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Paul B S Clarke - One of the best experts on this subject based on the ideXlab platform.
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Effects of nicotine and Chlorisondamine on cerebral glucose utilization in immobilized and freely‐moving rats
British Journal of Pharmacology, 2009Co-Authors: T Marenco, S Bernstein, Paul Cumming, Paul B S ClarkeAbstract:Chlorisondamine blocks central nicotinic receptors for many weeks via an unknown mechanism. Intracerebroventricular administration of [3H]-Chlorisondamine in rats results in an anatomically restricted and persistent intracellular accumulation of radioactivity. The initial aim of the present study was to test whether nicotinic receptor antagonism by Chlorisondamine is also anatomically restricted. Male adult rats were pretreated several times with nicotine to avoid the disruptive effects of the drug seen in drug-naive animals. They then received Chlorisondamine (10 μg i.c.v.) or saline, and local cerebral glucose utilization (LCGU) was measured 4 weeks later after acute nicotine (0.4 mg kg−1 s.c.) or saline administration. During testing, rats were partially immobilized. Nicotine significantly increased LCGU in the anteroventral thalamus and in superior colliculus. Chlorisondamine completely blocked the first of these effects. Chlorisondamine significantly reduced LCGU in the lateral habenula, substantia nigra pars compacta, ventral tegmental area, and cerebellar granular layer. The second experiment was of similar design, but the rats were not pre-exposed to nicotine, and were tested whilst freely-moving. Acute nicotine significantly increased LCGU in anteroventral thalamus, superior colliculus, medial habenula and dorsal lateral geniculate. Overall, however, nicotine significantly decreased LCGU. Most or all of the central effects of nicotine on LCGU were reversed by Chlorisondamine given 4 weeks beforehand. These findings suggest that Chlorisondamine blocks nicotinic effects widely within the brain. They also indicate that in freely-moving rats, nicotine can reduce or stimulate cerebral glucose utilization, depending on the brain area. British Journal of Pharmacology (2000) 129, 147–155; doi:10.1038/sj.bjp.0703005
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effects of nicotine and Chlorisondamine on cerebral glucose utilization in immobilized and freely moving rats
British Journal of Pharmacology, 2000Co-Authors: T Marenco, S Bernstein, Paul Cumming, Paul B S ClarkeAbstract:Chlorisondamine blocks central nicotinic receptors for many weeks via an unknown mechanism. Intracerebroventricular administration of [3H]-Chlorisondamine in rats results in an anatomically restricted and persistent intracellular accumulation of radioactivity. The initial aim of the present study was to test whether nicotinic receptor antagonism by Chlorisondamine is also anatomically restricted. Male adult rats were pretreated several times with nicotine to avoid the disruptive effects of the drug seen in drug-naive animals. They then received Chlorisondamine (10 μg i.c.v.) or saline, and local cerebral glucose utilization (LCGU) was measured 4 weeks later after acute nicotine (0.4 mg kg−1 s.c.) or saline administration. During testing, rats were partially immobilized. Nicotine significantly increased LCGU in the anteroventral thalamus and in superior colliculus. Chlorisondamine completely blocked the first of these effects. Chlorisondamine significantly reduced LCGU in the lateral habenula, substantia nigra pars compacta, ventral tegmental area, and cerebellar granular layer. The second experiment was of similar design, but the rats were not pre-exposed to nicotine, and were tested whilst freely-moving. Acute nicotine significantly increased LCGU in anteroventral thalamus, superior colliculus, medial habenula and dorsal lateral geniculate. Overall, however, nicotine significantly decreased LCGU. Most or all of the central effects of nicotine on LCGU were reversed by Chlorisondamine given 4 weeks beforehand. These findings suggest that Chlorisondamine blocks nicotinic effects widely within the brain. They also indicate that in freely-moving rats, nicotine can reduce or stimulate cerebral glucose utilization, depending on the brain area. British Journal of Pharmacology (2000) 129, 147–155; doi:10.1038/sj.bjp.0703005
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regulation of nicotinic receptors in rat brain following quasi irreversible nicotinic blockade by Chlorisondamine and chronic treatment with nicotine
British Journal of Pharmacology, 1994Co-Authors: H Elbizri, Paul B S ClarkeAbstract:Abstract 1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha-bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker Chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received Chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H]-nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, Chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of Chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up-regulation was neither mimicked nor blocked by Chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)
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Regulation of nicotinic receptors in rat brain following quasi-irreversible nicotinic blockade by Chlorisondamine and chronic treatment with nicotine.
