 microM), identified that R(+)-Zacopride and prazosin bound to two sites (pIC50: 7.59 and 5.28, respectively, for R(+)-Zacopride; 6.75 and 4.42, respectively, for prazosin) whereas S(-)-Zacopride and mianserin possessed relatively low affinity (pIC50: 4.37 and 3.80, respectively) while (-)sulpiride and 5-HT failed to compete for [125I]R(+)-Zacopride binding at concentrations up to 10 microM. Autoradiographic radioligand binding studies using [125I]R(+)-Zacopride (0.5 nM) identified a heterogeneous distribution of specific binding sites (defined by unlabelled R(+)-Zacopride, 1.0 microM) throughout the rat brain. In the presence of a saturating concentration of granisetron (1.0 microM), highest levels of specific [125I]R(+)-Zacopride, binding sites (defined by R(+)-Zacopride, 1.0 microM; R(+)-site), were detected in the olfactory tubercle, thalamus, corpus callosum, colliculus, dorsal and median raphe nucleus, spinal cord and the pons (8.0-13.0 fmol/mg). Moderate densities of R(+)-sites were located in the striatum, nucleus accumbens, substantia nigra, ventral tegmental area, globus pallidus, septal nuclei, frontal cortex and cerebellum (2.0-7.9 fmol/mg). In the hippocampus, amygdala and cortical areas. R(+)-site levels were low but detectable (0.1-1.9 fmol/mg). [125I]R(+)-Zacopride labelled R(+)-sites were also detected in some rat peripheral tissues, for instance kidney cortex, adrenal gland and liver (2.4-6.8 fmol/mg). The present results indicate that specific non-5-HT [125I]R(+)-Zacopride sites are heterogeneously distributed throughout the rat brain and are expressed in various peripheral tissues.
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autoradiographic distribution of 3h s Zacopride labelled 5 ht3 receptors in human brain
Journal of the Neurological Sciences, 1996Co-Authors: Rachel M C Parker, Janine M Barnes, Peter C Barber, Nicholas M BarnesAbstract:Autoradiographic binding studies using the 5-HT3 (5-hydroxytryptamine3) receptor radioligand, [3H]-(S)-Zacopride (0.5 nM), identified a heterogeneous distribution of specific binding sites (defined by granisetron, 1 microM) throughout the human brain. Highest radiolabelled 5-HT3 receptor densities were detected in discrete nuclei within the brainstem (nucleus tractus solitarius, area postrema, spinal trigeminal nerve nucleus; 50-200 fmol/mg tissue equivalent) with more modest levels of expression in the forebrain (e.g. hippocampus, nucleus accumbens, putamen, caudate; 4-17 fmol/mg tissue equivalent). Within the hippocampal formation, radiolabelled 5-HT3 receptors were differentially distributed with highest levels in the granule cell layer of the dentate gyrus. Saturation studies with [3H]-(S)-Zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-Zacopride (0.05-16 nM; non-specific binding defined by granisetron, 10 microM) binding to homogenates of human putamen indicated that [3H]-(S)-Zacopride labelled an apparently homogenous population of binding sites (Bmax = 72 + 7 fmol mg-1 protein, pKd = 8.69 +/- 0.09, Hill coefficient = 0.99 +/- 0.06, mean +/- SEM, n = 4). The pharmacological profile of [3H]-(S)-Zacopride binding to homogenates of putamen indicated the selective labelling of the human variant of the 5-HT3 receptor. The marked differences, however, in the pharmacology (e.g. low affinity for D-tubocurarine) and relative distribution (e.g. presence of 5-HT3 receptors in the human extrapyramidal system) of 5-HT3 receptors in the human forebrain when compared with other species further necessitates caution in predicting clinical responses based on data generated in animal models of disease.
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distribution and characterisation of the 3h s Zacopride labelled 5 ht3 receptor in pig forebrain
Brain Research, 1996Co-Authors: Stephanie Fletcher, Nicholas M BarnesAbstract:Abstract The present study demonstrates the presence and distribution of [ 3 H](S)-Zacopride labelled 5-HT 3 (5-hydroxytryptamine 3 ) receptors in pig forebrain, The pharmacological characterisation of 5-HT 3 receptor recognition sites in homogenates of pig cerebral cortex provides further evidence for inter-species variation in the pharmacology of the 5-HT 3 receptor.
