The Experts below are selected from a list of 318 Experts worldwide ranked by ideXlab platform
Atsuo Tahara - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo.
Naunyn-Schmiedeberg's archives of pharmacology, 2011Co-Authors: Atsuo Tahara, Toshiyuki Takasu, Eiji Kurosaki, Masanori Yokono, Daisuke Yamajuku, Rumi Kihara, Yuka Hayashizaki, Masakazu Imamura, Li Qun, Hiroshi TomiyamaAbstract:The Pharmacological Profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-d-glucitol compound with l-proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic Profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-Ay type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at Pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.
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Pharmacological Profile of ASP8497, a novel, selective, and competitive dipeptidyl peptidase-IV inhibitor, in vitro and in vivo
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: Yuka Someya, Atsuo Tahara, Akiko Matsuyama-yokono, Itsuro Nagase, Yasuhisa Fukunaga, Toshiyuki Takasu, Ryosuke Nakano, Masahiko Hayakawa, Masayuki ShibasakiAbstract:Dipeptidyl peptidase (DPP)-IV is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibitors are expected to become a useful new class of antidiabetic agent. This report describes the Pharmacological Profile of the novel DPP-IV inhibitor, ASP8497 [(2 S ,4 S )-4-fluoro-1-({[4-methyl-1-(methylsulfonyl)piperidin-4-yl]amino}acetyl)pyrrolidine-2-carbonitrile monofumarate], both in vitro and in vivo. ASP8497 inhibited DPP-IV in plasma from mice, dogs, and humans with median inhibition concentration (IC_50) values of 2.6 nM, 7.3 nM, and 6.2 nM, respectively. In contrast, ASP8497 did not potently inhibit human DPP8 or DPP9 activity (IC_50 = 1,700 nM and 100 nM, respectively) and exhibited selectivity against several proteases, including proline-specific proteases (IC_50 > 10 μM). Kinetic analysis indicated that ASP8497 is a competitive DPP-IV inhibitor. In normal mice, ASP8497 inhibited plasma DPP-IV activity even 12 h after administration. ASP8497 significantly inhibited increases in the blood glucose level during the oral glucose tolerance test (OGTT) conducted 0.5 h after administration. This was accompanied by increases in the plasma active GLP-1 and insulin levels. In addition, ASP8497 significantly inhibited increases in the blood glucose level during the OGTT conducted 8 h after administration. Furthermore, in Zucker fatty rats, ASP8497 dose dependently improved glucose tolerance with significance at doses of 1 mg/kg or higher. In contrast, ASP8497 did not cause hypoglycemia in fasted normal mice. These results indicate that ASP8497 is a potent, competitive, and selective DPP-IV inhibitor with antihyperglycemic activity.
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Pharmacological Profile of ym087 a novel potent nonpeptide vasopressin v1a and v2 receptor antagonist in vitro and in vivo
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Atsuo Tahara, Takeyuki Yatsu, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Toshiyuki Kusayama, Masahiro Takanashi, Akihiro TanakaAbstract:The biochemical and Pharmacological Profile of YM087, 4′-\[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d\]\[1\]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V1A receptors from rat liver and V2 receptors from rat kidney with Ki values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [3H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a Ki value of 44.4 nM, and at 100 μM did not affect the binding of [3H]AVP to anterior pituitary (V1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca++]i) itself, but suppressed AVP-induced increase in [Ca++]i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V1A and V2 receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.
