ABSTRACT
Twenty-one simplified analogues of the natural product domoic acid were designed, synthesized, and then characterized at homomeric kainic acid (KA) receptors (GluK1-3,5). LBG20304 displays a high affinity for homomeric GluK5 receptors (IC50 = 432 nM) with a >40-fold selectivity over homomeric GluK1-3 subtypes and â«100-fold selectivity over native AMPA and N-methyl d-aspartate receptors. Functional studies of LBG20304 on heteromeric GluK2/5 receptors show no agonist or antagonist functional response at 10 µM, while a concentration of 100 µM at neuronal slices (rat) shows low agonist activity. A molecular dynamics simulation of LBG20304, in a homology model of GluK5, suggests specific interactions with the GluK5 receptor and an occluded ligand binding domain, which is translated to agonist or partial agonist activity. LBG20304 is a new compound for the study of the role and function of the KA receptors with the aim of understanding the involvement of these receptors in health and disease.
Subject(s)
Kainic Acid , Molecular Dynamics Simulation , Receptors, Kainic Acid , Receptors, Kainic Acid/agonists , Receptors, Kainic Acid/metabolism , Receptors, Kainic Acid/antagonists & inhibitors , Receptors, Kainic Acid/chemistry , Kainic Acid/analogs & derivatives , Kainic Acid/pharmacology , Kainic Acid/metabolism , Ligands , Animals , Humans , Rats , Structure-Activity Relationship , Drug DiscoveryABSTRACT
Natural Killer T (NKT) cells play an important role in the immune response and can be activated by glycolipids presented by CD1d protein. We present MCS-0208, an unprecedented arylthioether-phytoceramide able to induce potent invariant NKT (iNKT) cell activation, notably when tested in human iNKT cells. This arylsphingolipid analog has a simple phenyl group containing a single hydroxyl substituent as a surrogate of the sugar ring. The phenylthioether structure contrasts with α-galactosylceramide (1), the prototypical glycolipid used to induce iNKT cell stimulation, where the galactose 2'-OH and 3'-OH substituents are accepted as the minimal footprint and considered critical for NKT T cell receptor (TCR) recognition. A computational study supports the recognition of aromatic compound by the CD1d and TCR proteins as radically new structures for NKT cell stimulation.
Subject(s)
Hydroxides/pharmacology , Natural Killer T-Cells/drug effects , Receptors, Antigen, T-Cell/immunology , Dose-Response Relationship, Drug , Humans , Hydroxides/chemistry , Molecular Docking Simulation , Molecular Structure , Natural Killer T-Cells/immunology , Structure-Activity RelationshipABSTRACT
Development of pharmacological tools for the ionotropic glutamate receptors (iGluRs) is imperative for the study and understanding of the role and function of these receptors in the central nervous system. We report the synthesis of 18 analogues of (2 S,3 R)-2-carboxy-3-pyrrolidine acetic acid (3a), which explores the effect of introducing a substituent on the ε-carbon (3c-q). A new synthetic method was developed for the efficient synthesis of racemic 3a and applied to give expedited access to 13 racemic analogues of 3a. Pharmacological characterization was carried out at native iGluRs, cloned homomeric kainate receptors (GluK1-3), NMDA receptors (GluN1/GluN2A-D), and excitatory amino acid transporters (EAAT1-3). From the structure-activity relationship studies, several new ligands emerged, exemplified by triazole 3p-d1, GluK3-preferring (GluK1/GluK3 Ki ratio of 15), and the structurally closely related tetrazole 3q-s3-4 that displayed 4.4-100-fold preference as an antagonist for the GluN1/GluN2A receptor ( Ki = 0.61 µM) over GluN1/GluN2B-D ( Ki = 2.7-62 µM).
Subject(s)
Glutamate Plasma Membrane Transport Proteins/metabolism , Proline/analogs & derivatives , Proline/pharmacology , Receptors, Ionotropic Glutamate/metabolism , Animals , Drug Design , Humans , Ligands , Models, Molecular , Proline/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
A new type of galactose mimetics has been synthesized following a straightforward synthetic approach based on cyclohexene olefin aziridination reactions directed by hydroxyl substituents. These enantiomerically pure galacto-configured N-aminoaziridines are potent irreversible inhibitors of Aspergillus oryzae and Escherichia coliß-galactosidases.
Subject(s)
Aspergillus oryzae/enzymology , Aziridines/chemistry , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/enzymology , Galactose/chemistry , beta-Galactosidase/antagonists & inhibitors , Aspergillus oryzae/drug effects , Escherichia coli/drug effects , Hydrogen-Ion Concentration , Kinetics , beta-Galactosidase/metabolismABSTRACT
A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, ß-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds.