Jacques Migeon | University of Washington (original) (raw)
Papers by Jacques Migeon
Journal of Biological Chemistry, Nov 1, 1994
We have used a luciferase reporter gene under the transcriptional control of a cAMP response elem... more We have used a luciferase reporter gene under the transcriptional control of a cAMP response element (CRE) to monitor the effects of G-protein alpha subunits on cAMP-regulated gene expression and to examine muscarinic acetylcholine receptor (mAChR) functional coupling to G-proteins. Expression in JEG-3 cells of a mutationally activated Gi alpha-2 in which glutamine 205 is replaced with leucine (Q205L) decreased forskolin-stimulated expression from the CRE-luciferase gene by up to 75%. Similarly, mutation of glycine 43 (corresponding to glycine 12 in p21ras) to valine decreased forskolin-stimulated expression from the CRE-luciferase gene by a maximum of 50%, indicating that this mutation activates the G-protein and is potentially oncogenic. Transfection of the activated Q205L G(o) alpha subunit decreased forskolin stimulation of CRE-luciferase expression. Transfected wild type G(o) alpha was also able to couple the m4 mAChR receptor to inhibition of AC. The amino-terminal myristoylation site was removed from wild type Gi alpha-2 and Q205L Gi alpha-2 by changing glycine 2 to alanine (G2A). Gi alpha-2 with the G2A and Q205L mutations was unable to decrease forskolin stimulation of CRE-mediated luciferase activity. Furthermore, G2A Gi alpha-2 was unable to couple the m4 mAChR to inhibition of AC. Thus, myristoylation is required both for the function of constitutively active Q205L Gi alpha-2 and for receptor-mediated activation of wild type Gi alpha-2.
Annals of the New York Academy of Sciences, May 1, 1995
Muscarinic acetylcholine receptors (mAChR) arc mcmbcrs of the superfamily of G-protein-coupled ce... more Muscarinic acetylcholine receptors (mAChR) arc mcmbcrs of the superfamily of G-protein-coupled cell surface rcccptors that are characterized by the presence of scvcn putativc transmembrane domains. Other members of this family includc alphaand beta-adrenergic receptors, the opsins, olfactory receptors, thc dopamine receptors, and the receptors for many neuropeptidc and glycoprotein hormones (see Dohlman et a/. I for review). The mAChR themselves represent a small gene family: thc gcncs for five subtypes of mAChR have been identified by molecular cloning. Muscarinic receptors are present in both the central and pcripheral nervous systems, cardiac and smooth musclc, and various exocrine glands (see Nathanson2 and Bonner3 for review). Muscarinic receptors produce functional responses either by regulating the activity of enzymes such as adenylyl cyclase (AC) or phospholipase C (PIX) which produce intracellular second mcsscngcrs, or by regulation of ion channels such as potassium and calcium channels. The ml, m3. and mS receptors couple preferentially to stimulation of PLC, and the m2 and m4 receptors couple preferentially to inhibition of AC. Howcvcr, the specificity of mAChR functional coupling is dcpendent both on levels of receptor expression and on the cell typc in which a givcn receptor or subtype is expressed (see Tietje & Nathansod and rcfcrences therein). Muscarinic receptor number can bc altcrcd in response to sustained agonist exposure. Short-term agonist cxposurc (s to niin) causes a rapid removal of mAChR from the cell surfacc (scquestration) whereas agonist exposure for longer periods of time (h) causes a decrease in total rcceptor number (downregulation). In this report we describe studies on the functional analysis of mAChR coupling mechanisms using a reporter gene system for the detection of mAChRmediated changes in intracellular CAMP levels. We also demonstrate that a tyrosine rcsidue in the intracellular carboxyl tail of the m2 receptor is important in agonistmediated down-regulation but is not required for agonist-mediated functional responsiveness or rcccptor scquestration. Finally. we also demonstrate that longterm agonist activation of mAChR in chick heart cells leads to decreases in the lcvcl of mAChR mRNA lcvcls.
