Jared K. Nelson

Synthesis and Biological Activity of Argiotoxin 636 and Analogues: Selective Antagonists for Ionotropic Glutamate Receptors

More discerning than the parent: Analogues of the polyamine toxin argiotoxin 636 (shown docked in the ion channel of an ionotropic glutamate (iGlu) receptor; N blue, O red) distinguish subtypes of iGlu receptors. Depending on which of the two internal amine groups is replaced with a methylene group, the analogue inhibits one or other of two receptor subtypes as potently as the natural compound, which itself inhibits both subtypes nonselectively.

Can selective ligands for glutamate binding proteins be rationally designed

A major neurotransmitter, L-Glutamate must be stored, transported and received, and these processes are mediated by proteins that bind this simple yet essential amino acid. Detailed evidence continues to emerge on the structure of Glu binding proteins, which includes both receptors and transporters. It appears that receptors and transporters bind to Glu in different conformations, which may present a pharmacological opportunity. This review will compare and contrast information available on Glu Receptors (AMPA, NMDA, KA and mGlu), excitatory amino acid transporters (EAATs), the system Xc- transporter (XCT) and the vesicular Glutamate transporter (GVT). The cross-reactivity of ligands which have been previously used to characterize the glutamate binding proteins with system Xc- raises some fundamental interpretational issues regarding the mechanisms through which these analogues produce CNS damage. Although at one time it was thought that unraveling selectivity among glutamate binding proteins was an intractable problem, recently the NMDA antagonist (memantine) has been approved for general medical practice for treatment of Alzheimers disease. Two other agents are in advanced clinical trials: an Ampakine for potential improvement of cognitive disorders, and a selective mGlu agonist for treatment of anxiety. The prospects for unraveling cross-reactivity will be weighed in light of a critical comparison of the glutamate binding protein targets.

Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter

Methamphetamine, a human vesicular monoamine transporter 2 (VMAT2) substrate, releases dopamine, serotonin, and norepinephrine from vesicles into the cytosol of presynaptic neurons and induces reverse transport by the monoamine transporters to increase extracellular neurotransmitters. Currently available radioligands for VMAT2 have considerable liabilities: The binding of [3H]dihydrotetrabenazine ([3H]DHTB) to a site on VMAT2 is not dependent on ATP, and [3H]reserpine binds almost irreversibly to VMAT2. Herein we demonstrate that several arylpiperidinylquinazolines (APQs) are potent inhibitors of [3H]reserpine binding at recombinant human VMAT2 expressed in HEK-293 cells. These compounds are biodiastereoselective and bioenantioselective. The lead radiolabeled APQ is unique because it binds reversibly to VMAT2 but does not bind the [3H]DHTB binding site. Furthermore, experimentation shows that several novel APQ ligands have high potency for inhibition of uptake by both HEK-VMAT2 cells and mouse striatal vesicles and may be useful tools for characterizing drug-induced effects on human VMAT2 expression and function.

Ethyl 5-(5-oxo-2,3-di­hydro-5H-oxazolo­[2,3-a]­isoindol-9b-yl­methyl)-4-(2,5,5-tri­methyl-1,3-dioxan-2-yl)­isoxazole-3-carboxyl­ate: the product of a novel synthetic method

The title compound, C24H28N2O7, is the product of a novel synthetic procedure in which a highly functionalized heterocycle is formed. The crystal packing involves dimers, utilizing non-classical weak C—H⋯O interactions (ca 3.36–3.46 A) and an antiparallel π–π interaction between two of the pseudo-aromatic isoxazole moieties. These dimers are associated into a three-dimensional network via further non-classical hydrogen bonding.