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Willy Malaisse - One of the best experts on this subject based on the ideXlab platform.
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Meglitinide analogs new insulinotropic agents for the treatment of non insulin dependent diabetes
Revue Médicale de Bruxelles, 2003Co-Authors: Willy MalaisseAbstract:En 1995, plusieurs molecules originales a l'etude en tant qu'agents insulinotropes pour le traitement du diabete de type 2 furent identifiees en tant qu'analogues du Meglitinide. Celui-ci etait connu comme representant la moitie non-sulfonyluree du glibenclamide. Trois de ces molecules originales, a savoir le repaglinide, le nateglinide et le mitiglinide sont ou seront disponibles dans un proche futur pour administration aux patients diabetiques. L'objet du present article est de passer en revue tant les etudes precliniques que les investigations cliniques realisees jusqu'a ce jour a propos des trois analogues du Meglitinide cites ci-dessus. Leur action insulinotrope semble attribuable, comme celle des sulfamides hypoglycemiants, a un effet primaire sur les canaux potassiques sensibles a l'ATP des cellules pancreatiques productrices d'insuline. Ces analogues du Meglitinide different l'un de l'autre, cependant, par leur efficience en tant qu'agents insulinotropes et le decours temporel de leurs effets biologiques, en particulier en ce qui concerne la reversibilite de tels effets.
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pharmacology of the Meglitinide analogs new treatment options for type 2 diabetes mellitus
Treatments in Endocrinology, 2003Co-Authors: Willy MalaisseAbstract:The expression Meglitinide analogs was introduced in 1995 to cover new molecules proposed as non-sulfonylurea insulinotropic agents and displaying structural analogy with Meglitinide, such as repaglinide, nateglinide, and mitiglinide. Meglitinide analogs display, as judged by conformation analysis, a U-shaped configuration similar to that of antihyperglycemic sulfonylureas such as glibenclamide (glyburide) and glimepi-ride. In rat pancreatic islets incubated in the presence of 7.0 mmol/L D-glucose, repaglinide and mitiglinide demonstrate comparable concentration-response relationships for stimulation of insulin release, with a threshold value <10 nmol/L and a maximal secretory response at about 10 nmol/L. Several findings indicate that Meglitinide analogs provoke the closing of adenosine triphosphate-sensitive potassium channels, with subsequent gating of voltage-sensitive calcium channels. The effects of Meglitinide analogs upon the binding of [3H]glibenclamide to islet cells membranes reinforces this concept. At variance, however, with other Meglitinide analogs, the ionic and secretory response to repaglinide (10 μmol/L) is not rapidly reversible in perifused rat islets. In experiments conducted in vivo in control and diabetic rats, repaglinide provokes a greater and more rapid increase in plasma insulin concentration and an earlier fall in glycemia than glibenclamide or glimepiride. Onset of effect is also more rapid and duration of effect shorter with nateglinide versus glibenclamide. In clinical studies, single or repeated daily administration of repaglinide increased plasma insulin concentration in a dose-dependent manner, with an incremental peak reached about 2 hours after repaglinide intake. Plasma concentrations of repaglinide are about 5.0 μg/L 2–2.5 hours after oral intake of the drug. Despite the slow reversibility of repaglinide action in vitro, this drug offers advantages over glibenclamide in terms of the possible occurrence of hypoglycemia if a meal is missed. In volunteers receiving a single oral dose of nateglinide (120mg) 10 minutes before a standardized 800 Kcal breakfast, the plasma insulin concentration was higher 5, 10, and 20 minutes after meal intake than when they received a single dose of repaglinide (0.5 or 2.0mg) or placebo 10 minutes before breakfast. Peak plasma concentrations of nateglinide were reached within 2 hours in most volunteers. Peak plasma concentrations of mitiglinide were reached 30 minutes after a single oral dose in a representative volunteer. Mitiglinide significantly suppressed meal-induced elevations in blood glucose concentrations in a study of patients with type 2 diabetes. In conclusion, two obvious differences among these Meglitinide analogs should be underlined. First, on a molar basis, nateglinide is somewhat less potent than repaglinide or mitiglinide, as an insulinotropic agent. The maximal secretory responses evoked by these three Meglitinide analogs are, however, identical to one another. Secondly, and as already mentioned, the functional effects of nateglinide and mitiglinide are more rapidly reversible than those of repaglinide, for instance in perifused rat islets. The Meglitinide analogs offer the advantage over the long-acting antihyperglycemic sulfonylurea glibenclamide of minimizing the risk of undesirable hypoglycemia.