Pharmaceutical Sciences Encyclopedia, Mar 15, 2010
Pharmacological investigations during the drug discovery and development process are broadly divi... more Pharmacological investigations during the drug discovery and development process are broadly divided into three distinct categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacological studies. Secondary pharmacodynamic studies form an important aspect of pharmacological investigations during the drug discovery process. This article discusses drivers for secondary pharmacodynamic studies, different strategic approaches to such studies, and the impact of pharmacological profiling on the drug discovery process. Keywords: secondary pharmacodynamics; drug discovery; drug development; pharmacological profiling; medicine–research
Journal of Biological Chemistry, Apr 1, 1994
We have used a luciferase reporter gene under the transcriptional control of a cAMP response elem... more We have used a luciferase reporter gene under the transcriptional control of a cAMP response element as a sensitive monitor of the regulation by muscarinic acetylcholine receptors (mAChRs) of intracellular cAMP levels and cAMP-regulated gene expression. Treatment with the muscarinic agonist carbachol results in an increase in luciferase activity in JEG-3 cells transiently transfected with mouse m1 (8-10-fold) and chick m4 (3-5-fold) mAChRs. Control experiments indicate that these responses are not due to a calcium-mediated pathway and are dependent upon a functional protein kinase A. The m1 and m4 responses are not sensitive to pertussus toxin and the m4 response was potentiated by it. Thus, these responses do not result from direct stimulation of adenylate cyclase by beta gamma subunits released from pertussis toxin-sensitive G-proteins. Atropine treatment of cells transfected with high levels of m4 mAChR, but not m1, causes an elevation in basal levels of cAMP response element-mediated luciferase expression in the absence of agonist. This suggests that the m4 receptor is spontaneously active and can cause constitutive inhibition of adenylyl cyclase that is relieved by atropine treatment. Surprisingly, the m4 receptor exhibits little if any agonist-induced inhibition of luciferase expression at either low or high levels of receptor expression. JEG-3 cells express Gi alpha-1 and Gi alpha-3 but not Gi alpha-2. Cotransfection of Gi alpha subunits with m4 demonstrates that the m4 receptor requires Gi alpha-2 for optimal agonist-mediated inhibition. Even in the presence of Gi alpha-2, high levels of receptor increased luciferase expression at high concentrations of agonist. Thus, the m4 mAChR can undergo a switch in functional coupling from inhibition to stimulation of adenylyl cyclase. This switch is dependent on the level of receptor expression, the subtypes of G-proteins coexpressed with the receptor, and the concentration of agonist. Furthermore, we demonstrate that the Gi alpha-2 G-protein alpha subunit preferentially couples the m4 mAChR to inhibition of adenylyl cyclase in JEG-3 cells.
Molecular Biology of the Cell, Jun 1, 1999
We identified a new Drosophila gene, peter pan (ppan), in a screen for larval growthdefective mut... more We identified a new Drosophila gene, peter pan (ppan), in a screen for larval growthdefective mutants. ppan mutant larvae do not grow and show minimal DNA replication but can survive until well after their heterozygotic siblings have pupariated. We cloned the ppan gene by P-element plasmid rescue. ppan belongs to a highly conserved gene family that includes Saccharomyces cerevisiae SSF1 and SSF2, as well as Schizosaccharomyces pombe, Arabidopsis, Caenorhabditis elegans, mouse, and human homologues. Deletion of both SSF1 and SSF2 in yeast is lethal, and depletion of the gene products causes cell division arrest. Mosaic analysis of ppan mutant clones in Drosophila imaginal disks and ovaries demonstrates that ppan is cell autonomous and required for normal mitotic growth but is not absolutely required for general biosynthesis or DNA replication. Overexpression of the wild-type gene causes cell death and disrupts the normal development of adult structures. The ppan gene family appears to have an essential and evolutionarily conserved role in cell growth.
European Journal of Biochemistry, 2001
Melanocortins are known to be involved in the regulation of feeding behavior. These hormones medi... more Melanocortins are known to be involved in the regulation of feeding behavior. These hormones mediate their effects through G-protein-coupled receptors by stimulating adenylate cyclase. In this study we describe the functional response of melanocortin 4 receptor (MC4R) and melanocortin 3 receptor (MC3R) in HEK 293T cells, by using a luciferase reporter gene under the transcriptional control of a cAMP-responsive element (CRE) as a monitor of intracellular cAMP levels and cAMP-regulated gene expression. We were able to show that MC4R and MC3R expressed in the human cell line HEK 293T stimulate transcription induced by stimulation with different analogs of a-melanocyte-stimulating hormone (a-MSH) at different levels. In our assay of CRE-mediated gene transcription activity, a-MSH-ND was the most efficient a-MSH analog for MC4R whereas NDP-MSH was the most efficient for MC3R. Changing the His6 residue of a-MSH-ND to Gln or Lys markedly decreased CRE-mediated luciferase activity for MC3R compared with MC4R. On analysis by modeling the receptor±ligand complex by NMR, [Gln6]a-MSH-ND and [Lys6]a-MSH-ND showed different conformational interactions between MC3R and MC4R. Furthermore, the maximum coupling efficiency of MC4R and MC3R to G proteins was different; MC4R showed only 30±50% of the maximum activity induced by MC3R. In total, our results suggest that a differential receptor±ligand interaction is involved and that the relative interactions of MC3R and MC4R with G protein are possibly quantitatively and qualitatively different.