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Pharmacological Profile of ym087 a novel nonpeptide dual vasopressin v1a and v2 receptor antagonist in dogs
European Journal of Pharmacology, 1997Co-Authors: Takeyuki Yatsu, Atsuo Tahara, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Akihiro Tanaka, Toichi TakenakaAbstract:Abstract The Pharmacological Profile of YM087 (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide monohydrochloride) was investigated in dogs. YM087 showed high affinity for vasopressin V1A and V2 receptors in radioligand receptor binding studies with dog platelets (V1A) and kidney (V2). Intravenously injected YM087 (3–100 μg/kg) dose dependently inhibited the pressor response to exogenous vasopressin in anesthetized dogs. Intravenous (10–100 μg/kg) and oral (30–300 μg/kg) administration of YM087 dose dependently increased urine flow with little effect on urinary sodium and potassium excretion in normally hydrated conscious dogs. Concomitantly, the urine osmolality dropped below the plasma osmolality (300 mOsm/kg H2O). In contrast, intravenously injected furosemide (300 μg/kg) increased urine flow with marked increases in urinary sodium and potassium excretion. These results indicate that YM087 is the first orally effective dual vasopressin V1A and V2 receptor antagonist and that it will be a new tool in the investigation of the physiological and pathophysiological role of vasopressin in the cardiovascular system and kidney. YM087 may be useful for the treatment of patients with congestive heart failure, renal diseases and water-retaining diseases.
Tomoyuki Kanda - One of the best experts on this subject based on the ideXlab platform.
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In vitro Pharmacological Profile of the A_2A receptor antagonist istradefylline
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A_2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A_2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro Pharmacological Profile of istradefylline as an A_2A receptor antagonist. Istradefylline exhibited high affinity for A_2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A_1, A_2B, and A_3) were lower than that for A_2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D_1, D_2, D_3, D_4, and D_5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol- O -methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A_2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A_2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A_2A receptor antagonist. The in vitro Pharmacological Profile of istradefylline helps to explain the in vivo Profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
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In vitro Pharmacological Profile of the A2A receptor antagonist istradefylline.
Naunyn-Schmiedeberg's archives of pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro Pharmacological Profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro Pharmacological Profile of istradefylline helps to explain the in vivo Profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
Akihiro Tanaka - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of ym087 a novel potent nonpeptide vasopressin v1a and v2 receptor antagonist in vitro and in vivo
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Atsuo Tahara, Takeyuki Yatsu, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Toshiyuki Kusayama, Masahiro Takanashi, Akihiro TanakaAbstract:The biochemical and Pharmacological Profile of YM087, 4′-\[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d\]\[1\]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V1A receptors from rat liver and V2 receptors from rat kidney with Ki values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [3H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a Ki value of 44.4 nM, and at 100 μM did not affect the binding of [3H]AVP to anterior pituitary (V1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca++]i) itself, but suppressed AVP-induced increase in [Ca++]i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V1A and V2 receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.
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Pharmacological Profile of ym087 a novel nonpeptide dual vasopressin v1a and v2 receptor antagonist in dogs
European Journal of Pharmacology, 1997Co-Authors: Takeyuki Yatsu, Atsuo Tahara, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Akihiro Tanaka, Toichi TakenakaAbstract:Abstract The Pharmacological Profile of YM087 (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide monohydrochloride) was investigated in dogs. YM087 showed high affinity for vasopressin V1A and V2 receptors in radioligand receptor binding studies with dog platelets (V1A) and kidney (V2). Intravenously injected YM087 (3–100 μg/kg) dose dependently inhibited the pressor response to exogenous vasopressin in anesthetized dogs. Intravenous (10–100 μg/kg) and oral (30–300 μg/kg) administration of YM087 dose dependently increased urine flow with little effect on urinary sodium and potassium excretion in normally hydrated conscious dogs. Concomitantly, the urine osmolality dropped below the plasma osmolality (300 mOsm/kg H2O). In contrast, intravenously injected furosemide (300 μg/kg) increased urine flow with marked increases in urinary sodium and potassium excretion. These results indicate that YM087 is the first orally effective dual vasopressin V1A and V2 receptor antagonist and that it will be a new tool in the investigation of the physiological and pathophysiological role of vasopressin in the cardiovascular system and kidney. YM087 may be useful for the treatment of patients with congestive heart failure, renal diseases and water-retaining diseases.
