(+/-)-(Z)-2-(Aminomethyl)-1-phenylcyclopropane-N,N-diethylcarbo xamide (milnacipran, 1), a clinically useful antidepressant, and its derivatives were prepared by an improved method and were evaluated as NMDA receptor antagonists. Of these, milnacipran (1), its N-methyl and N,N-dimethyl derivatives, 7 and 8, respectively, and its homologue 12 at the aminomethyl moiety had binding affinity for the receptor in vitro (IC50: 1, 6.3 +/- 0.3 microM; 7, 13 +/- 2.1 microM; 8, 88 +/- 1.4 microM; 12, 10 +/- 1.2 microM). These also protected mice from NMDA-induced lethality. These compounds would be important as anovel prototype for designing potent NMDA-receptor antagonists because of their characteristic structure, which clearly differentiated them from known competitive and noncompetitive antagonists to the receptor.

Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent- 2, and ent- 3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-face addition product 11b. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent- 2 and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.

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We study the electron and phonon thermalization in simple metals excited by a laser pulse. The thermalization is investigated numerically by solving the Boltzmann transport equation taking into account all the relevant scattering mechanism: the electron-electron, electron-phonon (e-ph), phonon-electron (ph-e), and phonon-phonon (ph-ph) scatterings. In the initial stage of the relaxation, most of the excitation energy is transferred from the electrons to phonons through the e-ph scattering. This creates hot high-frequency phonons due to the ph-e scatterings, followed by an energy redistribution between phonon subsystems through the ph-ph scatterings. This yields an overshoot of the total longitudinal-acoustic phonon energy at a time, across which a crossover occurs from a nonequilibrium state, where the e-ph and ph-e scatterings frequently occur, to a state, where the ph-ph scattering occurs to reach a thermal equilibrium. This picture is quite different from the scenario of the well-known two-temperature model (2TM). The behavior of the relaxation dynamics is compared with those calculated by several models, including the 2TM, the four-temperature model, and nonequilibrium electron or phonon models. The relationship between the relaxation time and the initial distribution function is also discussed.

The low-temperature electrical resistivity of corrugated semiconductor films is theoretically considered. Nanoscale corrugation enhances the electron-electron scattering contribution to the resistivity resulting in a stepwise resistivity development with increasing corrugation amplitude. The enhanced electron scattering is attributed to the curvature-induced potential energy that affects the motion of electrons confined to a thin curved film. Geometric conditions and microscopic mechanism of the stepwise resistivity are discussed in detail.