R J Naylor - One of the best experts on this subject based on the ideXlab platform.
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Zacopride a potent 5 ht3 antagonist
Journal of Pharmacy and Pharmacology, 2011Co-Authors: W W Smith, R J Naylor, L F Sancilio, J B Oweraatepo, L LambertAbstract:— The substituted benzamide derivative Zacopride was found to antagonize competitively the effects of 5-hydroxytryptamine (5-HT) on the guinea-pig ileum, the rabbit vagus nerve and the von Bezold Jarisch reflex in the rat. The potency of Zacopride was comparable with that of ICS 205–930 and it is concluded that Zacopride possesses 5-HT3 receptor antagonizing properties.
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3h Zacopride ligand for the identification of 5 ht3 recognition sites
Journal of Pharmacy and Pharmacology, 2011Co-Authors: Nicholas M Barnes, B Costall, R J NaylorAbstract:[3H]Zacopride displayed saturable binding to homogenates of the rat entorhinal cortex as measured by the inclusion of the 5-HT3 receptor antagonist BRL43694 in the incubation media. Scatchard analysis indicated a single high affinity binding site (KD 0.76 +/- 0.08 nM, Bmax 77.5 +/- 6.5 fmol (mg protein)-1) with a Hill slope close to unity. Other 5-HT3 receptor antagonists (Zacopride, ICS 205-930, GR38032F, GR65630, metoclopramide and cocaine) also competed for the binding site displacing 60% of the total [3H]Zacopride binding. 5-HT and 2-methyl-5-HT also were competitive antagonists for [3H]Zacopride binding whereas 5-HT1/5-HT2 agonists and antagonists, and agents acting on other neurotransmitter receptors had Ki values greater than 10(-5) M. It is concluded that [3H]Zacopride may prove a useful ligand for the study of 5-HT3 recognition sites.
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Zacopride anxiolytic profile in rodent and primate models of anxiety
Journal of Pharmacy and Pharmacology, 2011Co-Authors: B Costall, A M Domeney, M E Kelly, P A Gerrard, R J NaylorAbstract:— Zacopride, a substituted benzamide derivative, was compared with diazepam in three models of experimental or provoked anxiety. The drug's action (i) in reducing aversion to a brightly lit environment was assessed in mice using a two compartment black and white test box system, (ii) in disinhibiting a suppressed behaviour was measured in the rat social interaction test under high light/unfamiliar conditions and (iii) in antagonizing a defensive response in the marmoset was assessed using the threat of a human presence. Both Zacopride and diazepam enhanced exploratory behaviour and social interaction in the mouse and rat models and antagonized the defensive response in the marmoset, Zacopride being 100 times more potent than diazepam. It is concluded that the 5-HT3 receptor antagonist, Zacopride, alters rodent and primate behaviour in a manner consistent with that of an anxiolytic agent.
