The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
P. P. A. Humphrey - One of the best experts on this subject based on the ideXlab platform.
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The in vitro pharmacological profile of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: J. A. M. Smith, D. T. Beattie, D. Marquess, J.-p. Shaw, R. G. Vickery, P. P. A. HumphreyAbstract:The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT_4 receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT_4 receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT_4(c) (h5-HT_4(c)) receptor (pEC_50 = 8.3) and 5-HT_4 receptor-mediated relaxation of the rat esophagus (pEC_50 = 7.9) and contraction of the guinea pig colon (pEC_50 = 7.9). In all in vitro assays, TD-5108 was a high Intrinsic Activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower Intrinsic Activity. TD-5108 had high affinity (p K _i = 7.7) and selectivity (≥25-fold) for h5-HT_4(c) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT_2B and h5-HT_3A) and, at 3 μM, had no effect on human ether-à-go-go-related gene K^+ channels. In conclusion, TD-5108 is a selective 5-HT_4 receptor agonist in vitro. The high Intrinsic Activity and preferential binding of TD-5108 to 5-HT_4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.
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The in vivo gastrointestinal Activity of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: D. T. Beattie, J. A. M. Smith, D. Marquess, J.-p. Shaw, S. R. Armstrong, C. Sandlund, J. A. Taylor, P. P. A. HumphreyAbstract:The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The Activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT_4 receptor agonist, TD-5108, demonstrates robust in vivo Activity in the guinea pig, rat and dog gastrointestinal tracts.
Erling Rytter - One of the best experts on this subject based on the ideXlab platform.
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Fischer–Tropsch synthesis: Cobalt particle size and support effects on Intrinsic Activity and product distribution
Journal of Catalysis, 2008Co-Authors: Øyvind Borg, Pascal D. C. Dietzel, Aud I. Spjelkavik, Erik Z. Tveten, John C. Walmsley, S. Diplas, Sigrid Eri, Anders Holmen, Erling RytterAbstract:Abstract The influence of cobalt particle size in the range 3 to 18 nm on the Fischer–Tropsch synthesis Intrinsic Activity and product distribution was investigated over 26 alumina ( γ -Al 2 O 3 and α -Al 2 O 3 ) supported catalysts. A volcano-like curve was obtained for the γ -Al 2 O 3 based catalysts when the C 5+ selectivity was plotted as a function of the particle size. The maximum selectivity was located at 7–8 nm. This is the first time an optimum particle size has been identified. An apparent optimum size was also discovered for the series of α -Al 2 O 3 based catalysts. Interestingly, the C 5+ selectivity of the α -Al 2 O 3 based catalysts was higher than the selectivity of the γ -Al 2 O 3 based catalysts at all particle sizes. Thus, the selectivity is related both to the particle size and the support. No relation was observed between the cobalt particle size and the cobalt site-time yield.
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fischer tropsch synthesis cobalt particle size and support effects on Intrinsic Activity and product distribution
Journal of Catalysis, 2008Co-Authors: Øyvind Borg, Pascal D. C. Dietzel, Aud I. Spjelkavik, Erik Z. Tveten, John C. Walmsley, S. Diplas, Sigrid Eri, Anders Holmen, Erling RytterAbstract:Abstract The influence of cobalt particle size in the range 3 to 18 nm on the Fischer–Tropsch synthesis Intrinsic Activity and product distribution was investigated over 26 alumina ( γ -Al 2 O 3 and α -Al 2 O 3 ) supported catalysts. A volcano-like curve was obtained for the γ -Al 2 O 3 based catalysts when the C 5+ selectivity was plotted as a function of the particle size. The maximum selectivity was located at 7–8 nm. This is the first time an optimum particle size has been identified. An apparent optimum size was also discovered for the series of α -Al 2 O 3 based catalysts. Interestingly, the C 5+ selectivity of the α -Al 2 O 3 based catalysts was higher than the selectivity of the γ -Al 2 O 3 based catalysts at all particle sizes. Thus, the selectivity is related both to the particle size and the support. No relation was observed between the cobalt particle size and the cobalt site-time yield.
Lawrence Toll - One of the best experts on this subject based on the ideXlab platform.
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Small-molecule agonists and antagonists of the opioid receptor-like receptor (ORL1, NOP): ligand-based analysis of structural factors influencing Intrinsic Activity at NOP.
The AAPS journal, 2005Co-Authors: Nurulain Zaveri, Faming Jiang, Cris Olsen, Willma Polgar, Lawrence TollAbstract:The recently discovered fourth member of the opioid receptor family, the nociceptin receptor (NOP) and its endogenous ligand, the heptadecapeptide nociceptin, are involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small-molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents a brief overview of the several recently reported NOP ligands, classified as NOP agonists and antagonists, with an emphasis on the analysis of the structural features that may be important for modulating the agonist/antagonist profile (Intrinsic Activity) of these ligands. Structure-Activity relationships in our own series of dihydroindolinone-based NOP ligands and those of the various reported ligands indicate that the lipophilic substituent on the common basic nitrogen present in all NOP ligands plays a role in determining the agonist/antagonist profile of the NOP ligand. This analysis provides a basis for the rational drug design of NOP ligands of desired Intrinsic Activity and provides a framework for developing pharmacophore models for high affinity binding and Intrinsic Activity at the NOP receptor. Since NOP agonists and antagonists both have therapeutic value, rational approaches for obtaining both within a high-affinity binding class of compounds are very useful for designing potent and selective NOP ligands with the desired profile of Intrinsic efficacy.
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Small-molecule agonists and antagonists of the opioid receptor-like receptor (ORL1, NOP): ligand-based analysis of structural factors influencing Intrinsic Activity at NOP.
