Identification of Selective Agonists and Antagonists to G Protein-Activated Inwardly Rectifying Potassium Channels: Candidate Medicines for Drug Dependence and Pain

G protein-activated inwardly rectifying K+ (GIRK) channels have been known to play a key role in the rewarding and analgesic effects of opioids. To identify potent agonists and antagonists to GIRK channels, we examined various compounds for their ability to activate or inhibit GIRK channels. A total of 503 possible compounds with low molecular weight were selected from a list of fluoxetine derivatives at Pfizer Japan Inc. We screened these compounds by a Xenopus oocyte expression system. GIRK1/2 and GIRK1/4 heteromeric channels were expressed on Xenopus laevis oocytes at Stage V or VI. A mouse IRK2 channel, which is another member of inwardly rectifying potassium channels with similarity to GIRK channels, was expressed on the oocytes to examine the selectivity of the identified compounds to GIRK channels. For electrophysiological analyses, a two-electrode voltage clamp method was used. Among the 503 compounds tested, one compound and three compounds were identified as the most effective agonist and antagonists, respectively. All of these compounds induced only negligible current responses in the oocytes expressing the IRK2 channel, suggesting that these compounds were selective to GIRK channels. These effective and GIRK-selective compounds may be useful possible therapeutics for drug dependence and pain

Alternating-Spin Ladders in a Magnetic Field: New Magnetization Plateaux

We study numerically the formation of magnetization plateaux with the Lanczos method in 2-leg ladders with mixed spins of magnitudes $(S_1,S_2)=(1,1/2)$ located at alternating positions along the ladder and with dimerization $\gamma$. For interchain coupling $J'>0$ and $\gamma=0$, we find normalized plateaux at $m=1/3$ starting at zero field and $m=1$ (saturation), while when $\gamma \ne 0$ is columnar, another extra plateau at $m=2/3$ shows up. For $J'<0$, when $\gamma<\gamma_c(J')$ we find no plateau while for $\gamma>\gamma_c(J')$ we find four plateaux at $m=0,1/3,2/3,1$. We also apply several approximate analytical methods (Spin Wave Theory, Low-Energy Effective Hamiltonians and Bosonization) to understand these findings and to conjeture the behaviour of ferrimagnetic ladders with a bigger number of legs.Comment: REVTEX file, 7 pages, 6 eps Figure

Optimal Location of Two Laser-interferometric Detectors for Gravitational Wave Backgrounds at 100 MHz

Recently, observational searches for gravitational wave background (GWB) have been developed and given constraints on the energy density of GWB in a broad range of frequencies. These constraints have already resulted in the rejection of some theoretical models of relatively large GWB spectra. However, at 100 MHz, there is no strict upper limit from direct observation, though an indirect limit exists due to He4 abundance due to big-bang nucleosynthesis. In our previous paper, we investigated the detector designs that can effectively respond to GW at high frequencies, where the wavelength of GW is comparable to the size of a detector, and found that the configuration, a so-called synchronous-recycling interferometer is best at these sensitivity. In this paper, we investigated the optimal location of two synchronous-recycling interferometers and derived their cross-correlation sensitivity to GWB. We found that the sensitivity is nearly optimized and hardly changed if two coaligned detectors are located within a range 0.2 m, and that the sensitivity achievable in an experiment is far below compared with the constraint previously obtained in experiments.Comment: 17 pages, 6 figure