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Michael M White - One of the best experts on this subject based on the ideXlab platform.
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interaction of d Tubocurarine analogs with mutant 5 ht3 receptors
Neuropharmacology, 2002Co-Authors: Dong Yan, Michael M WhiteAbstract:Abstract d-Tubocurarine is a potent competitive antagonist of both the muscle-type nicotinic acetylcholine receptor (AChR) and the serotonin type-3 receptor (5HT3R). We have previously used a series of structural analogs of d-Tubocurarine to demonstrate that the ligand-binding domains of both receptors share common structural features. We have now extended these studies to examine the interaction of a series of d-Tubocurarine analogs with 5HT3Rs containing mutations at either of two residues within the ligand-binding domain of the receptor (W90F and R92A). The W90F mutation results in an approximately 2–4-fold decrease in the affinity of the analogs relative to wild-type receptors, while the R92A results in an approximately 8–10-fold increase in affinity. However, since the effect of a given mutation is more or less equivalent for all analogs, neither residue W90 nor R92 is likely to make a specific interaction with d-Tubocurarine itself. Rather, these two residues are likely to play a role in determining both the geometry of the binding site, as well as the overall environment that a ligand encounters in the binding site.
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interaction of d Tubocurarine analogs with the 5ht3 receptor
Neuropharmacology, 1998Co-Authors: Dong Yan, Steen E Pedersen, Michael M WhiteAbstract:Abstract d -Tubocurarine is a potent competitive antagonist of two members of the ligand-gated ion channel family, the muscle-type nicotinic acetylcholine receptor (AChR) and serotonin type-3 receptor (5HT 3 R). We have used a series of analogs of d -Tubocurarine to determine the effects of methylation, stereoisomerization and halogenation on the interaction of d -Tubocurarine with the 5HT 3 R. The affinities of the analogs for the 5HT 3 R span a 200-fold concentration range and fall into three broad groups. The first group, with affinity constants ( K i ) d -Tubocurarine and analogs modified at the nitrogens or 7′ hydroxyl. The fact that these compounds all have high affinity for the 5HT 3 R suggests that these portions of the ligand do not make interactions with the receptor that are critical for high-affinity binding. The second group, with K i 's in the 1–5 μM range, consists of analogs modified at the 12′-hydroxyl or the adjacent 13′-carbon, which suggests that this portion of the ligand makes interactions that are important for high-affinity binding. The third, very low affinity, group is a compound with altered stereoconfiguration at the 1 carbon, demonstrating the importance of proper configuration of the antagonist in ligand-receptor interactions. For the most part, this pattern of selectivity is similar to that for the AChR, suggesting that the structures of the ligand-binding sites of these two receptors share common structural features.
Katrina M. Richards - One of the best experts on this subject based on the ideXlab platform.
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the effect of rate of stimulation on force of contraction in a partially paralyzed rat phrenic nerve hemidiaphragm preparation
Anesthesia & Analgesia, 1997Co-Authors: Adrian J. England, Katrina M. RichardsAbstract:This study was performed to determine whether presynaptic receptor blockade could be differentiated from postsynaptic blockade by examining the effect of increasing rates of indirect stimulation on twitch height depression (THD) on partially paralyzed in vitro rat diaphragm preparations. We calculated the T200/T1 ratio (force of the 200th stimuli divided by the force of the first stimuli) at rates of 0.2 Hz, 0.5 Hz, 1 Hz, and 2 Hz using a drug concentration which provided approximately 20% THD during stimulation at 0.1 Hz. Markedly different T200/T1 ratios were demonstrated when hexamethonium, a drug with predominantly presynaptic effects, was compared with alpha bungarotoxin, a drug with predominantly postsynaptic effects. These results were then compared with those from vecuronium, rocuronium, mivacurium, and Tubocurarine. Both hexamethonium and rocuronium caused a marked decrease in T200/T1 ratio at higher rates of stimulation; alpha bungarotoxin caused a slight increase in T200/T1 ratio at higher rates of stimulation. The T200/T1 ratios produced by vecuronium, mivacurium, and Tubocurarine lay intermediate between hexamethonium and alpha bungarotoxin. Significant differences in T200/T1 ratios were found when alpha bungarotoxin was compared with all other drugs at 2 Hz. Hexamethonium and rocuronium produced significant differences in T200/T1 ratio from those of all the other drugs at 1 Hz and 2 Hz. There were significant differences in the T200/T1 ratio found after hexamethonium and rocuronium compared to alpha bungarotoxin at 0.5 Hz. No significant differences at any rate of stimulation were found between hexamethonium and rocuronium. No difference was observed in the effect of vecuronium, mivacurium, and Tubocurarine. We conclude that, if the observed effect is the result of hexamethonium acting predominantly at presynaptic sites and alpha bungarotoxin acting predominantly at postsynaptic sites, the relative contribution of small doses of nondepolarizing drugs at each site can be differentiated by determining the T200/T1 ratio at rates of 1 Hz or 2 Hz. Our results are consistent with the suggestion that small doses of rocuronium have marked presynaptic activity, but that vecuronium, mivacurium, and Tubocurarine have both pre- and postsynaptic effects.
