Mechanisms of Action of Currently Prescribed and Newly Developed Antiepileptic Drugs

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, -y-aminobutyric acid A (GABA A ) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABA A -receptor-mediated inhibition. Phenytoin, car-bamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the Af-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65554/1/j.1528-1157.1994.tb05955.x.pd

EXPLORING CONFORMATION SELECTIVE FAR INFRARED ACTION SPECTROSCOPY OF ISOLATED MOLECULES AND SOLVATED CLUSTERS

begin{wrapfigure}{r}{0pt} includegraphics[scale=0.25]{abstractdrawing.eps} end{wrapfigure} Far-Infrared (IR) spectroscopy has been labeled as a promising method for identifying structural motifs in large molecules. However, several hurdles have kept this promising spectral region from breaking through to widespread use for gas phase experiments. Normal modes in the far-IR mostly have weak intensities, and high brightness sources of far-IR radiation are rare. Moreover, standard density functional theory - applied to identify the specific molecular structure responsible for the measured IR spectra - does not reproduce features in the far-IR well. This mismatch can be attributed to the high degree of anharmonicity of many of the normal modes present in the far-IR. We have overcome these hurdles by combining an advanced laser source with novel experiments and high-level dynamical calculations. We present far-IR spectra of a family of phenolic molecules and solvated clusters, obtained using the free electron laser FELIX. By employing IR-UV ion-dip spectroscopy in the gas phase, we are able to obtain conformer specific far-IR spectra of isolated molecules or solvated clusters. The studied systems display both intra- and intermolecular hydrogen bonding, enabling us to study the merits of far-IR action spectroscopy for direct probing of these weak interactions. Moreover, the combination of far-IR experiments with quantum chemical calculations allows us to test the limits of the harmonic approximation in DFT calculations, and to test the possibilities of employing a more sophisticated technique, namely Born-Oppenheimer molecular dynamics