British Journal of Pharmacology, 1994Co-Authors: H. El‐bizri, Paul B S ClarkeAbstract:: 1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha-bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker Chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received Chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H]-nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, Chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of Chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up-regulation was neither mimicked nor blocked by Chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine. Chronic nicotine treatment also increased the Bmax (but not KD) of [125I]-alpha BTX binding in cerebral cortex (by 35%), hippocampus (by 46%) and midbrain (by 35%). Chlorisondamine altered neither Bmax nor KD when given alone, but significantly attenuated the nicotine-induced up-regulation of toxin binding sites in midbrain, with a similar trend in the other two regions.4. The finding that chronic receptor blockade neither mimicked nor blocked the agonist-induced up-regulation of [3H]-nicotine binding sites suggests that up-regulation of these receptors is not determined by their functional status. In contrast, it appears that chronic nicotine-induced up-regulation of[125I]-alpha BTX binding sites may result from receptor activation.
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The pharmacology of the nicotinic antagonist, Chlorisondamine, investigated in rat brain and autonomic ganglion
British Journal of Pharmacology, 1994Co-Authors: Paul B S Clarke, I. Chaudieu, H. El‐bizri, Patricia Boksa, M. Quik, B.a. Esplin, R. ČapekAbstract:1. A single administration of the ganglion blocker, Chlorisondamine (10 mg kg-1, s.c.) is known to produce a quasi-irreversible blockade of the central actions of nicotine in the rat. The mechanism of this persistent action is not known. It is also unclear whether Chlorisondamine can block neuronal responses to excitatory amino acids and whether chronic blockade of nicotinic responses also occurs in the periphery. 2. Acute administration of Chlorisondamine (10 mg kg-1, s.c.) to rats resulted in a blockade of central nicotinic effects (ataxia and prostration) when tested 1 to 14 days later, but caused no detectable cell death in tissue sections sampled throughout the rostrocaudal extent of the brain which were stained in order to reveal neuronal degeneration. 3. Long-term blockade of central nicotinic effects by Chlorisondamine was not associated with significant alterations in the density (Bmax) of high-affinity [3H]-nicotine binding to forebrain cryostat-cut sections. 4. In cultured dissociated mesencephalic cells of the foetal rat, Chlorisondamine and mecamylamine inhibited [3H]-dopamine release evoked by N-methyl-D-aspartate (NMDA, 10(-4) M), but only at high concentrations (IC50 approx. 600 and 70 microM, respectively). A high concentration of Chlorisondamine (10(-3) M) had no effect on responses to quisqualate (10(-5) M) and only slightly reduced responses to kainate (10(-4) M). Mecamylamine (10(-3) M) was ineffective against both agonists. 5. In adult rat hippocampal slices, Chlorisondamine depressed NMDA receptor-mediated synaptically-evoked field potentials, but again only at high concentrations (10(-4)-10(-3) M). Synaptic responses that were mediated by non-NMDA excitatory amino acid receptors were less affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Jon E Welch - One of the best experts on this subject based on the ideXlab platform.
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stress and endotoxin induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity
Journal of Neurochemistry, 1991Co-Authors: Adrian J Dunn, Jon E WelchAbstract:: Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker Chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock-and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by Chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by Chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the β-adrenergic antagonist propranolol but not by the α-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on β-as opposed to α-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to S-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.