Journal of Chemical Information and Modeling, 2006
We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large da... more We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drugenzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.
Annals of the New York Academy of Sciences, 1995
Current opinion in drug discovery & development, 2003
Computational methods are increasingly used to streamline and enhance the lead discovery and opti... more Computational methods are increasingly used to streamline and enhance the lead discovery and optimization process. However, accurate prediction of absorption, distribution, metabolism and excretion (ADME) and adverse drug reactions (ADR) is often difficult, due to the complexity of underlying physiological mechanisms. Modeling approaches have been hampered by the lack of large, robust and standardized training datasets. In an extensive effort to build such a dataset, the BioPrint database was constructed by systematic profiling of nearly all drugs available on the market, as well as numerous reference compounds. The database is composed of several large datasets: compound structures and molecular descriptors, in vitro ADME and pharmacology profiles, and complementary clinical data including therapeutic use information, pharmacokinetics profiles and ADR profiles. These data have allowed the development of computational tools designed to integrate a program of computational chemistry ...
La presente invention se rapporte a l'utilisation de l'Alverine ou de ses metabolites, le... more La presente invention se rapporte a l'utilisation de l'Alverine ou de ses metabolites, leurs sels et leurs esters, pour la preparation de compositions pharmaceutiques destinees a traiter la depression.
3 Approaches to Pharmacological Profiling 3.1 Factors Inffuencing the Approach to Secondary Pharm... more 3 Approaches to Pharmacological Profiling 3.1 Factors Inffuencing the Approach to Secondary Pharmacodynamics 3.2 In Vivo and In Vitro Approaches to Secondary Pharmacodynamics 3.3 Strategies for In Vitro Pharmacological Profiling
3D-pharmacophores have become popular in the last decade as descriptors for chemical similarity s... more 3D-pharmacophores have become popular in the last decade as descriptors for chemical similarity searching and combinatorial library design. These pharmacophores are typically encoded in large bitstrings, up to hundreds of millions of bits long. Research on other classes of chemical descriptors suggests that "chemical space" requires on the order of 10-20 dimensions. Many of the millions of dimensions are correlated or irrelevant and their large size makes them a less efficient representation for computation. We have developed an approach based on classical multidimensional scaling to determine the inherent dimensionality of these large chemical bitstrings (pharmacophore or otherwise), resulting in real-valued cartesian coordinates. We have also developed a novel approach to calculate much smaller bitstrings (hundreds of bits) that preserve the original pairwise similarity of the original large bitstrings. The new smaller space is general enough that it can be used for many...
Life Sciences, 1999
We have investigated the molecular mechanisms involved in the regulation of muscarinic acetylchol... more We have investigated the molecular mechanisms involved in the regulation of muscarinic acetylcholine receptor gene expression and localization and generated knockout mice to study the role of the M1 muscarinic receptor in vivo. We have used the MDCK cell system to demonstrate that different subtypes of mAChR can be targeted to different regions of polarized cells. We have also examined
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Biological Chemistry, Nov 1, 1994
We have used a luciferase reporter gene under the transcriptional control of a cAMP response elem... more We have used a luciferase reporter gene under the transcriptional control of a cAMP response element (CRE) to monitor the effects of G-protein alpha subunits on cAMP-regulated gene expression and to examine muscarinic acetylcholine receptor (mAChR) functional coupling to G-proteins. Expression in JEG-3 cells of a mutationally activated Gi alpha-2 in which glutamine 205 is replaced with leucine (Q205L) decreased forskolin-stimulated expression from the CRE-luciferase gene by up to 75%. Similarly, mutation of glycine 43 (corresponding to glycine 12 in p21ras) to valine decreased forskolin-stimulated expression from the CRE-luciferase gene by a maximum of 50%, indicating that this mutation activates the G-protein and is potentially oncogenic. Transfection of the activated Q205L G(o) alpha subunit decreased forskolin stimulation of CRE-luciferase expression. Transfected wild type G(o) alpha was also able to couple the m4 mAChR receptor to inhibition of AC. The amino-terminal myristoylation site was removed from wild type Gi alpha-2 and Q205L Gi alpha-2 by changing glycine 2 to alanine (G2A). Gi alpha-2 with the G2A and Q205L mutations was unable to decrease forskolin stimulation of CRE-mediated luciferase activity. Furthermore, G2A Gi alpha-2 was unable to couple the m4 mAChR to inhibition of AC. Thus, myristoylation is required both for the function of constitutively active Q205L Gi alpha-2 and for receptor-mediated activation of wild type Gi alpha-2.