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new esters of succinic acid and mixed molecules formed by such esters and a Meglitinide analog study of their insulinotropic potential
Pharmacological Research, 2000Co-Authors: Aouatif Laghmich, Laurence Ladriere, Heinz Dannacher, Fredrik Bjorkling, Willy MalaisseAbstract:Eighteen novel esters of succinic acid, including three mixed molecules formed of both succinic acid and nateglinide, were examined for their insulinotropic efficiency in isolated rat pancreatic islets. The secretory response to these esters at increasing concentrations of both d -glucose and the ester itself allowed to identify five esters judged of potential interest for further investigations. They include three molecules with CH(3)-O-CO-CH(2)-CH(2)-CO-NH-CH(R)-CO-O- sequence and two mixed molecules with a nateglinide moiety. The effects of the most potent molecule in the first group and that of two of the esters with a nateglinide moiety upon islet biosynthetic activity in vitro and insulin release in vivo, after either oral or intravenous administration were also investigated. The results suggested that mixed molecules formed of both a succinic acid ester and a Meglitinide analog may efficiently stimulate proinsulin biosynthesis and/or insulin release. Further work is required, however, to improve their modality of in vivo administration.
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uptake of tritiated mitiglinide by pancreatic pieces and islets
Diabetes research, 2000Co-Authors: Willy Malaisse, Francine Malaisse LagaeAbstract:The uptake of tritiated mitiglinide was investigated in isolated islets and tissue pieces prepared from the rat pancreas. In pancreatic islets, the uptake of the Meglitinide analog reached within 30min of incubation an equilibration value representing about 5 times the 3 HOH distribution space. This coincided with internatlization of [ 3 H]mitiglinide in the islet B-cells. The equilibration value for [ 3 H]mitiglinide uptake by pieces of pancreatic tissue was reached at a later time and represented no more than about half the 3 HOH distribution space. Despite these differences between isolated islets and pancreatic pieces, the absolute values and time course for [ 3 H]mitiglinide uptake were comparable in pieces of pancreas obtained from either control rats or animals injected with streptozotocin 4-7 days before sacrifice. These findings indicate that, despite the preferential labelling of the endocrine, relative to exocrine, moiety of the pancreas by [ 3 H]mitiglinide, this Meglitinide analog does not represent a promizing tool for selective imaging of the endocrine pancreas by a non-invasive procedure.
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effect of the Meglitinide analog s214o3 on cationic fluxes and insulin release in perifused rat pancreatic islets exposed to a high concentration of d glucose
Pharmacological Research, 1999Co-Authors: Karim Louchami, Hassan Jijakli, Willy MalaisseAbstract:Abstract The effect of the Meglitinide analog S21403 (10 μm) upon 86 Rb and 45 Ca outflow and insulin release was investigated in perifused rat islets exposed to a high concentration of d-glucose (16.7 mm) in order to simulate the situation found in diabetic patients. Under these conditions, S21403 provoked a rapid, sustained and rapidly reversible increase in 86 Rb outflow, 45 Ca efflux and insulin release. These effects were suppressed or reversed when the experiments were conducted in the absence of extracellular Ca 2+ . They support the view that S21043 could be used as a novel insulinotropic tool in the treatment of non-insulin-dependent diabetes mellitus, the cationic and secretory responses to the drug displaying a favourable time course for prompt and not unduly prolonged activation of islet B-cells.
Michel Vivaudou - One of the best experts on this subject based on the ideXlab platform.
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recognition of sulfonylurea receptor abcc8 9 ligands by the multidrug resistance transporter p glycoprotein abcb1 functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.
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Recognition of Sulfonylurea Receptor (ABCC8/9) Ligands bythe Multidrug Resistance Transporter P-glycoprotein. Functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.
Anis Bessadok - One of the best experts on this subject based on the ideXlab platform.
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recognition of sulfonylurea receptor abcc8 9 ligands by the multidrug resistance transporter p glycoprotein abcb1 functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.
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Recognition of Sulfonylurea Receptor (ABCC8/9) Ligands bythe Multidrug Resistance Transporter P-glycoprotein. Functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.
Malaisse Willy - One of the best experts on this subject based on the ideXlab platform.