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the influence of 5 ht2 and 5 ht4 receptor antagonists to modify drug induced disinhibitory effects in the mouse light dark test
British Journal of Pharmacology, 1997Co-Authors: R J NaylorAbstract:1 The ability of 5-HT2 and 5-HT4 receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box. 2 The 5-HT2A/2B/2C receptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose-related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box. 3 Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5-HT1A receptor ligands, 8-OH-DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5-HT3 receptor antagonists, ondansetron (100 fold) R(+)-Zacopride (100 fold) and S(−)-Zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)A receptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5-HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKB receptor antagonist CI-988, the angiotensin AT1 receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril. 4 The 5-HT4 receptor antagonists SDZ205-557, GR113808 and SB204070 caused dose-related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone. 5 GR113808 was also shown to cause a dose-related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8-OH-DPAT, buspirone, lesopitron, ondansetron, R(+)-Zacopride, sulpiride, tiapride, devazepide, CI-988, losarten, ceranapril and parachlorophenylalanine. 6 It was concluded that in BKW mice (a) the failure of 5-HT2 and 5-HT4 receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5-HT tone at the 5-HT2 and 5-HT4 receptors and (b) the enhancement by the 5-HT2 receptor antagonists and attenuation by the 5-HT4 receptor antagonists of drug-induced disinhibition indicates a plurality of 5-HT receptor involvement in the mediation of drug-induced disinhibitory profiles in the mouse. British Journal of Pharmacology (1997) 122, 1105–1118; doi:10.1038/sj.bjp.0701513
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differential modulation of extracellular levels of 5 hydroxytryptamine in the rat frontal cortex by r and s Zacopride
British Journal of Pharmacology, 1992Co-Authors: Nicholas M Barnes, B Costall, C H K Cheng, R J NaylorAbstract:1. The ability of various anxiolytic and potential anxiolytic agents to modify 5-hydroxytryptamine (5-HT) release in the frontal cortex of the rat was assessed by the microdialysis technique. 2. The benzodiazepine receptor agonist, diazepam (2.5 mg kg-1, i.p.), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.32 mg kg-1, s.c.) and the 5-HT1A receptor partial agonist buspirone (4.0 mg kg-1, i.p.) maximally reduced extracellular levels of 5-HT in the rat frontal cortex by approximately 50-60%, 70-80% and 30-40%, respectively. 3. (R)-Zacopride (1.0-100 micrograms kg-1, i.p.) dose-dependently reduced extracellular levels of 5-HT in the rat frontal cortex (approximately 80% maximal reduction) whereas the other 5-HT3 receptor antagonists ondansetron (10 micrograms kg-1, i.p.) and (S)-Zacopride (10-100 micrograms kg-1, i.p.) were ineffective. 4. In contrast to (S)-Zacopride (100 nM; administered via the microdialysis probe), (R)-Zacopride (1.0-100 nM; administered via the microdialysis probe) induced a concentration-dependent reduction in extracellular levels of 5-HT in the rat frontal cortex (approximately 70% maximal reduction). 5. In contrast to ondansetron (100 micrograms kg-1, i.p.), (S)-Zacopride (10-100 micrograms kg-1, i.p.) dose-dependently reversed the (R)-Zacopride (10 micrograms kg-1, i.p.) induced reduction in extracellular levels of 5-HT in the rat frontal cortex. The highest dose of (S)-Zacopride (100 micrograms kg-1, i.p.) completely prevented the (R)-Zacopride response.In addition, (S)-Zacopride (100 nM; administered via the microdialysis probe) attenuated the inhibitory action of (R)-Zacopride (10 nM; administered via the microdialysis probe) on extracellular levels of 5-HT in the rat frontal cortex.6. In conclusion, the present study provides further evidence of the ability of diazepam, 8-OH-DPAT and buspirone to reduce the activity of the central 5-hydroxytryptaminergic system in vivo. Furthermore,the results indicate that the ability of (R)-Zacopride to reduce the in vivo release of 5-HT in the rat frontal cortex does not correlate with its 5-HT3 receptor antagonism. However, the differential affinity of (R)- and (S)-Zacopride for a (S)-Zacopride-insensitive (R)-Zacopride site in rat cerebral cortex mirrors the relative activity of the two Zacopride stereoisomers to modify the in vivo release of 5-HT in the frontal cortex of the rat and their ability to release suppressed behaviour in animal models of anxiety.
H Gozlan - One of the best experts on this subject based on the ideXlab platform.
