Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors

Context-dependent inhibition of N-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases

Main Group Metal Halide Complexes with Sterically Hindered Thioureas XI. Complexes of Antimony(III) and Bismuth(III) Chlorides with a New Bidentate Thiourea — 1,1′-methylenebis(3-methyl-2H-imidazole-2-thione)

Bidentate 1,1\u27-methylenebis(3-methyl-2H-imidazole-2-thione) (L), SbCl3L, and BiCl3L were synthesized and characterized. SbCl3L is monoclinic, space group P21/c, a 11.812(9), b 7.699(4), c 18.100(9) Å, β 101.29(5)°, Z = 4, R = 0.042, Rw = 0.041. Geometry at Sb was distorted octahedral with bridging S atoms creating long zigzag chains of octahedra sharing vertexes cis to each other. Two Cl atoms are trans to each other, and the 3rd Cl is trans to the bridging S. The Sb-S bridges are 3.41 Å in length. There is not strong evidence for a stereospecific lone pair in the coordination sphere of Sb. The ligand forms an 8-membered ring with the Sb atom included. Solid state IR data showed little change in L vibrational modes normally sensitive to coordination; NMR gave evidence for a high degree of assocn

The Structure–Activity Relationship of a Tetrahydroisoquinoline Class of <i>N</i>‑Methyl‑d‑Aspartate Receptor Modulators that Potentiates GluN2B-Containing <i>N</i>‑Methyl‑d‑Aspartate Receptors

We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist. Multiple compounds potentiate the response of NMDARs with submicromolar EC₅₀ values. Analysis of enantiomeric pairs revealed that the <i>S</i>-(−) enantiomer is active at the GluN2B, GluN2C, and/or GluN2D subunits, whereas the <i>R</i>-(+) enantiomer is only active at GluN2C/D subunits. These results provide a starting point for the development of selective positive allosteric modulators for GluN2B-containing receptors

The 4,5-Double Bond of Ceramide Regulates Its Dipole Potential, Elastic Properties, and Packing Behavior

The biological activities of ceramides show a large variation with small changes in molecular structure. To help understand how the structure regulates the activity of this important lipid second messenger, we investigated the interfacial features of a series of synthetic ceramide analogs in monomolecular films at the argon-buffer interface. To minimize differences arising from the N-acyl moiety, each analog had either a N-hexadecanoyl or a N-cis-4-hexadecenoyl moiety amide linked to the nitrogen of the sphingosine backbone. We found that the trans 4,5-unsaturation in the sphingosine backbone promoted closer packing and lower compressibilities of ceramide analogs in interfaces relative to comparable saturated species. Moreover, structures with this feature exhibited dipole potentials as much as 150–250 mV higher than comparable compounds lacking 4,5-unsaturation. The results support the hypothesis by M.C. Yappert and co-workers that trans unsaturation in the vicinity of C4 of the sphingoid backbone augments intramolecular hydration/hydrogen bonding in the polar region. This intramolecular hydration may allow the close packing of the ceramide molecules and engender their high dipole potentials. These properties of ceramides and their analogs may be important determinants of biological function