Takeyuki Yatsu - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological Profile of ym087 a novel potent nonpeptide vasopressin v1a and v2 receptor antagonist in vitro and in vivo
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Atsuo Tahara, Takeyuki Yatsu, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Toshiyuki Kusayama, Masahiro Takanashi, Akihiro TanakaAbstract:The biochemical and Pharmacological Profile of YM087, 4′-\[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d\]\[1\]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride, a newly synthesized nonpeptide vasopressin (AVP) antagonist, was investigated in several in vitro and in vivo studies. YM087 showed high affinity for V1A receptors from rat liver and V2 receptors from rat kidney with Ki values of 0.48 and 3.04 nM, respectively. YM087 also inhibited [3H]oxytocin (OT) binding to rat uterus (OT receptors) plasma membranes with a Ki value of 44.4 nM, and at 100 μM did not affect the binding of [3H]AVP to anterior pituitary (V1B receptors) plasma membranes, which indicated that it had less affinity for these OT and V1B receptors. YM087 had no effect on cytosolic free calcium concentration ([Ca++]i) itself, but suppressed AVP-induced increase in [Ca++]i of cultured vascular smooth muscle cells at the same concentrations as the binding affinities. Furthermore, YM087 potently blocked AVP-induced cAMP production of cultured renal epithelium cells concentration dependently and had no agonistic activities. In in vivo studies, intravenous administration of YM087 inhibited the pressor response to exogenous AVP in pithed rats and produced an aquaretic effect in dehydrated conscious rats in a dose-dependent manner. These results demonstrate that YM087 is a potent and nonpeptide dual AVP V1A and V2 receptors antagonist and can be used in future studies to help clarify the physiological and pathophysiological roles of AVP.
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Pharmacological Profile of ym087 a novel nonpeptide dual vasopressin v1a and v2 receptor antagonist in dogs
European Journal of Pharmacology, 1997Co-Authors: Takeyuki Yatsu, Atsuo Tahara, Yuichi Tomura, Kohichi Wada, Junko Tsukada, Wataru Uchida, Akihiro Tanaka, Toichi TakenakaAbstract:Abstract The Pharmacological Profile of YM087 (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide monohydrochloride) was investigated in dogs. YM087 showed high affinity for vasopressin V1A and V2 receptors in radioligand receptor binding studies with dog platelets (V1A) and kidney (V2). Intravenously injected YM087 (3–100 μg/kg) dose dependently inhibited the pressor response to exogenous vasopressin in anesthetized dogs. Intravenous (10–100 μg/kg) and oral (30–300 μg/kg) administration of YM087 dose dependently increased urine flow with little effect on urinary sodium and potassium excretion in normally hydrated conscious dogs. Concomitantly, the urine osmolality dropped below the plasma osmolality (300 mOsm/kg H2O). In contrast, intravenously injected furosemide (300 μg/kg) increased urine flow with marked increases in urinary sodium and potassium excretion. These results indicate that YM087 is the first orally effective dual vasopressin V1A and V2 receptor antagonist and that it will be a new tool in the investigation of the physiological and pathophysiological role of vasopressin in the cardiovascular system and kidney. YM087 may be useful for the treatment of patients with congestive heart failure, renal diseases and water-retaining diseases.
Mayumi Saki - One of the best experts on this subject based on the ideXlab platform.
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In vitro Pharmacological Profile of the A_2A receptor antagonist istradefylline
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A_2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A_2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro Pharmacological Profile of istradefylline as an A_2A receptor antagonist. Istradefylline exhibited high affinity for A_2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A_1, A_2B, and A_3) were lower than that for A_2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D_1, D_2, D_3, D_4, and D_5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol- O -methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A_2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A_2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A_2A receptor antagonist. The in vitro Pharmacological Profile of istradefylline helps to explain the in vivo Profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
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In vitro Pharmacological Profile of the A2A receptor antagonist istradefylline.
Naunyn-Schmiedeberg's archives of pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A2A receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A2A receptor antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro Pharmacological Profile of istradefylline as an A2A receptor antagonist. Istradefylline exhibited high affinity for A2A receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine receptors (A1, A2B, and A3) were lower than that for A2A receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter receptors, including dopamine receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A receptor antagonist. The in vitro Pharmacological Profile of istradefylline helps to explain the in vivo Profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