Annals of the New York Academy of Sciences, May 1, 1995
Muscarinic acetylcholine receptors (mAChR) arc mcmbcrs of the superfamily of G-protein-coupled ce... more Muscarinic acetylcholine receptors (mAChR) arc mcmbcrs of the superfamily of G-protein-coupled cell surface rcccptors that are characterized by the presence of scvcn putativc transmembrane domains. Other members of this family includc alphaand beta-adrenergic receptors, the opsins, olfactory receptors, thc dopamine receptors, and the receptors for many neuropeptidc and glycoprotein hormones (see Dohlman et a/. I for review). The mAChR themselves represent a small gene family: thc gcncs for five subtypes of mAChR have been identified by molecular cloning. Muscarinic receptors are present in both the central and pcripheral nervous systems, cardiac and smooth musclc, and various exocrine glands (see Nathanson2 and Bonner3 for review). Muscarinic receptors produce functional responses either by regulating the activity of enzymes such as adenylyl cyclase (AC) or phospholipase C (PIX) which produce intracellular second mcsscngcrs, or by regulation of ion channels such as potassium and calcium channels. The ml, m3. and mS receptors couple preferentially to stimulation of PLC, and the m2 and m4 receptors couple preferentially to inhibition of AC. Howcvcr, the specificity of mAChR functional coupling is dcpendent both on levels of receptor expression and on the cell typc in which a givcn receptor or subtype is expressed (see Tietje & Nathansod and rcfcrences therein). Muscarinic receptor number can bc altcrcd in response to sustained agonist exposure. Short-term agonist cxposurc (s to niin) causes a rapid removal of mAChR from the cell surfacc (scquestration) whereas agonist exposure for longer periods of time (h) causes a decrease in total rcceptor number (downregulation). In this report we describe studies on the functional analysis of mAChR coupling mechanisms using a reporter gene system for the detection of mAChRmediated changes in intracellular CAMP levels. We also demonstrate that a tyrosine rcsidue in the intracellular carboxyl tail of the m2 receptor is important in agonistmediated down-regulation but is not required for agonist-mediated functional responsiveness or rcccptor scquestration. Finally. we also demonstrate that longterm agonist activation of mAChR in chick heart cells leads to decreases in the lcvcl of mAChR mRNA lcvcls.
