BIOMAT Database Logo BIOMAT Database Logo

Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [alphaxbeta3gamma2 (x = 1-3, 5, and 6)] via comparative molecular field analysis. 1998

Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Department of Chemistry, University of Wisconsin-Milwaukee, P.O. Box 413, Milwaukee, Wisconsin 53201, USA.

Affinities of a series of substituted imidazobenzodiazepines at recombinant alpha1beta3gamma2, alpha2beta3gamma2, alpha3beta3gamma2, alpha5beta3gamma2, and alpha6beta3gamma2 GABAA/benzodiazepine receptor subtypes are reported. Many of these ligands displayed high affinities (low-nanomolar to subnanomolar scale) at all five receptor subtypes. Furthermore, a number of imidazobenzodiazepines exhibited relatively good selectivity at the alpha5-containing receptor isoform. For example, ligand 27 (RY-023) demonstrated a 55-fold higher selectivity at alpha5beta3gamma2 isoforms in comparison to other receptor subtypes. The affinity ratio of alpha1 (the most prevalent subtype in the brain) to alpha5 of this series of ligands ranged from 60- to 75-fold for the most selective ligands. Studies of quantitative structure-activity relationships (QSAR) by means of comparative molecular field analysis (CoMFA) were carried out. As a result, examination of CoMFA models for all five receptor subtypes demonstrated their predictability for affinities of imidazobenzodiazepines at the five receptor subtypes. Regions of molecular fields which would favor or disfavor the binding affinity of a ligand at a specific receptor subtype were examined via CoMFA for alpha1, alpha2, alpha3, alpha5, and alpha6 subtypes. A CoMFA regression analysis was applied to predict the ratio of Ki alpha1/Ki alpha5, an index for the selectivity of a ligand at the alpha5 subtype. All of the CoMFA models offered good cross-validated correlations for the ligands in the test set as well as the ratios of Ki alpha1/Ki alpha5, which demonstrated their potential for prediction.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011869 Radioligand Assay Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders). Protein-Binding Radioassay,Radioreceptor Assay,Assay, Radioligand,Assay, Radioreceptor,Assays, Radioligand,Assays, Radioreceptor,Protein Binding Radioassay,Protein-Binding Radioassays,Radioassay, Protein-Binding,Radioassays, Protein-Binding,Radioligand Assays,Radioreceptor Assays
D011963 Receptors, GABA-A Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop. Benzodiazepine-Gaba Receptors,GABA-A Receptors,Receptors, Benzodiazepine,Receptors, Benzodiazepine-GABA,Receptors, Diazepam,Receptors, GABA-Benzodiazepine,Receptors, Muscimol,Benzodiazepine Receptor,Benzodiazepine Receptors,Benzodiazepine-GABA Receptor,Diazepam Receptor,Diazepam Receptors,GABA(A) Receptor,GABA-A Receptor,GABA-A Receptor alpha Subunit,GABA-A Receptor beta Subunit,GABA-A Receptor delta Subunit,GABA-A Receptor epsilon Subunit,GABA-A Receptor gamma Subunit,GABA-A Receptor rho Subunit,GABA-Benzodiazepine Receptor,GABA-Benzodiazepine Receptors,Muscimol Receptor,Muscimol Receptors,delta Subunit, GABA-A Receptor,epsilon Subunit, GABA-A Receptor,gamma-Aminobutyric Acid Subtype A Receptors,Benzodiazepine GABA Receptor,Benzodiazepine Gaba Receptors,GABA A Receptor,GABA A Receptor alpha Subunit,GABA A Receptor beta Subunit,GABA A Receptor delta Subunit,GABA A Receptor epsilon Subunit,GABA A Receptor gamma Subunit,GABA A Receptor rho Subunit,GABA A Receptors,GABA Benzodiazepine Receptor,GABA Benzodiazepine Receptors,Receptor, Benzodiazepine,Receptor, Benzodiazepine-GABA,Receptor, Diazepam,Receptor, GABA-A,Receptor, GABA-Benzodiazepine,Receptor, Muscimol,Receptors, Benzodiazepine GABA,Receptors, GABA A,Receptors, GABA Benzodiazepine,delta Subunit, GABA A Receptor,epsilon Subunit, GABA A Receptor,gamma Aminobutyric Acid Subtype A Receptors
D011994 Recombinant Proteins Proteins prepared by recombinant DNA technology. Biosynthetic Protein,Biosynthetic Proteins,DNA Recombinant Proteins,Recombinant Protein,Proteins, Biosynthetic,Proteins, Recombinant DNA,DNA Proteins, Recombinant,Protein, Biosynthetic,Protein, Recombinant,Proteins, DNA Recombinant,Proteins, Recombinant,Recombinant DNA Proteins,Recombinant Proteins, DNA
D012044 Regression Analysis Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see LINEAR MODELS) the relationship is constrained to be a straight line and LEAST-SQUARES ANALYSIS is used to determine the best fit. In logistic regression (see LOGISTIC MODELS) the dependent variable is qualitative rather than continuously variable and LIKELIHOOD FUNCTIONS are used to find the best relationship. In multiple regression, the dependent variable is considered to depend on more than a single independent variable. Regression Diagnostics,Statistical Regression,Analysis, Regression,Analyses, Regression,Diagnostics, Regression,Regression Analyses,Regression, Statistical,Regressions, Statistical,Statistical Regressions
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001569 Benzodiazepines A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. Benzodiazepine,Benzodiazepine Compounds