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characterisation of the non 5 ht3 high affinity r binding site for r Zacopride in brain and other tissues
European Journal of Pharmacology, 1993Co-Authors: Emma Jane Kidd, Michel Hamon, J C Levy, M Nielsen, H GozlanAbstract:Previous studies showed that whereas the potent 5-HT3 receptor antagonist only labels 5-HT3 receptor binding sites, the , labels these receptors and another class of high-affinity binding sites, named the R sites, in membranes from the rat cerebral cortex and NG 108-15 clonal cells (Kidd et al., Eur. J. Pharmacol. 211, 133, 1992). Further studies of R sites revealed that they existed not only in the cerebral cortex but also in various other areas of the rat brain and spinal cord. In addition, R sites were also found in post-mortem human brain tissues. Both in the rat and in man, the regional distribution of central R sites was markedly different from that of 5-HT3 receptors specifically labelled with . Under appropriate conditions for the specific labelling of R sites (with in the presence of 1.0 μM ondansetron to saturate 5-HT3 receptor binding sites — and 0.1 mM mianserin for the determination of non-specific binding), these R sites were also found in rat peripheral tissues (intestine > spleen > kidney > testicles = liver > adrenals > lung > heart). At least in the kidney and the liver, the pharmacological profile of R sites corresponded exactly to that found in NG 108-15 cells. R sites were also detected in membranes from C6 glioma cells and glial cells cultured from the whole cortex of new born rats. In contrast, no specific binding of to R sites could be found in membranes from N1E-115 neuroblastoma cells. Conversely, 5-HT3 receptors could be labelled by in the latter cells but not in C6 glioma and cultured glial cells. As expected from their glial location, the density of R sites increased in the rat hippocampus lesioned with kainic or ibotenic acid to induced local gliosis. In contrast, the density of hippocampal 5-HT3 receptors was unchanged in lesioned rats. Finally, the determination of the apparent molecular size of R sites by radiation inactivation gave a value (≈ 30 kDa) which was significantly lower than that of 5-HT3 receptor binding sites in the rat entorhinal cortex (40 kDa) and NG 108-15 cells (57 kDa). All these data clearly showed that R sites and 5-HT3 receptors are different molecular species. Whether R sites mediate the 5-HT3 receptor-unrelated actions of (R)-Zacopride deserves further investigations.
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quantitative autoradiographic mapping of 5 ht3 receptors in the rat cns using 125i iodo Zacopride and 3h Zacopride as radioligands
Synapse, 1992Co-Authors: A M Laporte, Michel Hamon, M Ponchant, T Koscielniak, D Verge, H GozlanAbstract:Substitution of the chlorine atom by a radio-iodine in position 5 in the Zacopride molecule yielded [125I]iodo-Zacopride that bound with high affinity (Kd = 4.3 nM) to 5-HT3 receptors in the rat central nervous system. Assays with membranes from the posterior (mainly entorhinal) cortex confirmed that the pharmacological properties and regional distribution of [125I]iodo-Zacopride-specific binding sites were identical with those of 5-HT3 sites labelled by the reference radioligand [3H]Zacopride. Autoradiographic investigations for the visualization and quantification of 5-HT3 receptors yielded similar results with both radioligands, but autoradiograms could be obtained after only 1-3 days of exposure of sections labelled with [125I]iodo-Zacopride, instead of 4-6 months using [3H]Zacopride. The highest density of 5-HT3 sites was found in the nucleus tractus solitarius followed by, in decreasing order, the dorsal motor nucleus of the vagus nerve, the superficial layers of the dorsal horn in the spinal cord, the nucleus of the spinal tract of the trigeminal nerve, and the area postrema. Significant labelling of 5-HT3 receptors was also observed in limbic areas (amygdala, hippocampus, frontal and entorhinal cortex), and to a much lower extent in the dorsal raphe nucleus, striatum, and substantia nigra. These multiple locations further support the idea that 5-HT3 receptors are probably involved in several 5-HT-mediated functions in the central nervous system.
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the potent 5 ht3 receptor antagonist r Zacopride labels an additional high affinity site in the central nervous system
European Journal of Pharmacology, 1992Co-Authors: Emma Jane Kidd, Isabelle Bouchelet De Vendegies, Jeanclaude Levy, Michel Hamon, H GozlanAbstract:The binding characteristics of [3H](S)-Zacopride were investigated in membranes from the rat entorhinal cortex and NG 108-15 clonal cells. In contrast to [3H](S)-Zacopride which bound solely to 5-HT3 receptors, [3H](R)-Zacopride recognized another class of binding sites, called the (R)-sites, in both membrane preparations. In addition to (R)-Zacopride (Ki=3–11 nM), only (R)-iodo-Zacopride, (R)-dechloro-Zacopride, prazosin and mianserin exhibited high to moderate affinity for the (R)-sites, whose possible functions remain to be established.
