The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 benzothiadiazine 1 1 dioxides toward an improvement in sulfonylurea receptor 1 selectivity and metabolism sta
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

  • new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 benzopyrans structurally related to cromakalim as Tissue selective pancreatic β cell katp channel openers
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Sophie Sebille, Marie-hélène Antoine, Pascal De Tullio, Bernard Pirotte, Xavier Florence, B Becker, Catherine Michaux, Johan Wouters, Philippe Lebrun
    Abstract:

    The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine Tissue (inhibition of insulin release) and on the vascular Smooth Muscle Tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic Tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic Tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.

  • synthesis and pharmacological evaluation of some n arylsulfonyl n methyl n 2 2 dimethyl 2h 1 benzopyran 4 yl ureas structurally related to cromakalim
    Bioorganic & Medicinal Chemistry, 2006
    Co-Authors: S Khelili, Pascal De Tullio, Philippe Lebrun, Bernard Pirotte
    Abstract:

    Some N-arylsulfonyl-N-methyl-N'-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas were prepared and evaluated as putative potassium channel openers on the vascular and uterine Smooth Muscle Tissue (myorelaxant effect), as well as on insulin-secreting pancreatic islets (inhibition of insulin release). The pharmacological results indicated that these compounds exhibited a marked biological activity on these three Tissues.

  • 4,6-Disubstituted 2,2-dimethylchromans structurally related to the K(ATP) channel opener cromakalim: design, synthesis, and effect on insulin release and vascular tone.
    Journal of medicinal chemistry, 2005
    Co-Authors: Sophie Sebille, Bénédicte Becker, Marie-hélène Antoine, Pascal De Tullio, Bernard Pirotte, Stéphane Boverie, Pierre Lebrun
    Abstract:

    Five series (ureas, thioureas, carbamates, sulfonylureas, and amides) of 4,6-disubstituted-2,2-dimethylchromans structurally related to cromakalim were prepared and evaluated, as putative ATP-sensitive potassium channel activators, on rat pancreatic islets and rat aorta rings. The biological data indicate that most compounds were, like the reference molecule cromakalim, more active on the vascular Smooth Muscle Tissue (myorelaxant effect on 30 mM KCl induced contractions of rat aorta rings) than on the pancreatic Tissue (inhibition of 16.7 mM glucose induced insulin release from rat pancreatic islets). However, some drugs (8h, 8i, 9f, 9g, 9h, and 9i) markedly inhibited insulin release and exhibited an activity equivalent or greater than that of diazoxide. Compounds 9h and 9i were also found to be more active on pancreatic beta-cells than on vascular Smooth Muscle cells. Last, the amide 6b was selected in order to examine its mechanism of action on vascular Smooth Muscle cells. Pharmacological results suggest that the compound acted as a K(ATP) channel opener. In conclusion, the present data indicate that appropriate structural modifications can generate dimethylchromans with pharmacological profiles different from that of cromakalim.

Pascal De Tullio - One of the best experts on this subject based on the ideXlab platform.

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 benzothiadiazine 1 1 dioxides toward an improvement in sulfonylurea receptor 1 selectivity and metabolism sta
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

  • new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 benzopyrans structurally related to cromakalim as Tissue selective pancreatic β cell katp channel openers
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Sophie Sebille, Marie-hélène Antoine, Pascal De Tullio, Bernard Pirotte, Xavier Florence, B Becker, Catherine Michaux, Johan Wouters, Philippe Lebrun
    Abstract:

    The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine Tissue (inhibition of insulin release) and on the vascular Smooth Muscle Tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic Tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic Tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.

  • synthesis and pharmacological evaluation of some n arylsulfonyl n methyl n 2 2 dimethyl 2h 1 benzopyran 4 yl ureas structurally related to cromakalim
    Bioorganic & Medicinal Chemistry, 2006
    Co-Authors: S Khelili, Pascal De Tullio, Philippe Lebrun, Bernard Pirotte
    Abstract:

    Some N-arylsulfonyl-N-methyl-N'-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas were prepared and evaluated as putative potassium channel openers on the vascular and uterine Smooth Muscle Tissue (myorelaxant effect), as well as on insulin-secreting pancreatic islets (inhibition of insulin release). The pharmacological results indicated that these compounds exhibited a marked biological activity on these three Tissues.