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Two daily administrations of glibenclamide or nateglinide for three days to normal rats fail to affect the glycemic and insulinemic responses to glucose of the same antidiabetics agents
'Wiley', 2004Co-Authors: Oguzhan Berrin, Jijakli Hassan, Sener Abdullah, Jurysta Cédric, Courtois Philippe, Malaisse WillyAbstract:Glibenclamide and nateglinide are two antidiabetic agents belonging, respectively, to the sulfonylurea and Meglitinide family. The major aim of the present study was to investigate whether the prior administration twice daily for three days of these agents to normal rats affects the plasma D-glucose and insulin responses to either enteral D-glucose or the same diabetic agents. Glibenclamide (1.0 μg/g body wt.) or nateglinide (50.0 μg/g body wt.) was given by gastric tubing mixed with 2.0 ml of a 0.5 % solution of carboxymethylcellulose. D-glucose (15 μmol/g body wt.) was administered as a 3.5 M solution. Except for a lower plasma D-glucose concentration in the glibenclamide group, no significant difference was found between the three groups of rats on the morning of the fourth day. Likewise, the plasma D-glucose and insulin responses to either D-glucose or the antidiabetic agents were not significantly different in control, glibenclamide- and nateglinide-pretreated rats. The time course for the increase in plasma insulin concentration and lowering of plasma D-glucose concentration was characterized by earlier peak and nadir values, respectively, in the rats receiving nateglinide rather than glibenclamide. These findings indicate that, in normal rats, the secretory responsiveness of insulin-producing cells and glucose homeostasis are not significantly affected by mid-term administration of either glibenclamide or nateglinide, despite the different time course of their effects on both insulin secretion and glycemia.FLWINinfo:eu-repo/semantics/publishedRéunion de la Société belge de Physiologie et de Pharmacologie fondamentales et cliniques, Gand, Belgium, 08/05/200
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Stimulation of insulin release in hereditarily diabetic rats by mixed molecules formed of nateglinide and a succinic acid ester.
2000Co-Authors: Ladrière Laurence, Björkling Fredrik, Malaisse WillyAbstract:Hereditarily diabetic Goto-Kakizaki rats were infused for 5 min with saline, containing as required nateglinide or mixed molecules (HD154 and HD166) with both a nateglinide moiety and a succinic acid ester moiety. The dose of these agents given intravenously amounted to 5.0 nmol/g body weight in all cases. All agents provoked a comparable early increase in plasma insulin concentration. However, HD154 and HD166, but not nateglinide itself, also caused a secondary rise in plasma insulin concentration 30 min after their infusion. It is proposed that mixed molecules formed of both a hypoglycemic sulfonylurea or Meglitinide analog and a succinic acid ester may be better able than the antidiabetic agents themselves to evoke a sustained stimulation of insulin release in non-insulin-dependent diabetes.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe
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New esters of succinic acid and mixed molecules formed by such esters and a Meglitinide analog: study of their insulinotropic potential.
'Elsevier BV', 2000Co-Authors: Laghmich Aouatif, Malaisse Willy, Björkling Fredrik, Dannacher H, Ladrière LaurenceAbstract:Eighteen novel esters of succinic acid, including three mixed molecules formed of both succinic acid and nateglinide, were examined for their insulinotropic efficiency in isolated rat pancreatic islets. The secretory response to these esters at increasing concentrations of both d -glucose and the ester itself allowed to identify five esters judged of potential interest for further investigations. They include three molecules with CH(3)-O-CO-CH(2)-CH(2)-CO-NH-CH(R)-CO-O- sequence and two mixed molecules with a nateglinide moiety. The effects of the most potent molecule in the first group and that of two of the esters with a nateglinide moiety upon islet biosynthetic activity in vitro and insulin release in vivo, after either oral or intravenous administration were also investigated. The results suggested that mixed molecules formed of both a succinic acid ester and a Meglitinide analog may efficiently stimulate proinsulin biosynthesis and/or insulin release. Further work is required, however, to improve their modality of in vivo administration.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe
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Long-term effects of glibenclamide and nateglinide upon pancreatic islet function in normal and diabetic rats.