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baroreceptor reflex inhibition induced by the stimulation of serotonin3 receptors in the nucleus tractus solitarius of the rat
Neuroscience, 1992Co-Authors: Nacera Merahi, Michel Hamon, H Gozlan, A M Laporte, Hakan S Orer, Raul LaguzziAbstract:Previous studies suggested that in the nucleus tractus solitarius, cardiovascular responses to serotonin may involve the simultaneous activation of more than one receptor subtype. In the present study, the cardiovascular effects of the local application of serotonin and different serotonin3 agonists and antagonists into the nucleus tractus solitarius were analysed in intact and unilaterally ganglionectomized rats. Unilateral injections of serotonin (5-15 nmol) produced a dose-dependent increase in blood pressure and partially antagonized the arterial baroreflex responses evoked by an i.v. injection of phenylephrine. Similar blood pressures response were obtained after unilateral microinjections of phenylbiguanide (5 nmol) and 2-methyl-serotonin (5 nmol), two serotonin3 receptor agonists. Bilateral microinjections of serotonin or phenylbiguanide produced more pronounced blood pressure effects and antagonized completely the baroreflex responses. Both blood pressure and baroreflex effects were antagonized by prior injections of specific serotonin3 antagonists such as Zacopride (100 pmol) and ondansetron (100 pmol). Concomitant autoradiographic studies performed in intact and ganglionectomized rats, using [125I]iodoZacopride, confirmed that serotonin3 receptors in the nucleus tractus solitarius are mainly located on vagal afferent fibers. In addition, serotonin microinjections made in the nucleus tractus solitarius ipsilateral to the ganglionectomy revealed a significant reduction in cardiovascular responses compared to intact animals. These results suggest that in the nucleus tractus solitarius of the rat, serotonin is involved in the reflex regulation of blood pressure through the stimulation of serotonin3 receptors presumably located on vagal afferent fibers. Since bicuculline antagonized the serotonin-mediated pressor responses, a serotonin3-dependent activation of an inhibitory GABAergic system within the nucleus tractus solitarius might be involved in blood pressure regulatory mechanisms.
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synthesis of 5 125i iodo Zacopride a new probe for 5 ht3 receptor binding sites
Journal of Labelled Compounds and Radiopharmaceuticals, 1991Co-Authors: M Ponchant, Michel Hamon, T Koscielniak, H GozlanAbstract:In an attempt to develop a specific probe of serotonin 5-HT3 receptors, various methods have been investigated to synthesize a radioiodinated derivative of the potent 5-HT3 antagonist Zacopride. The direct iodination of 5-dechloro-Zacopride 2 was performed using NaI in the presence of either chloramine T or iodo-beads. Irreproducible results or/and low yields were obtained by these methods. A third approach using a less oxidative medium allowed the synthesis of iodo-Zacopride 4 from 2 with N-iodo-succinimide or with NaI and N-chlorosuccinimide. Using this third condition, high yield was obtained (49%). However, the radioiodinated compound was contaminated by some “cold” Zacopride also formed during the reaction. A two step synthesis was successful to eliminate “cold” Zacopride but in lower yield (2-10%). Thus, 4-amino-2-methoxy-benzoate 5 was iodinated and then coupled with 3-aminoquinuclidine 8 to give 5-iodo-Zacopride 4. Radioactive synthesis was carried out in the same condition to give 5-[1251]-iodo-Zacopride 1 with a yield of 98%. The two enantiomers R-and S-5-[1251]-iodo-Zacopride were synthesized by direct iodination.
Ji-min Cao - One of the best experts on this subject based on the ideXlab platform.