  • 4,6-Disubstituted 2,2-dimethylchromans structurally related to the K(ATP) channel opener cromakalim: design, synthesis, and effect on insulin release and vascular tone.
    Journal of medicinal chemistry, 2005
    Co-Authors: Sophie Sebille, Bénédicte Becker, Marie-hélène Antoine, Pascal De Tullio, Bernard Pirotte, Stéphane Boverie, Pierre Lebrun
    Abstract:

    Five series (ureas, thioureas, carbamates, sulfonylureas, and amides) of 4,6-disubstituted-2,2-dimethylchromans structurally related to cromakalim were prepared and evaluated, as putative ATP-sensitive potassium channel activators, on rat pancreatic islets and rat aorta rings. The biological data indicate that most compounds were, like the reference molecule cromakalim, more active on the vascular Smooth Muscle Tissue (myorelaxant effect on 30 mM KCl induced contractions of rat aorta rings) than on the pancreatic Tissue (inhibition of 16.7 mM glucose induced insulin release from rat pancreatic islets). However, some drugs (8h, 8i, 9f, 9g, 9h, and 9i) markedly inhibited insulin release and exhibited an activity equivalent or greater than that of diazoxide. Compounds 9h and 9i were also found to be more active on pancreatic beta-cells than on vascular Smooth Muscle cells. Last, the amide 6b was selected in order to examine its mechanism of action on vascular Smooth Muscle cells. Pharmacological results suggest that the compound acted as a K(ATP) channel opener. In conclusion, the present data indicate that appropriate structural modifications can generate dimethylchromans with pharmacological profiles different from that of cromakalim.

Philippe Lebrun - One of the best experts on this subject based on the ideXlab platform.

  • Hydroxylated Analogues of ATP-Sensitive Potassium Channel Openers Belonging to the Group of 6- and/or 7-Substituted 3-Isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides: Toward an Improvement in Sulfonylurea Receptor 1 Selectivity and Metabolism S
    2016
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)­amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)­amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a

  • hydroxylated analogues of atp sensitive potassium channel openers belonging to the group of 6 and or 7 substituted 3 isopropylamino 4h 1 2 4 benzothiadiazine 1 1 dioxides toward an improvement in sulfonylurea receptor 1 selectivity and metabolism sta
    Journal of Medicinal Chemistry, 2011
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard Pirotte
    Abstract:

    Diversely substituted 3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides are known to be potent KATP channel openers, with several drugs being selective for the SUR1/Kir6.2 channel subtype. This work examined the biological activity, Tissue selectivity, and in vitro metabolic stability of hydroxylated analogues of 3-isopropylaminobenzothiadiazine dioxides. Because of the presence of a chiral center, the R and S isomers were prepared separately and characterized. R isomers were systematically found to be more potent and more selective than S isomers on pancreatic Tissue (compared to vascular Smooth Muscle Tissue), leading to compounds with an improved sulfonylurea receptor 1 (SUR1) selectivity. An in vitro metabolic study revealed that 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (1a) was rapidly biotransformed and led in part to a mixture of the corresponding (R)- and (S)-3-(1-hydroxy-2-propyl)amino-substituted derivatives. Radioisotopic experiments characterized one of the most potent and SUR1-selective enantiomers, (R)-7-chloro-3-(1-hydroxy-2-propyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxide 13a, as being a KATP channel opener. Moreover, 13a exhibited an enhanced metabolic stability. Such a compound can be considered as a new lead candidate displaying improved physicochemical (hydrosolubility) and pharmacological (Tissue selectivity) properties as well as improved metabolic stability compared to its nonhydroxylated counterpart, 1a.