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Stress- and endotoxin-induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity.
Journal of Neurochemistry, 1991Co-Authors: Adrian J Dunn, Jon E WelchAbstract:: Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker Chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock- and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by Chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by Chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on beta- as opposed to alpha-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to 5-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.
H Elbizri - One of the best experts on this subject based on the ideXlab platform.
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regulation of nicotinic receptors in rat brain following quasi irreversible nicotinic blockade by Chlorisondamine and chronic treatment with nicotine
British Journal of Pharmacology, 1994Co-Authors: H Elbizri, Paul B S ClarkeAbstract:Abstract 1. Chronic administration of nicotinic agonists in vivo increases the density of brain nicotinic binding sites. It has been proposed that this up-regulation results from agonist-induced functional blockade of nicotinic receptors. This hypothesis was tested by examining post mortem [3H]-nicotine and [125I]-alpha-bungarotoxin ([125I]-alpha BTX) binding following treatment in vivo with the quasi-irreversible and insurmountable CNS nicotinic blocker Chlorisondamine, given either alone or in combination with chronic nicotine administration. 2. In rats that had not received Chlorisondamine pretreatment, chronic nicotine administration (0.6 mg kg-1 s.c., twice daily for 12 days) increased [3H]-nicotine binding density (Bmax) in forebrain tissue sections by 19%, with no change in the apparent dissociation constant (KD). Chlorisondamine (10 mg kg-1, s.c.), given once prior to the chronic treatment phase, neither increased [3H]-nicotine binding by itself, nor altered the extent of nicotine-induced up-regulation. Nevertheless, Chlorisondamine pretreatment resulted in a persistent blockade of CNS nicotinic receptors, as demonstrated by complete block of acute locomotor responses to nicotine. 3. In a second experiment, [3H]-nicotine and [125I]-alpha BTX binding was measured in tissue homogenates prepared from several brain regions. In the absence of Chlorisondamine pretreatment, chronic nicotine administration (1 mg kg-1 s.c., twice daily for 12 days) increased the Bmax of [3H]-nicotine binding in the cerebral cortex (by 34%), striatum (by 28%), midbrain (by 16%) and hippocampus (by 36%); KD was unchanged. As before, this up-regulation was neither mimicked nor blocked by Chlorisondamine pretreatment (10 mg kg-1, s.c., given twice), despite persistent blockade of acute locomotor responses to nicotine.(ABSTRACT TRUNCATED AT 250 WORDS)
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blockade of nicotinic receptor mediated release of dopamine from striatal synaptosomes by Chlorisondamine and other nicotinic antagonists administered in vitro
British Journal of Pharmacology, 1994Co-Authors: H Elbizri, Paul B S ClarkeAbstract:Abstract 1. Central nicotinic receptor function examined in vitro, by measuring nicotine-induced [3H]-dopamine release from rat striatal synaptosomes. 2. The agonists (-)-nicotine, acetylcholine, 1,1-dimethyl-4-phenylpiperazinium (DMPP) and cytisine (10(-7)-10(-4) M) all increased [3H]-dopamine release in a concentration-dependent manner. Cytisine did not produce a full agonist response, compared to the other agonists. 3. The actions of nicotine, acetylcholine and cytisine were largely dependent on external Ca2+. In contrast, DMPP (10(-5) and 10(-4) M) evoked a marked release of [3H]-dopamine even in the absence of Ca2+. Nevertheless, in the presence of external Ca2+, responses to DMPP were completely blocked by the nicotinic antagonists Chlorisondamine and mecamylamine (5 x 10(-5) M); in the absence of external Ca2+, blockade was only partial. 4. Chlorisondamine, mecamylamine and dihydro-beta-erythroidine (10(-8)-10(-4) M) produced a concentration-dependent block of responses to nicotine (10(-6) M). Approximate IC50 values were 1.6, 0.3 and 0.2 x 10(-6), respectively. Chlorisondamine and mecamylamine blocked responses to nicotine (10(-7)-10(-4) M) insurmountably, whereas dihydro-beta-erythroidine behaved in a surmountable fashion. 5. The occurrence of use-dependent block was tested by briefly pre-exposing the synaptosomes to nicotine during superfusion with antagonist, and determining the response to a subsequent nicotine application. Consistent with a possible channel blocking action, brief pre-exposure to agonist increased the antagonist potency of Chlorisondamine (approximately 25 fold). No significant use-dependent block was detected with dihydro-beta-erythroidine.