'Elsevier BV', 1999Co-Authors: Laghmich Aouatif, Ladrière Laurence, Malaisse Lagae Francine, Malaisse WillyAbstract:Both control and hereditarily diabetic (Goto-Kakizaki) rats were administered twice daily for 7 days with an oral solution of carboxymethylcellulose containing, when required, glibenclamide (1.0 microgram g-1 body wt.) or nateglinide (50.0 micrograms g-1 body wt.). The increase in plasma D-glucose concentration and decrease in insulinogenic index caused by the bleeding and handling of the rats prior to sacrifice was more pronounced in the hyperglycaemic and hyperinsulinemic diabetic rats than in the control animals. Eighteen hours after the last oral loading, a sizeable fall in plasma D-glucose concentration and increase in plasma insulin concentration was only observed in the glibenclamide-treated control rats, indicating a more prolonged biological effect of the hypoglycaemic sulphonylurea, as compared to the Meglitinide analog. This coincided with the fact that the insulin content of the islets, their secretory response to a high concentration of D-glucose and their basal biosynthetic activity were more severely affected in glibenclamide than nateglinide-treated animals, especially in the control rats. It is proposed, therefore, that the Meglitinide analog, considered as a new insulinotropic tool for the treatment of non-insulin-dependent diabetic subjects, may offer the far-from-negligible advantage of minimising the risk of a sustained decrease in both islet insulin content and glycaemia.Journal ArticleResearch Support, Non-U.S. Gov'tCommunication lors du Group Contact "Endocrine Pancreas" (FNRS) et de la Belgian Society of Endocrinology, Liège (belgique), 12 December 1998.info:eu-repo/semantics/publishe
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Effect of the Meglitinide analog S21403 on cationic fluxes and insulin release in perifused rat pancreatic islets exposed to a high concentration of D-glucose
'Elsevier BV', 1999Co-Authors: Louchami Karim, Jijakli Hassan, Malaisse WillyAbstract:The effect of the Meglitinide analog S21403 (10 μM) upon 86Rb and 45Ca outflow and insulin release was investigated in perifused rat islets exposed to a high concentration of D-glucose (16.7 mM) in order to simulate the situation found in diabetic patients. Under these conditions, S21403 provoked a rapid, sustained and rapidly reversible increase in 86Rb outflow, 45Ca efflux and insulin release. These effects were suppressed or reversed when the experiments were conducted in the absence of extracellular Ca2+. They support the view that S21043 could be used as a novel insulinotropic tool in the treatment of non-insulin-dependent diabetes mellitus, the cationic and secretory responses to the drug displaying a favourable time course for prompt and not unduly prolonged activation of islet B-cells.SCOPUS: ar.jinfo:eu-repo/semantics/publishe
Francois Andre - One of the best experts on this subject based on the ideXlab platform.
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recognition of sulfonylurea receptor abcc8 9 ligands by the multidrug resistance transporter p glycoprotein abcb1 functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.
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Recognition of Sulfonylurea Receptor (ABCC8/9) Ligands bythe Multidrug Resistance Transporter P-glycoprotein. Functional similarities based on common structural features between two multispecific abc proteins
Journal of Biological Chemistry, 2011Co-Authors: Anis Bessadok, Elisabeth Garcia, Helene Jacquet, Solenne Martin, Alexia Garrigues, Nicolas Loiseau, Francois Andre, Stephane Orlowski, Michel VivaudouAbstract:ATP-sensitive K+ (KATP) channels are the target of a number of pharmacological agents, blockers like hypoglycemic sulfonylureas and openers like the hypotensive cromakalim and diazoxide. These agents act on the channel regulatory subunit, the sulfonylurea receptor (SUR), which is an ABC protein with homologies to P-glycoprotein (P-gp). P-gp is a multidrug transporter expressed in tumor cells and in some healthy tissues. Because these two ABC proteins both exhibit multispecific recognition properties, we have tested whether SUR ligands could be substrates of P-gp. Interaction with P-gp was assayed by monitoring ATPase activity of P-gp-enriched vesicles. The blockers glibenclamide, tolbutamide, and Meglitinide increased ATPase activity, with a rank order of potencies that correlated with their capacity to block KATP channels. P-gp ATPase activity was also increased by the openers SR47063 (a cromakalim analog), P1075 (a pinacidil analog), and diazoxide. Thus, these molecules bind to P-gp (although with lower affinities than for SUR) and are possibly transported by P-gp. Competition experiments among these molecules as well as with typical P-gp substrates revealed a structural similarity between drug binding domains in the two proteins. To rationalize the observed data, we addressed the molecular features of these proteins and compared structural models, computerized by homology from the recently solved structures of murine P-gp and bacterial ABC transporters MsbA and Sav1866. Considering the various residues experimentally assigned to be involved in drug binding, we uncovered several hot spots, which organized spatially in two main binding domains, selective for SR47063 and for glibenclamide, in matching regions of both P-gp and SUR.