  • new r s 3 4 dihydro 2 2 dimethyl 6 halo 4 phenylaminothiocarbonylamino 2h 1 benzopyrans structurally related to cromakalim as Tissue selective pancreatic β cell katp channel openers
    Bioorganic & Medicinal Chemistry, 2008
    Co-Authors: Sophie Sebille, Marie-hélène Antoine, Pascal De Tullio, Bernard Pirotte, Xavier Florence, B Becker, Catherine Michaux, Johan Wouters, Philippe Lebrun
    Abstract:

    The present work was aimed at exploring a series of R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(phenylaminothiocarbonylamino)-2H-1-benzopyrans structurally related to (+/-)-cromakalim and differently substituted at the 4- and 6-positions. The biological effects of these putative activators of ATP-sensitive potassium channels (K(ATP)) were characterized in vitro on the pancreatic endocrine Tissue (inhibition of insulin release) and on the vascular Smooth Muscle Tissue (relaxation of aorta rings). The biological activity of these new dimethylchroman derivatives was further compared to that of (+/-)-cromakalim, (+/-)-pinacidil, diazoxide and BPDZ 73. Structure-activity relationships indicated that an improved potency for the pancreatic Tissue was obtained by introducing a meta- or a para-electron-withdrawing group such as a chlorine atom on the C-4 phenyl ring, independently of the nature of the halogen atom at the 6-position of the benzopyran nucleus. Most original dimethylchroman thioureas were more potent than their 'urea' homologues and even more potent than diazoxide at inhibiting insulin release. Moreover, and unlike (+/-)-cromakalim or (+/-)-pinacidil, such compounds appeared to be highly selective towards the pancreatic Tissue. Radioisotopic and fluorimetric investigations indicated that the new drugs activated pancreatic K(ATP) channels. Lastly, conformational studies suggested that the urea/thiourea dimethylchromans can be regarded as hybrid compounds between cromakalim and pinacidil.

  • synthesis and pharmacological evaluation of some n arylsulfonyl n methyl n 2 2 dimethyl 2h 1 benzopyran 4 yl ureas structurally related to cromakalim
    Bioorganic & Medicinal Chemistry, 2006
    Co-Authors: S Khelili, Pascal De Tullio, Philippe Lebrun, Bernard Pirotte
    Abstract:

    Some N-arylsulfonyl-N-methyl-N'-(2,2-dimethyl-2H-1-benzopyran-4-yl)ureas were prepared and evaluated as putative potassium channel openers on the vascular and uterine Smooth Muscle Tissue (myorelaxant effect), as well as on insulin-secreting pancreatic islets (inhibition of insulin release). The pharmacological results indicated that these compounds exhibited a marked biological activity on these three Tissues.

  • 3 and 4 substituted 4h pyrido 4 3 e 1 2 4 thiadiazine 1 1 dioxides as potassium channel openers synthesis pharmacological evaluation and structure activity relationships
    Journal of Medicinal Chemistry, 1996
    Co-Authors: Pascal De Tullio, Philippe Lebrun, Jeanine Fontaine, L Dupont, R Ouedraogo, S Khelili, Carine Maggetto, Bernard Masereel
    Abstract:

    4-N-Subsituted and -unsubstituted 3-alkyl- and 3-(alkylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested vs diazoxide and selected 3-alkyl- and 3-(alkylamino)-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides as potassium channel openers on pancreatic and vascular Tissues. Several 4-N-unsubstituted 3-(alkylamino)pyridothiadiazines and some 3-(alkylamino)-7-chlorobenzothiadiazines were found to be more potent than diazoxide for the inhibition of the insulin-releasing process. Moreover, the 3-(alkylamino)pyridothiadiazines appeared to be more selective for the pancreatic than for the vascular Tissue. By means of the pharmacological results obtained on pancreatic B-cells, structure−activity relationships were deduced and a pharmacophoric model for the interaction of these drugs with their receptor site associated to the pancreatic KATP channel was proposed. According to their selectivity for the B-cell (endocrine Tissue) vs the vascular (Smooth Muscle Tissue) ionic channel, sel...

David J Mooney - One of the best experts on this subject based on the ideXlab platform.