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blockade of nicotinic receptor mediated release of dopamine from striatal synaptosomes by Chlorisondamine administered in vivo
British Journal of Pharmacology, 1994Co-Authors: H Elbizri, Paul B S ClarkeAbstract:: 1. The chronic nicotinic blockade produced following in vivo administration of Chlorisondamine was investigated in vitro. Nicotine-induced [3H]-dopamine release from striatal synaptosomes was used as a measure of central nicotinic receptor function. 2. In synaptosomal preparations from rats pretreated with a single administration of Chlorisondamine (10 mg kg-1, s.c.), 1, 7, 21, 42, 63 or 84 days before they were killed, responses to (-)-nicotine (10(-6) M) were blocked. 3. In vivo administration of Chlorisondamine (10 mg kg-1, s.c.), 7 days before rats were killed, produced a nicotinic blockade in vitro that was insurmountable even with a high concentration of (-)-nicotine (10(-4) M). 4. Both in vitro and in vivo administration of Chlorisondamine blocked nicotinic responses to acetylcholine (10(-4) M). In contrast, neither in vitro nor in vivo administration of Chlorisondamine reduced [3H]-dopamine release induced by high K+ (20 x 10(-3) M) or (+)-amphetamine (10(-6) M). 5. Nicotinic blockade resulting from in vitro administration of Chlorisondamine (10(-5) M) recovered partially after 60 min wash-out, and completely by 90 min. In contrast, no recovery was seen in synaptosomes prepared from rats pretreated with Chlorisondamine (10 mg kg-1, s.c.) in vivo. 6. Thus, in vivo treatment with Chlorisondamine results in a quasi-irreversible, insurmountable block of CNS nicotinic receptors. The persistence of this block ex vivo indicates that physical trapping by the blood brain barrier is not solely responsible for the persistent blockade seen in vivo. The resistance of this blockade to prolonged in vitro wash-out suggests that the underlying mechanism differs from that associated with in vitro administration.
Adrian J Dunn - One of the best experts on this subject based on the ideXlab platform.
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stress and endotoxin induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity
Journal of Neurochemistry, 1991Co-Authors: Adrian J Dunn, Jon E WelchAbstract:: Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker Chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock-and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by Chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by Chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the β-adrenergic antagonist propranolol but not by the α-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on β-as opposed to α-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to S-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.
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Stress- and endotoxin-induced increases in brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity.
Journal of Neurochemistry, 1991Co-Authors: Adrian J Dunn, Jon E WelchAbstract:: Stressful treatments and immune challenges have been shown previously to elevate brain concentrations of tryptophan. The role of the autonomic nervous system in this neurochemical change was investigated using pharmacological treatments that inhibit autonomic effects. Pretreatment with the ganglionic blocker Chlorisondamine did not alter the normal increases in catecholamine metabolites, but prevented the increase in brain tryptophan normally observed after footshock or restraint, except when the duration of the footshock period was extended to 60 min. The footshock- and restraint-related increases in 5-hydroxyindoleacetic acid (5-HIAA) were also prevented by Chlorisondamine. The increases in brain tryptophan caused by intraperitoneal injection of endotoxin or interleukin-1 (IL-1) were also prevented by Chlorisondamine pretreatment. The footshock-induced increases in brain tryptophan and 5-HIAA were attenuated by the beta-adrenergic antagonist propranolol but not by the alpha-adrenergic antagonist phenoxybenzamine or the muscarinic cholinergic antagonist atropine. Thus the autonomic nervous system appears to be involved in the stress-related changes in brain tryptophan, and this effect is due to the sympathetic rather than the parasympathetic limb of the system. Moreover, the main effect of the sympathetic nervous system is exerted on beta- as opposed to alpha-adrenergic receptors. We conclude that activation of the sympathetic nervous system is responsible for the stress-related increases in brain tryptophan, probably by enabling increased brain tryptophan uptake. Endotoxin and IL-1 also elevate brain tryptophan, presumably by a similar mechanism. The increase in brain tryptophan appears to be necessary to sustain the increased serotonin catabolism to 5-HIAA that occurs in stressed animals, and which may reflect increased serotonin release.
