No abstract

Identification of selective ion channel inhibitors represents a critical step for understanding the physiological role that these proteins play in native systems. In particular, voltage-gated potassium (K V 2) channels are widely expressed in tissues such as central nervous system, pancreas, and smooth muscle, but their particular contributions to cell function are not well understood. Although potent and selective peptide inhibitors of K V 2 channels have been characterized, selective small molecule K V 2 inhibitors have not been reported. For this purpose, highthroughput automated electrophysiology (IonWorks Quattro; Molecular Devices, Sunnyvale, CA) was used to screen a 200,000-compound mixture (10 compounds per sample) library for inhibitors of K V 2.1 channels. After deconvolution of 190 active samples, two compounds (A1 and B1) were identified that potently inhibit K V 2.1 and the other member of the K V 2 family, K V 2.2 (IC 50 , 0.1-0.2 ⌴), and that possess good selectivity over K V 1.2 (IC 50 Ͼ10 ⌴). Modeling studies suggest that these compounds possess a similar three-dimensional conformation. Compounds A1 and B1 are Ͼ10-fold selective over Na V channels and other K V channels and display weak activity (5-9 ⌴) on Ca V channels. The biological activity of compound A1 on native K V 2 channels was confirmed in electrophysiological recordings of rat insulinoma cells, which are known to express K V 2 channels. Medicinal chemistry efforts revealed a defined structure-activity relationship and led to the identification of two compounds (RY785 and RY796) without significant Ca V channel activity. Taken together, these newly identified channel inhibitors represent important tools for the study of K V 2 channels in biological systems.

The regional differences in hourly precipitation characteristics along the western coast of South China are investigated. The coastal area can be divided into three regions: two regions with large precipitation amounts to the west and east of the Leizhou Peninsula and another region with less precipitation over the Leizhou Peninsula. The precipitation center west of the Leizhou Peninsula (Dongxing station) is dominated by heavy precipitation, which frequently peaks in the early morning and has a long duration. The precipitation center east of the Leizhou Peninsula (Yangjiang station) has a high frequency of weak precipitation. There are two kinds of precipitation that occur at Yangjiang: short-duration precipitation in the afternoon and long-lasting precipitation in the morning. Over the Leizhou Peninsula (Zhanjiang station), precipitation mainly occurs over a short duration in the afternoon. The possible reasons for the different precipitation features are discussed. The morning precipitation at Dongxing is usually caused by deep convection. A large proportion of the morning precipitation events are locally generated events, which are closely related to the southerly winds and topographic barriers. Among the many possible factors affecting the morning precipitation at Yangjiang, the convergence between the land breeze and prevailing onshore airflow is an important one. The afternoon precipitation events affecting Yangjiang mostly originate over the mountains northwest of Yangjiang. Influenced by the curvature of the coastline and the relatively flat terrain over the Leizhou Peninsula, there is no convergence and less convection in the morning. However, the Leizhou Peninsula is prone to being influenced by daytime thermal forcings, which trigger afternoon precipitation.