Lacosamide, a novel anti-convulsant drug, shows efficacy with a wide safety margin in rodent models for epilepsy.

This paper comprises a series of experiments in rodent models of partial and generalized epilepsy which were designed to describe the anti-convulsant profile of the functionalized amino acid lacosamide. Lacosamide was effective against sound-induced seizures in the genetically susceptible Frings mouse, against maximal electroshock test (MES)-induced seizures in rats and mice, in the rat hippocampal kindling model of partial seizures, and in the 6Hz model of psychomotor seizures in mice. The activity in the MES test in both mice (4.5mg/kg i.p.) and rats (3.9 mg/kg p.o.) fell within the ranges previously reported for most clinically available anti-epileptic drugs. At both the median effective dose for MES protection, as well as the median toxic dose for rotorod impairment, lacosamide elevated the seizure threshold in the i.v. pentylenetetrazol seizure test, suggesting that it is unlikely to be pro-convulsant at high doses. Lacosamide was inactive against clonic seizures induced by subcutaneous administration of the chemoconvulsants pentylenetetrazol, bicuculline, and picrotoxin, but it did inhibit NMDA-induced seizures in mice and showed full efficacy in the homocysteine model of epilepsy. In summary, the overall anti-convulsant profile of lacosamide appeared to be unique, and the drug displayed a good margin of safety in those tests in which it was effective. These results suggest that lacosamide may have the potential to be clinically useful for at least the treatment of generalized tonic-clonic and partial-onset epilepsies, and support ongoing clinical trials in these indications.

Trans-cis isomerization of arylether dendrimers with azobenzene core and terminal hydroxy groups.

Azobenzene-cored arylether dendrimers 2a-2c with polar hydroxy groups at the periphery have been prepared from hydroboration-oxidation reaction of azobenzene-cored arylether dendrimers 1a-1c with nonpolar vinyl groups at the periphery. Trans-->cis photoisomerization of central azo group has been investigated by UV-vis spectral changes after photolysis. The results show that dendrimers 1a-1c and 2a-2c in methanol/dichloromethane (1/1, v/v) have carried out trans-cis isomerization. Reaction rate for trans-->cis photoisomerization of 2a-2c with polar hydroxy groups increases with increasing generation upon irradiation of 350 nm. On the other hand, the reaction rate of cis-->trans thermal back isomerization for 2a-2c decreases with increasing the generation. This result is somewhat different from that for 1a-1c with nonpolar vinyl groups. Both the reaction rates of trans-->cis photoisomerization and cis-->trans thermal back isomerization for 1a-1c decrease in higher generation.

Synthesis of nanoparticle-cored dendrimers by convergent dendritic functionalization of monolayer-protected nanoparticles.

This article presents a synthesis method for nanoparticle-cored dendrimers (NCDs), which have dendritic architectures around a monolayer-protected gold nanoparticle. The synthesis method is based on a strategy in which the synthesis of monolayer-protected nanoparticles is followed by adding dendrons on functionalized nanoparticles by a single coupling reaction. NMR spectroscopy, IR spectroscopy, and thermogravimetric analysis (TGA) characterizations confirmed the successful coupling reaction between dendrons with different generations ([G1], [G2], and [G3]) and COOH-functionalized nanoparticles ( approximately Au201L71). The dendrimer wedge density also could be controlled by reacting nanoparticles having different loading of COOH groups ( approximately 60 and approximately 10% COOH of the 71 ligands per gold nanoparticle) with functionalized dendrons. Transmission electron microscope results showed that this synthesis strategy maintains the average size of the nanoparticle core during dendron coupling reactions. This control over the composition and core size makes the systematic study of NCDs with different generations possible. The chemical stability of NCDs was found to be affected by dendron generation around the nanoparticle core. The current-potential response of NCD films on microelectrode arrays exhibited better electrical conductivity for NCDs with lower dendron generation.

Novel stereoselective synthesis of functionalized oxazolidinones from chiral aziridines.

Enantiomerically pure N-(R)-alpha-methylbenzyl-4(R)-(chloromethyl)oxazolidinones (4R)-5a-k were synthesized in one step and high yields from various aziridine-2-methanols (S)-2a-k by intramolecular cyclization with phosgene. The alpha-methylbenzyl substituent on the nitrogen was easily cleaved to give both enanatiomers of 4-(chloromethyl)oxazolidinones (R)-7a and (S)-7a. (R)-7a was used for the efficient syntheses of (L)-homophenylalaninol analogues (S)-12a-j. We also applied the same methodology to prepare oxazolidinones 9a-c containing a heteroatom-substituted alkyl group at C-4 in high yields.