The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Craig V Jordan - One of the best experts on this subject based on the ideXlab platform.
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selective estrogen Receptor Modulation concept and consequences in cancer
Cancer Cell, 2004Co-Authors: Craig V JordanAbstract:Abstract Extended exposure to the selective estrogen Receptor modulators (SERMs) such as raloxifene to prevent osteoporosis and tamoxifen or the aromatase inhibitors to treat or prevent breast cancer are established therapeutic strategies. However, there are now clearly defined consequences of exhaustive antihormonal therapy in breast cancer. Ultimately, drug resistance to SERMs and aromatase inhibitors enhances cancer cell survival but a paradoxical supersensitivity to estrogen action develops that causes cancer cell apoptosis. The future exploitation of these novel data will allow selective killing of cancer with fewer side effects for patients.
V.c. Jordan - One of the best experts on this subject based on the ideXlab platform.
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Selective estrogen Receptor Modulation: a personal perspective.
Cancer Research, 2001Co-Authors: V.c. JordanAbstract:Professor Paul Ehrlich is the father of experimental chemotherapy. During the first decade of the 20th Century, he reasoned that compounds could be synthesized to exhibit selective toxicity on a parasite without affecting the host. The synthesis, laboratory evaluation, and clinical development of
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Selective Estrogen Receptor Modulation
Cancer Research, 2001Co-Authors: A.s. Levenson, V.c. JordanAbstract:Professor Paul Ehrlich is the father of experimental chemotherapy. During the first decade of the 20th Century, he reasoned that compounds could be synthesized to exhibit selective toxicity on a parasite without affecting the host. The synthesis, laboratory evaluation, and clinical development of
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Selective oestrogen Receptor Modulation
European Journal of Cancer, 1999Co-Authors: A.s. Levenson, V.c. JordanAbstract:Abstract Knowledge of the mechanism of action and pharmacology of tamoxifen and raloxifene, for the prevention of breast cancer and osteoporosis respectively, has opened the door for the discovery of multifunctional medicines. There is now the potential to prevent osteoporosis, coronary heart disease, breast and endometrial cancer in postmenopausal women with elevated risk factors.
Anthony G Phillips - One of the best experts on this subject based on the ideXlab platform.
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d1 Receptor Modulation of hippocampal prefrontal cortical circuits integrating spatial memory with executive functions in the rat
The Journal of Neuroscience, 1998Co-Authors: Jeremy K Seamans, Stan B Floresco, Anthony G PhillipsAbstract:Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D1 and D2 Receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D1 antagonist SCH-23390 (0.05, 0.5, or 5 μg/μl), but not the D2anatagonist sulpiride (0.05, 0.5, or 5 μg/μl), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D1 Receptors in modulating activity in hippocampal–PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 Receptor activation in the PFC and D1 Receptor Modulation of hippocampal inputs to the PFC. These data suggest that D1Receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA Modulation of limbic–PFC circuits during behavior.
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D1 Receptor Modulation of Hippocampal–Prefrontal Cortical Circuits Integrating Spatial Memory with Executive Functions in the Rat
The Journal of Neuroscience, 1998Co-Authors: Jeremy K Seamans, Stan B Floresco, Anthony G PhillipsAbstract:Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D1 and D2 Receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D1 antagonist SCH-23390 (0.05, 0.5, or 5 μg/μl), but not the D2anatagonist sulpiride (0.05, 0.5, or 5 μg/μl), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D1 Receptors in modulating activity in hippocampal–PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 Receptor activation in the PFC and D1 Receptor Modulation of hippocampal inputs to the PFC. These data suggest that D1Receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA Modulation of limbic–PFC circuits during behavior.
Ilse M Beck - One of the best experts on this subject based on the ideXlab platform.
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selective glucocorticoid Receptor Modulation new directions with non steroidal scaffolds
Pharmacology & Therapeutics, 2015Co-Authors: Nora Sundahl, Jolien Bridelance, Claude Libert, Karolien De Bosscher, Ilse M BeckAbstract:Abstract Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid Receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid Receptor agonists (SEGRAs) or selective glucocorticoid Receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid Receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid Receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid Receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid Receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid Receptor therapies.
Trung L. Pham - One of the best experts on this subject based on the ideXlab platform.
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GABAA Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value
Pharmacology, 2016Co-Authors: Robert J. Brosnan, Trung L. PhamAbstract:Background: The Modulation of N-methyl-D-aspartate Receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate γ-aminobutyric acid type A (GABAA) Receptors. We hypothesized that GABAA Receptor Modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. Methods: GABAA Receptors consisting of human α1 and rat β2 and γ2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABAA Receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. Results: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABAA Receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABAA Receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6-diisopropyl substituents also caused channel opening in the absence of GABA. Conclusions: The molar water solubility cut-off for GABAA Receptor Modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABAA Receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance.
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Hydrocarbon molar water solubility predicts NMDA vs. GABAA Receptor Modulation
BMC Clinical Pharmacology, 2014Co-Authors: Robert J. Brosnan, Trung L. PhamAbstract:Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABAA) Receptors. Clinical and experimental anesthetics exhibiting Receptor family specificity often have low water solubility. We hypothesized that the molar water solubility of a hydrocarbon could be used to predict Receptor Modulation in vitro. GABAA (α1β2γ2s) or NMDA (NR1/NR2A) Receptors were expressed in oocytes and studied using standard two-electrode voltage clamp techniques. Hydrocarbons from 14 different organic functional groups were studied at saturated concentrations, and compounds within each group differed only by the carbon number at the ω-position or within a saturated ring. An effect on GABAA or NMDA Receptors was defined as a 10% or greater reversible current change from baseline that was statistically different from zero. Hydrocarbon moieties potentiated GABAA and inhibited NMDA Receptor currents with at least some members from each functional group modulating both Receptor types. A water solubility cut-off for NMDA Receptors occurred at 1.1 mM with a 95% CI = 0.45 to 2.8 mM. NMDA Receptor cut-off effects were not well correlated with hydrocarbon chain length or molecular volume. No cut-off was observed for GABAA Receptors within the solubility range of hydrocarbons studied. Hydrocarbon Modulation of NMDA Receptor function exhibits a molar water solubility cut-off. Differences between unrelated Receptor cut-off values suggest that the number, affinity, or efficacy of protein-hydrocarbon interactions at these sites likely differ.