Dong Yan - One of the best experts on this subject based on the ideXlab platform.
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interaction of d Tubocurarine analogs with mutant 5 ht3 receptors
Neuropharmacology, 2002Co-Authors: Dong Yan, Michael M WhiteAbstract:Abstract d-Tubocurarine is a potent competitive antagonist of both the muscle-type nicotinic acetylcholine receptor (AChR) and the serotonin type-3 receptor (5HT3R). We have previously used a series of structural analogs of d-Tubocurarine to demonstrate that the ligand-binding domains of both receptors share common structural features. We have now extended these studies to examine the interaction of a series of d-Tubocurarine analogs with 5HT3Rs containing mutations at either of two residues within the ligand-binding domain of the receptor (W90F and R92A). The W90F mutation results in an approximately 2–4-fold decrease in the affinity of the analogs relative to wild-type receptors, while the R92A results in an approximately 8–10-fold increase in affinity. However, since the effect of a given mutation is more or less equivalent for all analogs, neither residue W90 nor R92 is likely to make a specific interaction with d-Tubocurarine itself. Rather, these two residues are likely to play a role in determining both the geometry of the binding site, as well as the overall environment that a ligand encounters in the binding site.
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interaction of d Tubocurarine analogs with the 5ht3 receptor
Neuropharmacology, 1998Co-Authors: Dong Yan, Steen E Pedersen, Michael M WhiteAbstract:Abstract d -Tubocurarine is a potent competitive antagonist of two members of the ligand-gated ion channel family, the muscle-type nicotinic acetylcholine receptor (AChR) and serotonin type-3 receptor (5HT 3 R). We have used a series of analogs of d -Tubocurarine to determine the effects of methylation, stereoisomerization and halogenation on the interaction of d -Tubocurarine with the 5HT 3 R. The affinities of the analogs for the 5HT 3 R span a 200-fold concentration range and fall into three broad groups. The first group, with affinity constants ( K i ) d -Tubocurarine and analogs modified at the nitrogens or 7′ hydroxyl. The fact that these compounds all have high affinity for the 5HT 3 R suggests that these portions of the ligand do not make interactions with the receptor that are critical for high-affinity binding. The second group, with K i 's in the 1–5 μM range, consists of analogs modified at the 12′-hydroxyl or the adjacent 13′-carbon, which suggests that this portion of the ligand makes interactions that are important for high-affinity binding. The third, very low affinity, group is a compound with altered stereoconfiguration at the 1 carbon, demonstrating the importance of proper configuration of the antagonist in ligand-receptor interactions. For the most part, this pattern of selectivity is similar to that for the AChR, suggesting that the structures of the ligand-binding sites of these two receptors share common structural features.
Steen E Pedersen - One of the best experts on this subject based on the ideXlab platform.
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interaction of d Tubocurarine analogs with the 5ht3 receptor
Neuropharmacology, 1998Co-Authors: Dong Yan, Steen E Pedersen, Michael M WhiteAbstract:Abstract d -Tubocurarine is a potent competitive antagonist of two members of the ligand-gated ion channel family, the muscle-type nicotinic acetylcholine receptor (AChR) and serotonin type-3 receptor (5HT 3 R). We have used a series of analogs of d -Tubocurarine to determine the effects of methylation, stereoisomerization and halogenation on the interaction of d -Tubocurarine with the 5HT 3 R. The affinities of the analogs for the 5HT 3 R span a 200-fold concentration range and fall into three broad groups. The first group, with affinity constants ( K i ) d -Tubocurarine and analogs modified at the nitrogens or 7′ hydroxyl. The fact that these compounds all have high affinity for the 5HT 3 R suggests that these portions of the ligand do not make interactions with the receptor that are critical for high-affinity binding. The second group, with K i 's in the 1–5 μM range, consists of analogs modified at the 12′-hydroxyl or the adjacent 13′-carbon, which suggests that this portion of the ligand makes interactions that are important for high-affinity binding. The third, very low affinity, group is a compound with altered stereoconfiguration at the 1 carbon, demonstrating the importance of proper configuration of the antagonist in ligand-receptor interactions. For the most part, this pattern of selectivity is similar to that for the AChR, suggesting that the structures of the ligand-binding sites of these two receptors share common structural features.
