Identification of a New Class of Inhibitors of the Voltage-Gated Potassium Channel, Kv1.3, with Immunosuppressant Properties

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• 作者：William A. Schmalhofer ; Jianming Bao ; Owen B. McManus ; Brian Green ; Mary Matyskiela ; Denise Wunderler ; Randal M. Bugianesi ; John P. Felix ; Markus Hanner ; Ana-Rosa Linde-Arias ; Cristiano G. Ponte ; Luci
• 刊名：Biochemistry
• 出版年：2002
• 出版时间：June 18, 2002
• 年：2002
• 卷：41
• 期：24
• 页码：7781 - 7794
• 全文大小：183K
• 年卷期：v.41,no.24(June 18, 2002)
• ISSN：1520-4995

文摘

The voltage-gated potassium channel, K_v1.3, is a novel target for development ofimmunosuppressants. Using a functional ⁸⁶Rb⁺ efflux assay, a new class of high-affinity K_v1.3 inhibitorshas been identified. The initial active in this series, 4-phenyl-4-[3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl]cyclohexanone (PAC), which is representative of a disubstituted cyclohexyl (DSC) template, displaysa K_i of ca. 300 nM and a Hill coefficient near 2 in the flux assay and in voltage clamp recordings ofK_v1.3 channels in human T-lymphocytes. PAC displays excellent specificity as it only blocks membersof the K_v1 family of potassium channels but does not affect many other types of ion channels, receptors,or enzyme systems. Block of K_v1.3 by DSC analogues occurs with a well-defined structure-activityrelationship. Substitution at the C-1 ketone of PAC generates trans (down) and cis (up) isomer pairs.Whereas many DSC derivatives do not display selectivity in their interaction with different K_v1.x channels,trans DSC derivatives distinguish between K_v1.x channels based on their rates of C-type inactivation.DSC analogues reversibly inhibit the Ca²⁺-dependent pathway of T cell activation in in vitro assays.Together, these data suggest that DSC derivatives represent a new class of immunosuppressant agentsand that specific interactions of trans DSC analogues with channel conformations related to C-typeinactivation may permit development of selective K_v1.3 channel inhibitors useful for the safe treatmentof autoimmune diseases.