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Zacopride exerts an antiarrhythmic effect by specifically stimulating the cardiac inward rectifier potassium current in rabbits exploration of a new antiarrhythmic strategy
Current Pharmaceutical Design, 2020Co-Authors: Yuanyuan Lin, Qing-hua Liu, Qi-long Feng, Baozhong Zhu, Xiaojie Bai, Bingmei Chang, Yanlin Guo, Ji-min CaoAbstract:Background Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that Zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats. Objective Our aims were to confirm that the antiarrhythmic effects of Zacopride are mediated by selectively enhancing IK1 in rabbits. Methods The effects of Zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of Zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro. Results Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 μmol/L Zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by Zacopride (0.1-10 μmol/L) in a concentration- dependent manner. Furthermore, Zacopride at 1 μmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes. Conclusion Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.
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ik1 channel agonist Zacopride suppresses ventricular arrhythmias in conscious rats with healing myocardial infarction
Life Sciences, 2019Co-Authors: Xu-wen Zhai, Li Zhang, Qi-long Feng, Ji-min Cao, Dongming Wang, Xi Qiao, Lijun Zhang, Qing-hua LiuAbstract:Abstract Aims Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. Methods Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. Key findings In the telemetric rats post-MI, Zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, Zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by Zacopride treatment. Significance IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.
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ik1 channel agonist Zacopride alleviates cardiac hypertrophy and failure via alterations in calcium dyshomeostasis and electrical remodeling in rats
Frontiers in Pharmacology, 2019Co-Authors: Qing-hua Liu, Li Zhang, Xu-wen Zhai, Qi-long Feng, Xi Qiao, Lijun Zhang, Jin Wang, Xiaoze Ren, Xiaona Cao, Ji-min CaoAbstract:Intracellular Ca2+ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (IK1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of IK1 currents is a compensation for IK1 deficit and a novel modulation for cardiac Ca2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo, cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10, and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1 to 3 days SD rat pups and treated with 1 μmol/L Iso for 24 h in vitro. The effects of Zacopride, a selective IK1/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 μg/kg in vivo and 1 μmol/L in vitro. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca2+ (P < 0.01 or P < 0.05) and lower SR Ca2+ content (P < 0.01 or P < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p-CaMKII, p-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (P < 0.01), APD prolongation (P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca2+ homeostasis, normalized the RP (P < 0.05), and abbreviated APD (P < 0.01), thus lowered cytosolic [Ca2 +]i (P < 0.01 or P < 0.05). IK1channel blocker BaCl2 or chloroquine largely reversed the cardioprotection of Zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac IK1, Zacopride prevents Iso-induced electrical remodeling around intracellular Ca2+ overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.
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the ik1 kir2 1 channel agonist Zacopride prevents and cures acute ischemic arrhythmias in the rat
PLOS ONE, 2017Co-Authors: Xu-wen Zhai, Li Zhang, Qi-long Feng, Ji-min Cao, Yan Zhang, Yunfei Guo, Ying Yang, Dongming Wang, Yifan Niu, Qing-hua LiuAbstract:Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that Zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of Zacopride (i.v. infusion) were observed in the settings of pre-treatment (Zacopride given 3 min prior to coronary occlusion), post-treatment (Zacopride given 3 min after coronary occlusion) and therapeutic treatment (Zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, Zacopride (15 μg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 μmol/L Zacopride were reversed by 1 μmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that Zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, Zacopride (1 μmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, Zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by Zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.
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on the risk concerns of Zacopride a moderate ik1 channel agonist with cardiac protective action
Journal of Cardiovascular Pharmacology, 2014Co-Authors: Ji-min CaoAbstract:Zacopride, an IK1 agonist with moderate potency, could exert significant antiarrhythmic and cardiac protective effects. To date, there is no report to show that Zacopride is proarrhythmic in both experimental studies and clinical trials. However, in certain cardiac pathological conditions, especially short QT syndrome and certain reentry tachycardia, Zacopride is not suggested. Further studies are needed to precisely evaluate the potential arrhythmogenic risk of Zacopride.
Qing-hua Liu - One of the best experts on this subject based on the ideXlab platform.