  • Smooth Muscle cell adhesion to Tissue engineering scaffolds
    Biomaterials, 2000
    Co-Authors: Janeta Nikolovski, David J Mooney
    Abstract:

    Abstract Synthetic polyesters of lactic and glycolic acid, and the extracellular matrix molecule collagen are among the most widely-utilized scaffolding materials in Tissue engineering. However, the mechanism of cell adhesion to these Tissue engineering scaffolds has not been extensively studied. In this paper, the mechanism of adhesion of Smooth Muscle cells to these materials was investigated. Vitronectin was found to be the predominant matrix protein adsorbed from serum-containing medium onto polyglycolic acid, poly(lactic co-glycolic) acid, and collagen two-dimensional films and three-dimensional scaffolds. Fibronectin adsorbed to both materials as well, although to a much lower density. Smooth Muscle cell adhesion was mediated through specific integrin receptors interacting with these adsorbed proteins, as evidenced by both immunostaining and blocking studies. The receptors involved in adhesion included the αvβ5 to vitronectin, the α5β1 to fibronectin and the α2β1 to collagen I. Identification of the specific receptors used to adhere to these polymers clarifies why Smooth Muscle Tissue development differs on these scaffolds, and may allow one to design Tissue formation by controlling the surface chemistry of Tissue engineering scaffolds.

  • cyclic mechanical strain regulates the development of engineered Smooth Muscle Tissue
    Nature Biotechnology, 1999
    Co-Authors: Byungsoo Kim, Janeta Nikolovski, Jeffrey Bonadio, David J Mooney
    Abstract:

    We show that the appropriate combinations of mechanical stimuli and polymeric scaffolds can enhance the mechanical properties of engineered Tissues. The mechanical properties of Tissues engineered from cells and polymer scaffolds are significantly lower than the native Tissues they replace. We hypothesized that application of mechanical stimuli to engineered Tissues would alter their mechanical properties. Smooth Muscle Tissue was engineered on two different polymeric scaffolds and subjected to cyclic mechanical strain. Short-term application of strain increased proliferation of Smooth Muscle cells (SMCs) and expression of collagen and elastin, but only when SMCs were adherent to specific scaffolds. Long-term application of cyclic strain upregulated elastin and collagen gene expression and led to increased organization in Tissues. This resulted in more than an order of magnitude increase in the mechanical properties of the Tissues.

  • engineering Smooth Muscle Tissue with a predefined structure
    Journal of Biomedical Materials Research, 1998
    Co-Authors: Byungsoo Kim, David J Mooney
    Abstract:

    Nonwoven meshes of polyglycolic acid (PGA) fibers are attractive synthetic extracellular matrices (ECMs) for Tissue engineering and have been used to engineer many types of Tissues. However, these synthetic ECMs lack struc- tural stability and often cannot maintain their original struc- ture during Tissue development. This makes it difficult to design an engineered Tissue with a predefined configuration and dimensions. In this study, we investigated the ability of PGA fiber-based matrices bonded at their fiber crosspoints with a secondary polymer, poly-L-lactic acid (PLLA), to re- sist cellular contractile forces and maintain their predefined structure during the process of Smooth Muscle (SM) Tissue development in vitro. Physically bonded PGA matrices ex- hibited a 10- to 35-fold increase in the compressive modulus over unbonded PGA matrices, depending on the mass of PLLA utilized to bond the PGA matrices. In addition, the bonded PGA matrices degraded much more slowly than the unbonded matrices. The PLLA bonding of PGA matrices had no effect on the ability of cells to adhere to the matrices. After 7 weeks in culture, the bonded matrices maintained 101 ± 4% of their initial volume and an approximate original shape while the unbonded matrices contracted t o5±1 % of their initial volume with an extreme change in their shape. At this time the bonded PGA matrices had a high cellularity, with Smooth Muscle cells (SMCs) and ECM proteins pro- duced by these cells (e.g., elastin) filling the pores between PGA fibers. This study demonstrated that physically bonded PGA fiber-based matrices allow the maintenance of the con- figuration and dimensions of the original matrices and the development of a new Tissue in a predefined three- dimensional structure. This approach may be useful for en- gineering a variety of Tissues of various structures and shapes, and our study demonstrates the importance of matching both the initial mechanical properties and the deg- radation rate of a matrix to the specific Tissue one is engi- neering. © 1998 John Wiley & Sons, Inc. J Biomed Mater Res, 41, 322-332, 1998.