Pharmaceutical Sciences Encyclopedia, Mar 15, 2010
Pharmacological investigations during the drug discovery and development process are broadly divi... more Pharmacological investigations during the drug discovery and development process are broadly divided into three distinct categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacological studies. Secondary pharmacodynamic studies form an important aspect of pharmacological investigations during the drug discovery process. This article discusses drivers for secondary pharmacodynamic studies, different strategic approaches to such studies, and the impact of pharmacological profiling on the drug discovery process. Keywords: secondary pharmacodynamics; drug discovery; drug development; pharmacological profiling; medicine–research
Journal of Biological Chemistry, Apr 1, 1994
We have used a luciferase reporter gene under the transcriptional control of a cAMP response elem... more We have used a luciferase reporter gene under the transcriptional control of a cAMP response element as a sensitive monitor of the regulation by muscarinic acetylcholine receptors (mAChRs) of intracellular cAMP levels and cAMP-regulated gene expression. Treatment with the muscarinic agonist carbachol results in an increase in luciferase activity in JEG-3 cells transiently transfected with mouse m1 (8-10-fold) and chick m4 (3-5-fold) mAChRs. Control experiments indicate that these responses are not due to a calcium-mediated pathway and are dependent upon a functional protein kinase A. The m1 and m4 responses are not sensitive to pertussus toxin and the m4 response was potentiated by it. Thus, these responses do not result from direct stimulation of adenylate cyclase by beta gamma subunits released from pertussis toxin-sensitive G-proteins. Atropine treatment of cells transfected with high levels of m4 mAChR, but not m1, causes an elevation in basal levels of cAMP response element-mediated luciferase expression in the absence of agonist. This suggests that the m4 receptor is spontaneously active and can cause constitutive inhibition of adenylyl cyclase that is relieved by atropine treatment. Surprisingly, the m4 receptor exhibits little if any agonist-induced inhibition of luciferase expression at either low or high levels of receptor expression. JEG-3 cells express Gi alpha-1 and Gi alpha-3 but not Gi alpha-2. Cotransfection of Gi alpha subunits with m4 demonstrates that the m4 receptor requires Gi alpha-2 for optimal agonist-mediated inhibition. Even in the presence of Gi alpha-2, high levels of receptor increased luciferase expression at high concentrations of agonist. Thus, the m4 mAChR can undergo a switch in functional coupling from inhibition to stimulation of adenylyl cyclase. This switch is dependent on the level of receptor expression, the subtypes of G-proteins coexpressed with the receptor, and the concentration of agonist. Furthermore, we demonstrate that the Gi alpha-2 G-protein alpha subunit preferentially couples the m4 mAChR to inhibition of adenylyl cyclase in JEG-3 cells.
Molecular Biology of the Cell, Jun 1, 1999
We identified a new Drosophila gene, peter pan (ppan), in a screen for larval growthdefective mut... more We identified a new Drosophila gene, peter pan (ppan), in a screen for larval growthdefective mutants. ppan mutant larvae do not grow and show minimal DNA replication but can survive until well after their heterozygotic siblings have pupariated. We cloned the ppan gene by P-element plasmid rescue. ppan belongs to a highly conserved gene family that includes Saccharomyces cerevisiae SSF1 and SSF2, as well as Schizosaccharomyces pombe, Arabidopsis, Caenorhabditis elegans, mouse, and human homologues. Deletion of both SSF1 and SSF2 in yeast is lethal, and depletion of the gene products causes cell division arrest. Mosaic analysis of ppan mutant clones in Drosophila imaginal disks and ovaries demonstrates that ppan is cell autonomous and required for normal mitotic growth but is not absolutely required for general biosynthesis or DNA replication. Overexpression of the wild-type gene causes cell death and disrupts the normal development of adult structures. The ppan gene family appears to have an essential and evolutionarily conserved role in cell growth.
European Journal of Biochemistry, 2001
Melanocortins are known to be involved in the regulation of feeding behavior. These hormones medi... more Melanocortins are known to be involved in the regulation of feeding behavior. These hormones mediate their effects through G-protein-coupled receptors by stimulating adenylate cyclase. In this study we describe the functional response of melanocortin 4 receptor (MC4R) and melanocortin 3 receptor (MC3R) in HEK 293T cells, by using a luciferase reporter gene under the transcriptional control of a cAMP-responsive element (CRE) as a monitor of intracellular cAMP levels and cAMP-regulated gene expression. We were able to show that MC4R and MC3R expressed in the human cell line HEK 293T stimulate transcription induced by stimulation with different analogs of a-melanocyte-stimulating hormone (a-MSH) at different levels. In our assay of CRE-mediated gene transcription activity, a-MSH-ND was the most efficient a-MSH analog for MC4R whereas NDP-MSH was the most efficient for MC3R. Changing the His6 residue of a-MSH-ND to Gln or Lys markedly decreased CRE-mediated luciferase activity for MC3R compared with MC4R. On analysis by modeling the receptor±ligand complex by NMR, [Gln6]a-MSH-ND and [Lys6]a-MSH-ND showed different conformational interactions between MC3R and MC4R. Furthermore, the maximum coupling efficiency of MC4R and MC3R to G proteins was different; MC4R showed only 30±50% of the maximum activity induced by MC3R. In total, our results suggest that a differential receptor±ligand interaction is involved and that the relative interactions of MC3R and MC4R with G protein are possibly quantitatively and qualitatively different.