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Zacopride exerts an antiarrhythmic effect by specifically stimulating the cardiac inward rectifier potassium current in rabbits exploration of a new antiarrhythmic strategy
Current Pharmaceutical Design, 2020Co-Authors: Yuanyuan Lin, Qing-hua Liu, Qi-long Feng, Baozhong Zhu, Xiaojie Bai, Bingmei Chang, Yanlin Guo, Ji-min CaoAbstract:Background Zacopride, a potent antagonist of 5-HT3 receptors and an agonist of 5-HT4 receptors, is a gastrointestinal prokinetic agent. In a previous study, we discovered that Zacopride selectively stimulated the inward rectifier potassium current (IK1) in the rat and that agonizing IK1 prevented or eliminated aconitine-induced arrhythmias in rats. Objective Our aims were to confirm that the antiarrhythmic effects of Zacopride are mediated by selectively enhancing IK1 in rabbits. Methods The effects of Zacopride on the function of the main ion channels were investigated using a whole-cell patch-clamp technique in rabbits. Effects of Zacopride on cardiac arrhythmias were also explored experimentally both in vivo and in vitro. Results Zacopride moderately enhanced cardiac IK1 but had no apparent action on voltage-gated sodium current (INa), L- type calcium current (ICa-L), sodium-calcium exchange current (INa/Ca), transient outward potassium current (Ito), or delayed rectifier potassium current (IK) in rabbits. Zacopride also had a marked antiarrhythmic effect in vivo and in vitro. We proved that the resting membrane potential (RMP) was hyperpolarized in the presence of 1 μmol/L Zacopride, and the action potential duration (APD) at 90% repolarization (APD90) was shortened by Zacopride (0.1-10 μmol/L) in a concentration- dependent manner. Furthermore, Zacopride at 1 μmol/L significantly decreased the incidence of drug-induced early afterdepolarization (EAD) in rabbit ventricular myocytes. Conclusion Zacopride is a selective agonist of rabbit cardiac IK1 and that IK1 enhancement exerts potential antiarrhythmic effects.
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ik1 channel agonist Zacopride suppresses ventricular arrhythmias in conscious rats with healing myocardial infarction
Life Sciences, 2019Co-Authors: Xu-wen Zhai, Li Zhang, Qi-long Feng, Ji-min Cao, Dongming Wang, Xi Qiao, Lijun Zhang, Qing-hua LiuAbstract:Abstract Aims Arrhythmogenesis of chronic myocardial infarction (MI) is associated with the prolongation of action potential, reduction of inward rectifier potassium (IK1, Kir) channels and hyper-activity of Calcium/calmodulin-dependent kinase II (CaMKII) in cardiomyocytes. Zacopride, a selective IK1 agonist, was applied to clarify the cardioprotection of IK1 agonism via a CaMKII signaling on arrhythmias post-MI. Methods Male SD rats were implanted wireless transmitter in the abdominal cavity and subjected to left main coronary artery ligation or sham operation. The telemetric ECGs were monitored per day throughout 4 weeks. At the endpoint, isoproterenol (1.28 mg/kg, i.v.) was administered for provocation test. The expressions of Kir2.1 (dominant subunit of IK1 in ventricle) and CaMKII were detected by Western-blotting. Key findings In the telemetric rats post-MI, Zacopride significantly reduced the episodes of atrioventricular conduction block (AVB), premature ventricular contraction (PVC), ventricular tachycardia (VT) and ventricular fibrillation (VF), without significant effect on superventricular premature contraction (SPVC). In provocation test, Zacopride suppressed the onset of ventricular arrhythmias in conscious PMI or sham rats. The expression of Kir2.1 was significantly downregulated and p-CaMKII was upregulated post-MI, whereas both were restored by Zacopride treatment. Significance IK1/Kir2.1 might be an attractive target for pharmacological controlling of lethal arrhythmias post MI.