Hay Yan J. Wang - One of the best experts on this subject based on the ideXlab platform.
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The high specific activity tritium labeling of the ganglion-blocking nicotinic antagonist Chlorisondamine
Journal of Labelled Compounds and Radiopharmaceuticals, 2020Co-Authors: Josef Zezula, Hay Yan J. Wang, Amina S Woods, Roy A Wise, Arthur E. Jacobson, Kenner C. RiceAbstract:Summary Chlorisondamine is a bisquaternary ganglion-blocking nicotinic antagonist that accumulates in dopaminergic, serotonergic, and noradrenergic cell bodies; the mechanism of uptake and time-course of retrograde transport are not known. Chlorisondamine could possibly be taken into monoaminergic neurons when blocked nicotinic receptors on those cells are internalized. In order to more easily study the mechanism of the capture and recycling of Chlorisondamine, a ligand is needed that has high specific activity. For that purpose, we now report the preparation of 3 H-labeled Chlorisondamine (4,5,6,7-tetrachloro-2-[ 3 H]methyl-2-(2-trimethylammoniumethyl)-isoindolinium diiodide) of high specific activity (94 Ci/mmol). The compound was synthesized by quarternization of 4,5,6,7-tetrachloro-2-(2-trimethylammoniumethylisoindolinium iodide with pertritiated methyl iodide in dimethylformamide at high temperature in a sealed vessel. Copyright # 2006 John Wiley & Sons, Ltd.
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study of the interaction of Chlorisondamine and Chlorisondamine analogues with an epitope of the alpha 2 neuronal acetylcholine nicotinic receptor subunit
Journal of Proteome Research, 2005Co-Authors: Hay Yan J. Wang, Roy A Wise, Andrew E Taggi, Jerrold Meinwald, Amina S WoodsAbstract:Chlorisondamine (CHL), a neuronal nicotinic ganglionic blocker, when injected in the cerebral ventricle of rats chronically blocks the increase in locomotion and rearing by subcutaneous nicotine injection. The blocking of the ion channel(s) prevents nicotine from exerting its rewarding effects on the CNS. When administered intraperitoneally, a dose 400−500 times the intracerebroventricular one is needed to cross the blood-brain barrier and to generate the same level of nicotine antagonism, resulting in severe side-effects, thus making it unlikely to be used as a therapeutical compound. Three CHL analogues, 2-(indolin-1-yl)-N,N,N-trimethylethanaminium iodide, 2-(1,3-dioxoisoindolin-2-yl)- N,N,N-trimethylethanaminium iodide, and 2-(1H-indole-3-carboxamido)- N,N,N-trimethylethanaminium iodide, were synthesized in the hope of circumventing the parent compound's shortcomings. They all share a modified indole ring, lack the four chlorines CHL carries, and have one tertiary amine and one quaternary amine. The CH...