Aaps Journal, 2005Co-Authors: Nurulain T. Zaveri, Faming Jiang, Cris M. Olsen, Willma E. Polgar, Lawrence TollAbstract:The recently discovered fourth member of the opioid receptor family, the nociceptin receptor (NOP) and its endogenous ligand, the heptadecaptide nociceptin, are involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small-molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents a brief overview of the several recently reported NOP ligands, classified as NOP agonists and antagonists, with an emphasis on the analysis of the structural features that may be important for modulating the agonist/antagonist profile (Intrinsic Activity) of these ligands. Structure-Activity relationships in our own series of dihydroindolinone-based NOP ligands and those of the various reported ligands indicate that the lipophilic substituent on the common basic nitrogen present in all NOP ligands plays a role in determining the agonist/antagonist profile of the NOP ligand. This analysis provides a basis for the rational drug design of NOP ligands of desired Intrinsic Activity and provides a framework for developing pharmacophore models for high affinity binding and Intrinsic Activity at the NOP receptor. Since NOP agonists and antagonists both have therapeutic value, rational approaches for obtaining both within a high-affinity binding class of compounds are very useful for designing potent and selective NOP ligands with the desired profile of Intrinsic efficacy.
Yasuaki Okamoto - One of the best experts on this subject based on the ideXlab platform.
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Effect of sulfidation atmosphere on the hydrodesulfurization Activity of SiO2-supported Co-Mo sulfide catalysts: Local structure and Intrinsic Activity of the active sites
Journal of Catalysis, 2009Co-Authors: Yasuaki Okamoto, Kazuya Hioka, Kenichi Arakawa, Takashi Fujikawa, Takeshi Ebihara, Takeshi KubotaAbstract:The effects of the sulfidation atmosphere on the local structure and Intrinsic Activity of the active sites, Co–Mo–S, are studied with SiO2-supported Co–Mo sulfide catalysts prepared by a chemical vapor deposition method using Co(CO)3NO. The Co–Mo sulfide catalysts were sulfided in a stream of 10% H2S/H2 or 10% H2S/He or their combinations. The Intrinsic Activity of Co–Mo/SiO2 presulfided in H2S/He is 1.6 times as high as that of Co–Mo–S Type II presulfided in H2S/H2 for the hydrodesulfurization (HDS) of thiophene, demonstrating that the location and/or local structure of Co–Mo–S are varied by the sulfidation atmosphere as well as by the MoS2-support interaction. The catalysts were characterized by X-ray absorption fine structure and transmission electron microscope. It is suggested that the Intrinsic activities of Co–Mo–S on the S-edge and Mo-edge of MoS2 particles are distinctly different for HDS. Extended X-ray absorption fine structure analysis shows a good correlation between the coordination number of Co–S and the Intrinsic Activity of “active Co–Mo–S”.
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Effect of Boron Addition on the Intrinsic Activity of Al2O3-Supported Cobalt–Tungsten and Cobalt–Molybdenum Sulfide Catalysts for the Hydrodesulfurization of Thiophene
Bulletin of the Chemical Society of Japan, 2006Co-Authors: Usman, Takeshi Kubota, Yasuaki OkamotoAbstract:The effect of boron addition was studied on the Intrinsic Activity of Al2O3-supported cobalt–molybdenum and cobalt–tungsten sulfide catalysts prepared by a CVD technique using [Co(CO)3NO] as a prec...
J. A. M. Smith - One of the best experts on this subject based on the ideXlab platform.
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The in vitro pharmacological profile of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: J. A. M. Smith, D. T. Beattie, D. Marquess, J.-p. Shaw, R. G. Vickery, P. P. A. HumphreyAbstract:The in vitro pharmacological profile of TD-5108, a novel, selective 5-HT_4 receptor agonist, was compared to that of clinically efficacious gastroprokinetic 5-HT_4 receptor agonists. TD-5108 produced an elevation of cyclic adenosine monophosphate in human embryonic kidney 293 cells expressing the human recombinant 5-HT_4(c) (h5-HT_4(c)) receptor (pEC_50 = 8.3) and 5-HT_4 receptor-mediated relaxation of the rat esophagus (pEC_50 = 7.9) and contraction of the guinea pig colon (pEC_50 = 7.9). In all in vitro assays, TD-5108 was a high Intrinsic Activity agonist, unlike tegaserod, mosapride, and cisapride which, in the majority of test systems, had lower Intrinsic Activity. TD-5108 had high affinity (p K _i = 7.7) and selectivity (≥25-fold) for h5-HT_4(c) receptors over other biogenic amine receptors. TD-5108 was >500-fold selective over other 5-HT receptors (including h5-HT_2B and h5-HT_3A) and, at 3 μM, had no effect on human ether-à-go-go-related gene K^+ channels. In conclusion, TD-5108 is a selective 5-HT_4 receptor agonist in vitro. The high Intrinsic Activity and preferential binding of TD-5108 to 5-HT_4 over other 5-HT receptors may result in an improved clinical profile for the treatment of gastrointestinal disorders of reduced motility.
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The in vivo gastrointestinal Activity of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity
Naunyn-Schmiedeberg's Archives of Pharmacology, 2008Co-Authors: D. T. Beattie, J. A. M. Smith, D. Marquess, J.-p. Shaw, S. R. Armstrong, C. Sandlund, J. A. Taylor, P. P. A. HumphreyAbstract:The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT_4 receptor agonist with high Intrinsic Activity, was compared to that of the clinically studied gastrointestinal pro-kinetic agents, tegaserod, cisapride and mosapride. The Activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT_4 receptor agonist, TD-5108, demonstrates robust in vivo Activity in the guinea pig, rat and dog gastrointestinal tracts.