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ik1 channel agonist Zacopride alleviates cardiac hypertrophy and failure via alterations in calcium dyshomeostasis and electrical remodeling in rats
Frontiers in Pharmacology, 2019Co-Authors: Qing-hua Liu, Li Zhang, Xu-wen Zhai, Qi-long Feng, Xi Qiao, Lijun Zhang, Jin Wang, Xiaoze Ren, Xiaona Cao, Ji-min CaoAbstract:Intracellular Ca2+ overload, prolongation of the action potential duration (APD), and downregulation of inward rectifier potassium (IK1) channel are hallmarks of electrical remodeling in cardiac hypertrophy and heart failure (HF). We hypothesized that enhancement of IK1 currents is a compensation for IK1 deficit and a novel modulation for cardiac Ca2+ homeostasis and pathological remodeling. In adult Sprague-Dawley (SD) rats in vivo, cardiac hypertrophy was induced by isoproterenol (Iso) injection (i.p., 3 mg/kg/d) for 3, 10, and 30 days. Neonatal rat ventricular myocytes (NRVMs) were isolated from 1 to 3 days SD rat pups and treated with 1 μmol/L Iso for 24 h in vitro. The effects of Zacopride, a selective IK1/Kir2.1 channel agonist, on cardiac remodeling/hypertrophy were observed in the settings of 15 μg/kg in vivo and 1 μmol/L in vitro. After exposing to Iso for 3 days and 10 days, rat hearts showed distinct concentric hypertrophy and fibrosis and enhanced pumping function (P < 0.01 or P < 0.05), then progressed to dilatation and dysfunction post 30 days. Compared with the age-matched control, cardiomyocytes exhibited higher cytosolic Ca2+ (P < 0.01 or P < 0.05) and lower SR Ca2+ content (P < 0.01 or P < 0.05) all through 3, 10, and 30 days of Iso infusion. The expressions of Kir2.1 and SERCA2 were downregulated, while p-CaMKII, p-RyR2, and cleaved caspase-3 were upregulated. Iso-induced electrophysiological abnormalities were also manifested with resting potential (RP) depolarization (P < 0.01), APD prolongation (P < 0.01) in adult cardiomyocytes, and calcium overload in cultured NRVMs (P < 0.01). Zacopride treatment effectively retarded myocardial hypertrophy and fibrosis, preserved the expression of Kir2.1 and some key players in Ca2+ homeostasis, normalized the RP (P < 0.05), and abbreviated APD (P < 0.01), thus lowered cytosolic [Ca2 +]i (P < 0.01 or P < 0.05). IK1channel blocker BaCl2 or chloroquine largely reversed the cardioprotection of Zacopride. We conclude that cardiac electrical remodeling is concurrent with structural remodeling. By enhancing cardiac IK1, Zacopride prevents Iso-induced electrical remodeling around intracellular Ca2+ overload, thereby attenuates cardiac structural disorder and dysfunction. Early electrical interventions may provide protection on cardiac remodeling.
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the ik1 kir2 1 channel agonist Zacopride prevents and cures acute ischemic arrhythmias in the rat
PLOS ONE, 2017Co-Authors: Xu-wen Zhai, Li Zhang, Qi-long Feng, Ji-min Cao, Yan Zhang, Yunfei Guo, Ying Yang, Dongming Wang, Yifan Niu, Qing-hua LiuAbstract:Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that Zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of Zacopride (i.v. infusion) were observed in the settings of pre-treatment (Zacopride given 3 min prior to coronary occlusion), post-treatment (Zacopride given 3 min after coronary occlusion) and therapeutic treatment (Zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, Zacopride (15 μg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 μmol/L Zacopride were reversed by 1 μmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that Zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, Zacopride (1 μmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, Zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by Zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.
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activation of ik1 channel by Zacopride attenuates left ventricular remodeling in rats with myocardial infarction
Journal of Cardiovascular Pharmacology, 2014Co-Authors: Chengfang Liu, Li Zhang, Qing-hua Liu, Xu-wen Zhai, Qi-long Feng, Xiang-li Cui, Enli Liu, Tiane Luo, Weifang Zhang, Zhi-qing ZhaoAbstract:Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 µg/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with Zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in Zacopride-treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, Zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of Zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by Zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.
