Identification of a New Class of Inhibitors of the Voltage-Gated Potassium Channel, Kv1.3, with Immunosuppressant Properties
| Autor: | Owen B. McManus, Gloria C. Koo, Mary Jo Staruch, Mary Matyskiela, Randal M. Bugianesi, Markus Hanner, John P. Felix, William A. Schmalhofer, Denise Wunderler, B G Green, Robert S. Slaughter, Ana-Rosa Linde-Arias, Cristiano G. Ponte, Gregory J. Kaczorowski, Lucia Velasco, Kathleen M. Rupprecht, William H. Parsons, Shouwu Miao, Maria L. Garcia, Jianming Bao |
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| Rok vydání: | 2002 |
| Předmět: |
Intracellular Fluid
Monoiodotyrosine Patch-Clamp Techniques Potassium Channels Ketone Stereochemistry Phenylalanine T-Lymphocytes Voltage clamp Guinea Pigs Scorpion Venoms CHO Cells Lymphocyte Activation Transfection Biochemistry Cell Line Cricetinae Potassium Channel Blockers medicine Animals Humans Patch clamp Ion channel chemistry.chemical_classification Alanine Binding Sites Kv1.3 Potassium Channel Cyclohexanones Chemistry Potassium channel blocker Voltage-gated potassium channel Triterpenes Potassium channel Rats Potassium Channels Voltage-Gated Tyrosine Selectivity Immunosuppressive Agents medicine.drug |
| Zdroj: | Biochemistry. 41:7781-7794 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | The voltage-gated potassium channel, K(v)1.3, is a novel target for development of immunosuppressants. Using a functional (86)Rb(+) efflux assay, a new class of high-affinity K(v)1.3 inhibitors has 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, displays a K(i) of ca. 300 nM and a Hill coefficient near 2 in the flux assay and in voltage clamp recordings of K(v)1.3 channels in human T-lymphocytes. PAC displays excellent specificity as it only blocks members of the K(v)1 family of potassium channels but does not affect many other types of ion channels, receptors, or enzyme systems. Block of K(v)1.3 by DSC analogues occurs with a well-defined structure-activity relationship. 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(v)1.x channels, trans DSC derivatives distinguish between K(v)1.x channels based on their rates of C-type inactivation. DSC analogues reversibly inhibit the Ca(2+)-dependent pathway of T cell activation in in vitro assays. Together, these data suggest that DSC derivatives represent a new class of immunosuppressant agents and that specific interactions of trans DSC analogues with channel conformations related to C-type inactivation may permit development of selective K(v)1.3 channel inhibitors useful for the safe treatment of autoimmune diseases. |
| Databáze: | OpenAIRE |
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