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Pascal De Tullio - One of the best experts on this subject based on the ideXlab platform.
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7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Journal of Medicinal Chemistry, 2017Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars OlsenAbstract:We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine Dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine Dioxide AMPApam to reach the nanomolar range.
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7‑Phenoxy-Substituted 3,4-Dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
2017Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars OlsenAbstract:We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine Dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine Dioxide AMPApam to reach the nanomolar range
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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
2016Co-Authors: Pascal De Tullio, Fabian Somers, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, Patrice Chiap, Bernard PirotteAbstract: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
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positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine Dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
Journal of Medicinal Chemistry, 2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
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Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg
Bernard Pirotte - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract:Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine Dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-Dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-Dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency
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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
2016Co-Authors: Pascal De Tullio, Fabian Somers, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, Patrice Chiap, Bernard PirotteAbstract: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
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1,4,2-Benzo/pyridodithiazine 1,1-Dioxides Structurally Related to the ATP-Sensitive Potassium Channel Openers 1,2,4-Benzo/pyridothiadiazine 1,1-Dioxides Exert a Myorelaxant Activity Linked to a Distinct Mechanism of Action
2013Co-Authors: Bernard Pirotte, Xavier Florence, Pascal De Tullio, Fabian Somers, Stéphane Boverie, Eric Goffin, Philippe LebrunAbstract:The synthesis of diversely substituted 3-alkyl/aralkyl/arylamino-1,4,2-benzodithiazine 1,1-Dioxides and 3-alkylaminopyrido[4,3-e]-1,4,2-dithiazine 1,1-Dioxides is described. Their biological activities on pancreatic β-cells and on smooth muscle cells were compared to those of the reference ATP-sensitive potassium channel (KATP channel) openers diazoxide and 7-chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxide. The aim was to assess the impact on biological activities of the replacement of the 1,2,4-thiadiazine ring by an isosteric 1,4,2-dithiazine ring. Most of the dithiazine analogues were found to be inactive on the pancreatic tissue, although some compounds bearing a 1-phenylethylamino side chain at the 3-position exerted a marked myorelaxant activity. Such an effect did not appear to be related to the opening of KATP channels but rather reflected a mechanism of action similar to that of calcium channel blockers. Tightly related 3-(1-phenylethyl)sulfanyl-4H-1,2,4-benzothiadiazine 1,1-Dioxides were also found to exert a pronounced myorelaxant activity, resulting from both a KATP channel activation and a calcium channel blocker mechanism. The present work highlights the critical importance of an intracyclic NH group at the 4-position, as well as an exocyclic NH group linked to the 3-position of the benzo- and pyridothiadiazine Dioxides, for activity on KATP channels
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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, 2011Co-Authors: Pascal De Tullio, Philippe Lebrun, Annecatherine Servais, Marianne Fillet, Florian Gillotin, F Somers, Patrice Chiap, Bernard PirotteAbstract: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.
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Chloro-substituted 3-alkylamino-4h-1,2,4-benzothiadiazine 1,1-Dioxides as ATP-sensitive potassium channel activators: Impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity
Journal of Medicinal Chemistry, 2010Co-Authors: Bernard Pirotte, Pierre Fraikin, Xavier Florence, Philip Wahl, Quynh Anh Nguyen, John Bondo Hansen, Pascal De Tullio, Fabian Somers, Pierre LebrunAbstract:The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.
Eric Goffin - One of the best experts on this subject based on the ideXlab platform.
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7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Journal of Medicinal Chemistry, 2017Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars OlsenAbstract:We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine Dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine Dioxide AMPApam to reach the nanomolar range.
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7‑Phenoxy-Substituted 3,4-Dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
2017Co-Authors: Eric Goffin, Pascal De Tullio, Thomas Drapier, Anja Probst Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Lars OlsenAbstract:We report here the synthesis of 7-phenoxy-substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4-cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine Dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine Dioxide AMPApam to reach the nanomolar range
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Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract:Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine Dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-Dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-Dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency
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positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine Dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
Journal of Medicinal Chemistry, 2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
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Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg
Pierre Francotte - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract:Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine Dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-Dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-Dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency
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positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine Dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
Journal of Medicinal Chemistry, 2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
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Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg
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development of thiophenic analogues of benzothiadiazine Dioxides as new powerful potentiators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid ampa receptors
Journal of Medicinal Chemistry, 2013Co-Authors: Pierre Francotte, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, E Graindorge, Sylvie Challal, Nathalie Rogez, Olivier Nosjean, Danielhenri CaignardAbstract:On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-Dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-Dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-Dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low...