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interaction of d Tubocurarine analogs with the torpedo nicotinic acetylcholine receptor methylation and stereoisomerization affect site selective competitive binding and binding to the noncompetitive site
Journal of Biological Chemistry, 1995Co-Authors: Steen E Pedersen, Rao V L PapineniAbstract:Analogs of d-Tubocurarine were used to determine the individual effects of methylation, stereoisomerization, and halogenation of d-Tubocurarine on the affinity for each of the two acetylcholine (ACh) binding sites of the Torpedo nicotinic acetylcholine receptor (AChR) and for the noncompetitive antagonist site. Eight analogs were synthesized, including three new compounds: 7'-O-methyl-chondocurarine, 12'-O-methyl-chondocurarine, and 13'-bromo-d-Tubocurarine. The two ACh sites differ in their affinities for d-Tubocurarine by 400-fold, as shown by inhibition of [3H]ACh binding, whereas the affinity ratio for metocurine, the trimethylated derivative of d-Tubocurarine, is reduced to 30 due to a decreased affinity for the high affinity site. Binding analysis of five d-Tubocurarine analogs demonstrates that methylation of the phenols alone is responsible for the observed changes in affinity. Substitution with bromine or iodine at the 13'-position affected affinity at both sites with a net increase in site selectivity. Stereoisomers of d-tubocurare had decreased affinity for only the high affinity ACh site. Thus, the ring systems, including the 12'- and 13'-positions and the 1-position stereocenter, appear to be important in discriminating between the two ACh binding sites. Desensitization of the AChR was measured by increased affinity for [3H]phencyclidine. Binding to only the single, high affinity acetylcholine binding site, comprised by the alpha gamma-subunits, was required for partial desensitization of the AChR by d-Tubocurarine and its analogs. Stronger desensitization, to the same extent observed in the presence of the agonist carbamylcholine, occurred upon binding by iodonated or brominated d-Tubocurarine. Interaction of the analogs at the noncompetitive antagonist site of the AChR was also measured by [3H]phencyclidine binding. The bis-tertiary ammonium analogs of either the d- or l-stereoisomers bound to the noncompetitive antagonist binding site of the AChR with 100-fold higher affinity than the corresponding quaternary ammonium analogs.
Adrian J. England - One of the best experts on this subject based on the ideXlab platform.
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the effect of rate of stimulation on force of contraction in a partially paralyzed rat phrenic nerve hemidiaphragm preparation
Anesthesia & Analgesia, 1997Co-Authors: Adrian J. England, Katrina M. RichardsAbstract:This study was performed to determine whether presynaptic receptor blockade could be differentiated from postsynaptic blockade by examining the effect of increasing rates of indirect stimulation on twitch height depression (THD) on partially paralyzed in vitro rat diaphragm preparations. We calculated the T200/T1 ratio (force of the 200th stimuli divided by the force of the first stimuli) at rates of 0.2 Hz, 0.5 Hz, 1 Hz, and 2 Hz using a drug concentration which provided approximately 20% THD during stimulation at 0.1 Hz. Markedly different T200/T1 ratios were demonstrated when hexamethonium, a drug with predominantly presynaptic effects, was compared with alpha bungarotoxin, a drug with predominantly postsynaptic effects. These results were then compared with those from vecuronium, rocuronium, mivacurium, and Tubocurarine. Both hexamethonium and rocuronium caused a marked decrease in T200/T1 ratio at higher rates of stimulation; alpha bungarotoxin caused a slight increase in T200/T1 ratio at higher rates of stimulation. The T200/T1 ratios produced by vecuronium, mivacurium, and Tubocurarine lay intermediate between hexamethonium and alpha bungarotoxin. Significant differences in T200/T1 ratios were found when alpha bungarotoxin was compared with all other drugs at 2 Hz. Hexamethonium and rocuronium produced significant differences in T200/T1 ratio from those of all the other drugs at 1 Hz and 2 Hz. There were significant differences in the T200/T1 ratio found after hexamethonium and rocuronium compared to alpha bungarotoxin at 0.5 Hz. No significant differences at any rate of stimulation were found between hexamethonium and rocuronium. No difference was observed in the effect of vecuronium, mivacurium, and Tubocurarine. We conclude that, if the observed effect is the result of hexamethonium acting predominantly at presynaptic sites and alpha bungarotoxin acting predominantly at postsynaptic sites, the relative contribution of small doses of nondepolarizing drugs at each site can be differentiated by determining the T200/T1 ratio at rates of 1 Hz or 2 Hz. Our results are consistent with the suggestion that small doses of rocuronium have marked presynaptic activity, but that vecuronium, mivacurium, and Tubocurarine have both pre- and postsynaptic effects.
