Synthesis of a Series of Novel 3,9-Disubstituted Phenanthrenes as Analogues of Known NMDA Receptor Allosteric Modulators.

9-Substituted phenanthrene-3-carboxylic acids have been reported to have allosteric modulatory activity at the NMDA receptor. This receptor is activated by the excitatory neurotransmitter L-glutamate and has been implicated in a range of neurological disorders such as schizophrenia, epilepsy and chronic pain and neurodegenerative disorders such as Alzheimer's disease. Herein, the convenient synthesis of a wide range of novel 3,9-disubstituted phenanthrene derivatives starting from a few common intermediates is described.

Structure-activity relationships for allosteric NMDA receptor inhibitors based on 2-naphthoic acid.

Over-activation of N-methyl-d-aspartate (NMDA) receptors is critically involved in many neurological conditions, thus there has been considerable interest in developing NMDA receptor antagonists. We have recently identified a series of naphthoic and phenanthroic acid compounds that allosterically modulate NMDA receptors through a novel mechanism of action. In the present study, we have determined the structure-activity relationships of 18 naphthoic acid derivatives for the ability to inhibit the four GluN1/GluN2(A-D) NMDA receptor subtypes.

Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors.

Competitive N-methyl-d-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N(1)-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family.

A novel family of negative and positive allosteric modulators of NMDA receptors.

The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds.

Mapping the ligand binding sites of kainate receptors: molecular determinants of subunit-selective binding of the antagonist [3H]UBP310.

Kainate receptors (KARs) modulate synaptic transmission and plasticity, and their dysfunction has been linked to several disease states such as epilepsy and chronic pain. KARs are tetramers formed from five different subunits. GluK1-3 are low affinity kainate binding subunits, whereas GluK4/5 bind kainate with high affinity.

Ca2+-calmodulin increases RyR2 open probability yet reduces ryanoid association with RyR2.

We have shown that physiological levels of Ca(2+)-calmodulin (Ca(2+)CaM; 50-100 nM) activate cardiac ryanodine receptors (RyR2) incorporated into bilayers and increase the frequency of Ca(2+) sparks and waves in cardiac cells. In contrast, it is well known that Ca(2+)CaM inhibits [(3)H]ryanodine binding to cardiac sarcoplasmic reticulum. Since the [(3)H]ryanodine binding technique does not reflect the effects of Ca(2+)CaM on RyR2 open probability (Po), we have investigated, using the reversible ryanoid, ryanodol, whether Ca(2+)CaM can directly influence the binding of ryanoids to single RyR2 channels independently of Po.

Rapid resensitization of purinergic receptor function in human platelets.

Background: Adenosine diphosphate (ADP) is a critical regulator of platelet activation, mediating its actions through two G protein-coupled receptors (GPCRs), the P2Y(1) and P2Y(12) purinergic receptors. Recently, we demonstrated that both receptors desensitize and internalize in human platelets by differential kinase-dependent mechanisms.

Objectives: To demonstrate whether responses to P2Y(1) and P2Y(12) purinergic receptors resensitize in human platelets and determine the role of receptor traffic in this process.

A new synthesis of phosphoramidates: inhibitors of the key bacterial enzyme aspartate semi-aldehyde dehydrogenase.

A new, mild and high yielding synthesis of phosphoramidates is described: potassium salts of carboxylic acids are treated with ethylchloroformate and the resulting activated anhydride-carbonates are then treated with LiNH-P(O)(OEt)2 in situ--the methodology is especially suited to acid sensitive systems featuring BOC, tBu or acetal protecting groups.

Difluoromethylene analogues of aspartyl phosphate: the first synthetic inhibitors of aspartate semi-aldehyde dehydrogenase.

The difluoromethylene analogue of aspartyl phosphate 6 has been prepared by the fluoride catalysed coupling of diethyl trimethylsilyldifluoromethyl phosphonate with an appropriate aldehyde followed by Dess-Martin oxidation and deprotection; the deprotected compound inhibited (KI 95 microM) aspartate semi-aldehyde dehydrogenase, a key enzyme involved in bacterial amino acid and peptidoglycan biosynthesis.

Aspartyl phosphonates and phosphoramidates: the first synthetic inhibitors of bacterial aspartate-semialdehyde dehydrogenase.

The synthesis of methylene phosphonate, difluoromethylene phosphonate and phosphoramidate analogues of aspartyl phosphate, together with reduced analogues, is described. These compounds were shown to be effective inhibitors of aspartate-semialdehyde dehydrogenase (ASA-DH) from Escherichia coli. However, despite the structural similarity of the compounds, different patterns of inhibition were observed, indicative of two phases of recognition and binding.