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design synthesis and pharmacology of novel 7 substituted 3 4 dihydro 2h 1 2 4 benzothiadiazine 1 1 Dioxides as positive allosteric modulators of ampa receptors
Journal of Medicinal Chemistry, 2007Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Gaëlle Dintilhac, L. Danober, Pierre Lestage, E Graindorge, Jeanyves Thomas, Danielhenri CaignardAbstract:A series of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides have been synthesized and evaluated as potentiators of AMPA receptors. Attention was paid to the impact of the substituent introduced at the 7-position of the heterocycle. The biological evaluation was achieved by measuring the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most potent compound, 4-ethyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxide (12a) was found to be active in an object recognition test in rats demonstrating cognition enhancing effects in vivo after oral administration.
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Synthesis and Pharmacology of Mono‑, Di‑, and Trialkyl-Substituted 7‑Chloro-3,4-dihydro‑2H‑1,2,4-benzothiadiazine 1,1-Dioxides Combined with X‑ray Structure Analysis to Understand the Unexpected Structure–Activity Relationship at AMPA Receptors
2016Co-Authors: Anja Probst Larsen, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, Pierre Francotte, Danielhenri Caignard, Karla Frydenvang, Daniel Tapken, Bernard PirotteAbstract:Positive allosteric modulators of 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA)-type ionotropic glutamate receptors are promising compounds for treatment of neurological disorders, for example, Alzheimer’s disease. Here, we report synthesis and pharmacological evaluation of a series of mono-, di-, or trialkyl-substituted 7-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides, comprising in total 16 new modulators. The trisubstituted compounds 7b, 7d, and 7e revealed potent activity (EC2× = 2.7–4.3 μM; concentration of compound responsible for a 2-fold increase of the AMPA mediated response) as AMPA receptor potentiators in an in vitro cellular fluorescence assay (FLIPR). The 4-cyclopropyl compound 7f was found to be considerably less potent (EC2× = 60 μM), in contrast to previously described 4-monoalkyl-substituted benzothiadiazine Dioxides for which the cyclopropyl group constitutes the best choice of substituent. 7b was subjected to X-ray structural analysis in complex with the GluA2 ligand-binding domain. We propose an explanation of the unexpected structure–activity relationship of this new series of mono-, di-, and trialkyl-substituted 1,2,4-benzothiadiazine 1,1-Dioxide compounds. The methyl substituent in the 3-position directs the binding mode of the 1,2,4-benzothiadiazine 1,1-Dioxide (BTD) scaffold. When a methyl substituent is present in the 3-position of the BTD, additional methyl substituents in both the 2- and 4-positions increase potency, whereas introduction of a 4-cyclopropyl group does not enhance potency of 2,3,4-alkyl-substituted BTDs. A hydrogen bond donor in the 2-position of the BTD is not necessary for modulator potency
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positive allosteric modulators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid receptors belonging to 4 cyclopropyl 3 4 dihydro 2h 1 2 4 pyridothiadiazine Dioxides and diversely chloro substituted 4 cyclopropyl 3 4 dihydro 2h 1 2 4 benzot
Journal of Medicinal Chemistry, 2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The "8-aza" compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood-brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
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Positive Allosteric Modulators of 2‑Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4‑Cyclopropyl-3,4-dihydro‑2H‑1,2,4-benzo
2014Co-Authors: Pierre Francotte, Pierre Fraikin, Pascal De Tullio, Eric Goffin, Lars Olsen, Karla Frydenvang, Annbeth Norholm, Taru Deva, Sylvie Challal, Jeanyves ThomasAbstract:Two 4-ethyl-substituted pyridothiadiazine Dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine Dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-Dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine Dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg
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development of thiophenic analogues of benzothiadiazine Dioxides as new powerful potentiators of 2 amino 3 3 hydroxy 5 methylisoxazol 4 yl propionic acid ampa receptors
Journal of Medicinal Chemistry, 2013Co-Authors: Pierre Francotte, Pierre Fraikin, Eric Goffin, L. Danober, Pierre Lestage, E Graindorge, Sylvie Challal, Nathalie Rogez, Olivier Nosjean, Danielhenri CaignardAbstract:On the basis of the results obtained in previous series of AMPA potentiators belonging to 3,4-dihydro-2H-benzo- and 3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-Dioxides, the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-Dioxides. Owing to the sulfur position, three series of compounds were developed and their activity as AMPA potentiators was characterized. In each of the developed series, potent compounds were discovered. After screening the selected active compounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-Dioxide (24) appeared as the most promising compound and was further evaluated. Its effects on long-term potentiation in vivo and on AMPA-mediated noradrenaline release were measured to predict its potential cognitive enhancing properties. Finally, an object recognition test performed in mice revealed that 24 was able to significantly enhance cognition, after oral administration, at doses as low...
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Chloro-substituted 3-alkylamino-4h-1,2,4-benzothiadiazine 1,1-Dioxides as ATP-sensitive potassium channel activators: Impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity
Journal of Medicinal Chemistry, 2010Co-Authors: Bernard Pirotte, Pierre Fraikin, Xavier Florence, Philip Wahl, Quynh Anh Nguyen, John Bondo Hansen, Pascal De Tullio, Fabian Somers, Pierre LebrunAbstract:The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-Dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.
