neodysiherbaine-a and dysiherbaine

neodysiherbaine-a has been researched along with dysiherbaine* in 4 studies

Other Studies

4 other study(ies) available for neodysiherbaine-a and dysiherbaine

ArticleYear
Binding and selectivity of the marine toxin neodysiherbaine A and its synthetic analogues to GluK1 and GluK2 kainate receptors.
    Journal of molecular biology, 2011, Oct-28, Volume: 413, Issue:3

    Dysiherbaine (DH) and neodysiherbaine A (NDH) selectively bind and activate two kainate-type ionotropic glutamate receptors, GluK1 and GluK2. The ligand-binding domains of human GluK1 and GluK2 were crystallized as bound forms with a series of DH analogues including DH, NDH, 8-deoxy-NDH, 9-deoxy-NDH and 8,9-dideoxy-NDH (MSVIII-19), isolated from natural sources or prepared by total synthesis. Since the DH analogues exhibit a wide range of binding affinities and agonist efficacies, it follows that the detailed analysis of crystal structure would provide us with a significant opportunity to elucidate structural factors responsible for selective binding and some aspects of gating efficacy. We found that differences in three amino acids (Thr503, Ser706 and Ser726 in GluK1 and Ala487, Asn690 and Thr710 in GluK2) in the ligand-binding pocket generate differences in the binding modes of NDH to GluK1 and GluK2. Furthermore, deletion of the C(9) hydroxy group in NDH alters the ligand conformation such that it is no longer suited for binding to the GluK1 ligand-binding pocket. In GluK2, NDH pushes and rotates the side chain of Asn690 (substituted for Ser706 in GluK1) and disrupts an interdomain hydrogen bond with Glu409. The present data support the idea that receptor selectivities of DH analogues resulted from the differences in the binding modes of the ligands in GluK1/GluK2 and the steric repulsion of Asn690 in GluK2. All ligands, regardless of agonist efficacy, induced full domain closure. Consequently, ligand efficacy and domain closure did not directly coincide with DH analogues and the kainate receptors.

    Topics: Alanine; Bridged Bicyclo Compounds, Heterocyclic; Crystallography, X-Ray; GluK2 Kainate Receptor; Glutamic Acid; Humans; Marine Toxins; Models, Chemical; Models, Molecular; Protein Binding; Protein Conformation; Receptors, Kainic Acid

2011
Pharmacological activity of C10-substituted analogs of the high-affinity kainate receptor agonist dysiherbaine.
    Neuropharmacology, 2010, Volume: 58, Issue:3

    Kainate receptor antagonists have potential as therapeutic agents in a number of neuropathologies. Synthetic modification of the convulsant marine toxin neodysiherbaine A (NDH) previously yielded molecules with a diverse set of pharmacological actions on kainate receptors. Here we characterize three new synthetic analogs of NDH that contain substituents at the C10 position in the pyran ring of the marine toxin. The analogs exhibited high-affinity binding to the GluK1 (GluR5) subunit and lower affinity binding to GluK2 (GluR6) and GluK3 (GluR7) subunits in radioligand displacement assays with recombinant kainate and AMPA receptors. As well, the natural toxin NDH exhibited approximately 100-fold selectivity for GluK2 over GluK3 subunits, which was attributable to the C8 hydroxyl group in NDH. We used molecular dynamic simulations to determine the specific interactions between NDH and residues within the ligand-binding domains of these two kainate receptor subunits that contribute to the divergent apparent affinities for the compound. These data demonstrate that interactions with the GluK1 subunit are preserved in analogs with substitutions at C10 in NDH and further reveal the determinants of selectivity and pharmacological activity of molecules acting on kainate receptor subunits, which could aid in design of additional compounds that target these receptors.

    Topics: Alanine; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Transformed; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists; Glutamic Acid; Green Fluorescent Proteins; Humans; Kainic Acid; Ligands; Membrane Potentials; Models, Molecular; Molecular Dynamics Simulation; Molecular Structure; Mutagenesis, Site-Directed; Patch-Clamp Techniques; Protein Subunits; Radioligand Assay; Receptors, Kainic Acid; Structure-Activity Relationship; Time Factors; Transfection; Tritium

2010
Total synthesis and biological evaluation of neodysiherbaine A and analogues.
    The Journal of organic chemistry, 2006, Jul-07, Volume: 71, Issue:14

    Dysiherbaine (1) and its congener neodysiherbaine A (2) are naturally occurring excitatory amino acids with selective and potent agonistic activity for ionotropic glutamate receptors. We describe herein the total synthesis of 2 and its structural analogues 3-8. Advanced key intermediate 16 was employed as a branching point to assemble a series of these analogues 3-8 with respect to the C8 and C9 functionalities, which would not have been accessible through manipulations of the natural product itself. The synthesis of key intermediate 16 features (i) stereocontrolled C-glycosylation to set the C6 stereocenter, (ii) concise synthesis of the bicyclic ether skeleton through chemo- and stereoselective dihydroxylation of the exo-olefin and stereoselective epoxidation of the endo-olefin, followed by epoxide ring opening/5-exo ring closure, and (iii) catalytic asymmetric hydrogenation of enamide ester to construct the amino acid appendage. A preliminary biological evaluation of analogues for their in vivo toxicity against mice and binding affinity for glutamate receptors showed that both the type and stereochemistry of the C8 and C9 functional groups affected the subtype selectivity of dysiherbaine analogues for members of the kainic acid receptor family.

    Topics: Alanine; Animals; Binding, Competitive; Biological Assay; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Dose-Response Relationship, Drug; Humans; Injections, Intraventricular; Mice; Molecular Structure; Receptors, Kainic Acid; Seizures; Stereoisomerism; Structure-Activity Relationship

2006
Divergent pharmacological activity of novel marine-derived excitatory amino acids on glutamate receptors.
    The Journal of pharmacology and experimental therapeutics, 2005, Volume: 314, Issue:3

    Kainate receptors show a particular affinity for a variety of natural source compounds, including dysiherbaine (DH), a potent agonist derived from the marine sponge Dysidea herbacea. In this study, we characterized the pharmacological activity and structural basis for subunit selectivity of neodysiherbaine (neoDH) and MSVIII-19, which are natural and synthetic analogs of DH, respectively. NeoDH and MSVIII-19 differ from DH in the composition of two functional groups that confer specificity and selectivity for ionotropic glutamate receptors. In radioligand binding assays, neoDH displayed a 15- to 25-fold lower affinity relative to that of DH for glutamate receptor (GluR)5 and GluR6 kainate receptor subunits but a 7-fold higher affinity for kainate (KA)2 subunits, whereas MSVIII-19 displaced [(3)H]kainate only from GluR5 subunits but not GluR6 or KA2 subunits. NeoDH was an agonist for kainate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in patch-clamp recordings; in contrast, MSVIII-19 acted as a potent antagonist for homomeric GluR5 receptor currents with weaker activity on other kainate and AMPA receptors. Neither neoDH nor MSVIII-19 activated group I metabotropic GluRs. Homology modeling suggests that two critical amino acids confer the high degree of selectivity between the dysiherbaine analogs and the GluR5 and KA2 subunits. In summary, these data describe the pharmacological activity of two new compounds, one of which is a selective GluR5 receptor antagonist that will be of use for understanding native receptor function and designing more selective ligands for kainate receptors.

    Topics: Alanine; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Excitatory Amino Acids; Humans; Kainic Acid; Models, Molecular; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, Metabotropic Glutamate

2005