Abstract:
: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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Schmalhofer WA,Bao J,McManus OB,Green B,Matyskiela M,Wunderler D,Bugianesi RM,Felix JP,Hanner M,Linde-Arias AR,Ponte CG,Velasco L,Koo G,Staruch MJ,Miao S,Parsons WH,Rupprecht K,Slaughter RS,Kaczorowski GJ,Garcia MLdoi
10.1021/bi025722csubject
Has Abstractpub_date
2002-06-18 00:00:00pages
7781-94issue
24eissn
0006-2960issn
1520-4995pii
bi025722cjournal_volume
41pub_type
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