  • engineering Smooth Muscle Tissue with a predefined structure
    Journal of Biomedical Materials Research, 1998
    Co-Authors: Byungsoo Kim, David J Mooney
    Abstract:

    Nonwoven meshes of polyglycolic acid (PGA) fibers are attractive synthetic extracellular matrices (ECMs) for Tissue engineering and have been used to engineer many types of Tissues. However, these synthetic ECMs lack structural stability and often cannot maintain their original structure during Tissue development. This makes it difficult to design an engineered Tissue with a predefined configuration and dimensions. In this study, we investigated the ability of PGA fiber-based matrices bonded at their fiber crosspoints with a secondary polymer, poly-L-lactic acid (PLLA), to resist cellular contractile forces and maintain their predefined structure during the process of Smooth Muscle (SM) Tissue development in vitro. Physically bonded PGA matrices exhibited a 10- to 35-fold increase in the compressive modulus over unbonded PGA matrices, depending on the mass of PLLA utilized to bond the PGA matrices. In addition, the bonded PGA matrices degraded much more slowly than the unbonded matrices. The PLLA bonding of PGA matrices had no effect on the ability of cells to adhere to the matrices. After 7 weeks in culture, the bonded matrices maintained 101 +/- 4% of their initial volume and an approximate original shape while the unbonded matrices contracted to 5 +/- 1% of their initial volume with an extreme change in their shape. At this time the bonded PGA matrices had a high cellularity, with Smooth Muscle cells (SMCs) and ECM proteins produced by these cells (e.g., elastin) filling the pores between PGA fibers. This study demonstrated that physically bonded PGA fiber-based matrices allow the maintenance of the configuration and dimensions of the original matrices and the development of a new Tissue in a predefined three-dimensional structure. This approach may be useful for engineering a variety of Tissues of various structures and shapes, and our study demonstrates the importance of matching both the initial mechanical properties and the degradation rate of a matrix to the specific Tissue one is engineering.

  • optimizing seeding and culture methods to engineer Smooth Muscle Tissue on biodegradable polymer matrices
    Biotechnology and Bioengineering, 1998
    Co-Authors: Byungsoo Kim, Andrew J Putnam, Thomas J Kulik, David J Mooney
    Abstract:

    The engineering of functional Smooth Muscle (SM) Tissue is critical if one hopes to successfully replace the large number of Tissues containing an SM compo- nent with engineered equivalents. This study reports on the effects of SM cell (SMC) seeding and culture condi- tions on the cellularity and composition of SM Tissues engineered using biodegradable matrices (5 ◊ 5 mm, 2- mm thick) of polyglycolic acid (PGA) fibers. Cells were seeded by injecting a cell suspension into polymer ma- trices in Tissue culture dishes (static seeding), by stirring polymer matrices and a cell suspension in spinner flasks (stirred seeding), or by agitating polymer matrices and a cell suspension in tubes with an orbital shaker (agitated seeding). The density of SMCs adherent to these matri- ces was a function of cell concentration in the seeding solution, but under all conditions a larger number (ap- proximately 1 order of magnitude) and more uniform distribution of SMCs adherent to the matrices were ob- tained with dynamic versus static seeding methods. The dynamic seeding methods, as compared to the static method, also ultimately resulted in new Tissues that had a higher cellularity, more uniform cell distribution, and greater elastin deposition. The effects of culture condi- tions were next studied by culturing cell-polymer con- structs in a stirred bioreactor versus static culture condi- tions. The stirred culture of SMC-seeded polymer matri- ces resulted in Tissues with a cell density of 6.4 ± 0.8 ◊ 10 8 cells/cm 3 after 5 weeks, compared to 2.0 ± 1.1 ◊ 10 8 cells/ cm 3 with static culture. The elastin and collagen synthe- sis rates and deposition within the engineered Tissues were also increased by culture in the bioreactors. The elastin content after 5-week culture in the stirred biore- actor was 24 ± 3%, and both the elastin content and the cellularity of these Tissues are comparable to those of native SM Tissue. New Tissues were also created in vivo when dynamically seeded polymer matrices were im- planted in rats for various times. In summary, the system defined by these studies shows promise for engineering a Tissue comparable in many respects to native SM. This engineered Tissue may find clinical applications and pro- vide a tool to study molecular mechanisms in vascular development. © 1998 John Wiley & Sons, Inc. Biotechnol Bio- eng 57: 46-54, 1998.