Journal of Chemical Information and Modeling, 2006
We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large da... more We report the QSAR modeling of cytochrome P450 3A4 (CYP3A4) enzyme inhibition using four large data sets of in vitro data. These data sets consist of marketed drugs and drug-like compounds all tested in four assays measuring the inhibition of the metabolism of four different substrates by the CYP3A4 enzyme. The four probe substrates are benzyloxycoumarin, testosterone, benzyloxyresorufin, and midazolam. We first show that using state-of-the-art QSAR modeling approaches applied to only one of these four data sets does not lead to predictive models that would be useful for in silico filtering of chemical libraries. We then present the development and the testing of a multiple pharmacophore hypothesis (MPH) that is formulated as a conceptual extension of the traditional QSAR approach to modeling the promiscuous binding of a large variety of drugs to CYP3A4. In the simplest form, the MPH approach takes advantage of the multiple substrate data sets and identifies the binding of test compounds as either proximal or distal relative to that of a given substrate. Application of the approach to the in silico filtering of test compounds for potential inhibitors of CYP3A4 is also presented. In addition to an improvement in the QSAR modeling for the inhibition of CYP3A4, the results from this modeling approach provide structural insights into the drugenzyme interactions. The existence of multiple inhibition data sets in the BioPrint database motivates the original development of the concept of a multiple pharmacophore hypothesis and provides a unique opportunity for formulating alternative strategies of QSAR modeling of the inhibition of the in vitro metabolism of CYP3A4.
Annals of the New York Academy of Sciences, 1995
Current opinion in drug discovery & development, 2003
Computational methods are increasingly used to streamline and enhance the lead discovery and opti... more Computational methods are increasingly used to streamline and enhance the lead discovery and optimization process. However, accurate prediction of absorption, distribution, metabolism and excretion (ADME) and adverse drug reactions (ADR) is often difficult, due to the complexity of underlying physiological mechanisms. Modeling approaches have been hampered by the lack of large, robust and standardized training datasets. In an extensive effort to build such a dataset, the BioPrint database was constructed by systematic profiling of nearly all drugs available on the market, as well as numerous reference compounds. The database is composed of several large datasets: compound structures and molecular descriptors, in vitro ADME and pharmacology profiles, and complementary clinical data including therapeutic use information, pharmacokinetics profiles and ADR profiles. These data have allowed the development of computational tools designed to integrate a program of computational chemistry ...
La presente invention se rapporte a l'utilisation de l'Alverine ou de ses metabolites, le... more La presente invention se rapporte a l'utilisation de l'Alverine ou de ses metabolites, leurs sels et leurs esters, pour la preparation de compositions pharmaceutiques destinees a traiter la depression.
3 Approaches to Pharmacological Profiling 3.1 Factors Inffuencing the Approach to Secondary Pharm... more 3 Approaches to Pharmacological Profiling 3.1 Factors Inffuencing the Approach to Secondary Pharmacodynamics 3.2 In Vivo and In Vitro Approaches to Secondary Pharmacodynamics 3.3 Strategies for In Vitro Pharmacological Profiling
3D-pharmacophores have become popular in the last decade as descriptors for chemical similarity s... more 3D-pharmacophores have become popular in the last decade as descriptors for chemical similarity searching and combinatorial library design. These pharmacophores are typically encoded in large bitstrings, up to hundreds of millions of bits long. Research on other classes of chemical descriptors suggests that "chemical space" requires on the order of 10-20 dimensions. Many of the millions of dimensions are correlated or irrelevant and their large size makes them a less efficient representation for computation. We have developed an approach based on classical multidimensional scaling to determine the inherent dimensionality of these large chemical bitstrings (pharmacophore or otherwise), resulting in real-valued cartesian coordinates. We have also developed a novel approach to calculate much smaller bitstrings (hundreds of bits) that preserve the original pairwise similarity of the original large bitstrings. The new smaller space is general enough that it can be used for many...
Life Sciences, 1999
We have investigated the molecular mechanisms involved in the regulation of muscarinic acetylchol... more We have investigated the molecular mechanisms involved in the regulation of muscarinic acetylcholine receptor gene expression and localization and generated knockout mice to study the role of the M1 muscarinic receptor in vivo. We have used the MDCK cell system to demonstrate that different subtypes of mAChR can be targeted to different regions of polarized cells. We have also examined
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods
Journal of Pharmacological and Toxicological Methods