Related Publications

Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Studies of molecular pharmacophore/receptor models for GABAA/benzodiazepine receptor subtypes: binding affinities of substituted beta-carbolines at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.
July 1999, Drug design and discovery,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Studies of molecular pharmacophore/receptor models for GABAA/BzR subtypes: binding affinities of symmetrically substituted pyrazolo[4,3-c]quinolin-3-ones at recombinant alpha x beta 3 gamma 2 subtypes and quantitative structure-activity relationship studies via a comparative molecular field analysis.
July 1999, Drug design and discovery,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Pseudoreceptor models and 3D-QSAR for imidazobenzodiazepines at GABA A/BzR subtypes alphaxbeta3gamma2 [x = 1-3, 5, and 6] via flexible atom receptor model.
January 2004, Journal of chemical information and computer sciences,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
High affinity central benzodiazepine receptor ligands. Part 2: quantitative structure-activity relationships and comparative molecular field analysis of pyrazolo[4,3-c]quinolin-3-ones.
February 2001, Bioorganic & medicinal chemistry,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Comparative analysis of predictive models for nongenotoxic hepatocarcinogenicity using both toxicogenomics and quantitative structure-activity relationships.
July 2011, Chemical research in toxicology,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Quantitative structure-activity relationships/comparative molecular field analysis (QSAR/CoMFA) for receptor-binding properties of halogenated estradiol derivatives.
November 1994, Journal of medicinal chemistry,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Quantitative structure-activity relationships and comparative molecular field analysis of TIBO derivatised HIV-1 reverse transcriptase inhibitors.
November 1999, Journal of computer-aided molecular design,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Genetic neural networks for quantitative structure-activity relationships: improvements and application of benzodiazepine affinity for benzodiazepine/GABAA receptors.
December 1996, Journal of medicinal chemistry,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Synthesis, structure-activity relationships, and molecular modeling studies of N-(indol-3-ylglyoxylyl)benzylamine derivatives acting at the benzodiazepine receptor.
December 1996, Journal of medicinal chemistry,
Q Huang, and R Liu, and P Zhang, and X He, and R McKernan, and T Gan, and D W Bennett, and J M Cook
Receptor surface models. 2. Application to quantitative structure-activity relationships studies.
June 1995, Journal of medicinal chemistry,
Copied contents to your clipboard!