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  • targeting extra oral bitter taste receptors modulates gastrointestinal motility with effects on satiation
    Scientific Reports, 2015
    Co-Authors: Bert Avau, Alessandra Rotondo, Theo Thijs, Christopher N Andrews, Pieter Janssen, Jan Tack, Inge Depoortere
    Abstract:

    Bitter taste receptors (TAS2Rs) are present in extra-oral Tissues, including gut endocrine cells. This study explored the presence and mechanism of action of TAS2R agonists on gut Smooth Muscle in vitro and investigated functional effects of intra-gastric administration of TAS2R agonists on gastric motility and satiation. TAS2Rs and taste signalling elements were expressed in Smooth Muscle Tissue along the mouse gut and in human gastric Smooth Muscle cells (hGSMC). Bitter tastants induced concentration and region-dependent contractility changes in mouse intestinal Muscle strips. Contractions induced by denatonium benzoate (DB) in gastric fundus were mediated via increases in intracellular Ca2+ release and extracellular Ca2+-influx, partially masked by a hyperpolarizing K+-efflux. Intra-gastric administration of DB in mice induced a TAS2R-dependent delay in gastric emptying. In hGSMC, bitter compounds evoked Ca2+-rises and increased ERK-phosphorylation. Healthy volunteers showed an impaired fundic relaxation in response to nutrient infusion and a decreased nutrient volume tolerance and increased satiation during an oral nutrient challenge test after intra-gastric DB administration. These findings suggest a potential role for intestinal TAS2Rs as therapeutic targets to alter gastrointestinal motility and hence to interfere with hunger signalling.

  • Motilin receptor: A model for development of prokinetics
    Digestive Diseases and Sciences, 1994
    Co-Authors: Theo L. Peeters, Inge Depoortere
    Abstract:

    Erythromycin and related macrolides act as Smooth Muscle and neural receptors to contract rabbit duodenum and induce phase III migrating motor complex (MMC) activity in intact dogs. A recently developed motilin antagonist confirms that motility effects of erythromycin are mediated by motilin receptors. Despite species, organ, and Tissue heterogeneity of motilin receptors, binding experiments with rodent antral Smooth Muscle Tissue provide a good model for the development of this new class of prokinetics.

  • solubilization and characterization of motilin receptor complexes from rabbit antral Smooth Muscle Tissue
    Journal of Receptor Research, 1993
    Co-Authors: Inge Depoortere, T L Peeters, Gaston Vantrappen
    Abstract:

    In the present study, the motilin receptor was characterized by enzymatic digestion studies and by solubilization of the motilin-receptor complex from prelabeled membranes using the anionic detergent cholic acid. Motilin binding was significantly decreased by preincubation of membranes of rabbit antral Tissue with trypsin, phospholipase A2, C, D, dithiothreitol and 2-mercaptoethanol but not by neuraminidase and beta-galactosidase. Treatment of prelabeled membranes with 1% cholic acid resulted in solubilization of 24 +/- 5% of the proteins and 65 +/- 3% of the radioactivity. The latter was for 77 +/- 4% due to the presence of the motilin-receptor complex as estimated with PEG-precipitation. Upon gel-filtration on Superose 6 the complex partially dissociated but 43 +/- 3% eluted with macromolecular components in the void volume. This peak was not detected when membranes were first incubated with unlabeled motilin. Further disaggregation was accomplished by the addition of 0.5 M NaCl to the elution buffer. The chromatographic profile then showed a peak of about 370 kDa and a second one of 100 kDa. The latter value probably reflects the molecular mass of a single 125I-motilin-receptor-complex.