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Direct tissue analysis of phospholipids in rat brain using MALDI-TOFMS and MALDI-ion mobility-TOFMS
Journal of the American Society for Mass Spectrometry, 2005Co-Authors: Shelley N. Jackson, Hay Yan J. Wang, Thomas Egan, M. Ugarov, Amina S Woods, J. Albert SchultzAbstract:After water, lipids are the most common biomolecules found in the brain (12%). A brief perusal of the physiology, anatomy, and pathophysiology of the brain illustrates the importance of lipids. Recent advances in mass spectrometry have allowed the direct probing of tissues. However, most studies have focused on proteins. In the present work, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and MALDI-ion mobility (IM)-TOFMS were employed for direct analysis of phospholipids in rat brain tissue. Molecular ions (MH^+) corresponding to phosphatidylcholines, phosphatidylethanolamines, and sphingomyelin, were recorded. When studying pharmacology, we learn that many therapeutic compounds are stored in the body’s adipose tissue. MALDI-TOFMS and MALDI- IM-TOFMS were thus used to analyze rat brain tissue with Chlorisondamine added directly onto the tissue slice. With both techniques, noncovalent complexes between the tissue phospholipids and Chlorisondamine were detected. In addition, MALDI-IM-TOFMS of noncovalent complexes between phospholipids and Chlorisondamine displayed a mobility between that of an isobaric lipid and peptide.
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Direct tissue analysis of phospholipids in rat brain using MALDI-TOFMS and MALDI-ion mobility-TOFMS
Journal of the American Society for Mass Spectrometry, 2005Co-Authors: Shelley N. Jackson, Hay Yan J. Wang, Thomas Egan, M. Ugarov, A S Woods, J. Albert SchultzAbstract:After water, lipids are the most common biomolecules found in the brain (12%). A brief perusal of the physiology, anatomy, and pathophysiology of the brain illustrates the importance of lipids. Recent advances in mass spectrometry have allowed the direct probing of tissues. However, most studies have focused on proteins. In the present work, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and MALDI-ion mobility (IM)-TOFMS were employed for direct analysis of phospholipids in rat brain tissue. Molecular ions (MH+) corresponding to phosphatidylcholines, phosphatidylethanolamines, and sphingomyelin, were recorded. When studying pharmacology, we learn that many therapeutic compounds are stored in the body's adipose tissue. MALDI-TOFMS and MALDI- IM-TOFMS were thus used to analyze rat brain tissue with Chlorisondamine added directly onto the tissue slice. With both techniques, noncovalent complexes between the tissue phospholipids and Chlorisondamine were detected. In addition, MALDI-IM-TOFMS of noncovalent complexes between phospholipids and Chlorisondamine displayed a mobility between that of an isobaric lipid and peptide. © 2004 American Society for Mass Spectrometry.
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interaction of Chlorisondamine with the neuronal nicotinic acetylcholine receptor
Journal of Proteome Research, 2003Co-Authors: Amina S Woods, Hay Yan J. Wang, Susanne C Moyer, Roy A WiseAbstract:: An epitope was found on the alpha2-nicotinic isoform of the neuronal nicotinic acetylcholine receptor that would likely form salt bridges with quaternary ammonium compounds and a cation-pi interaction with the pi-cloud of an aromatic ring. Chlorisondamine, a nicotinic antagonist, exerts a long-lasting, if not permanent, blockade of the ion channel gated by acetylcholine. Blocking of the ion channel prevents nicotine from exerting its rewarding effect on the CNS. Chlorisondamine contains two quaternary ammonium groups and a tetrachloroisoindoline ring. We propose that Chlorisondamine interacts with an epitope on the alpha2 isoform of the rat neuronal nicotinic receptor (residues 388-402, GEREETEEEEEEEDE), where one or both of the quaternary ammonium groups of Chlorisondamine form a salt bridge with dither a glutamic acid side chain or a phosphate group, whereas the tetrachlorobenzene portion of the tetrachloroisoindoline ring interacts with the guanidinium group of arginine in a cation-pi association: In this work, a new way of probing the interaction of a receptor epitope (alpha2) with organic molecules (Chlorisondamine and hexachlorobenzene) was undertaken using matrix assisted laser desorption/ionization mass spectrometry.