Kv1.3-blocking 5-phenylalkoxypsoralens: A new class of immunomodulators

Julia Vennekamp, Heike Wulff, Christine Beeton, Peter A. Calabresi, Stephan Grissmer, Wolfram Hänsel, K. George Chandy

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen (Psora-4), blocked Kv1.3 in a use-dependent manner, with a Hill coefficient of 2 and an EC50 value of 3 nM, by preferentially binding to the C-type inactivated state of the channel. Psora-4 is the most potent small-molecule Kv1.3 blocker known. It exhibited 17- to 70-fold selectivity for Kv1.3 over closely related Kv1-family channels (Kv1.1, Kv1.2, Kv1.4, and Kv1.7) with the exception of Kv1.5 (EC50, 7.7 nM) and showed no effect on human ether-a-go-go-related channel, Kv3.1, the calcium-activated K+ channels (IKCa1, SK1-SK3, and BKCa), or the neuronal Nav1.2 channel. In a test of in vivo toxicity in rats, Psora-4 did not display any signs of acute toxicity after five daily subcutaneous injections at 33 mg/kg body weight. Psora-4 selectively suppressed the proliferation of human and rat myelin-specific effector memory T cells with EC50 values of 25 and 60 nM, respectively, without persistently suppressing peripheral blood naive and central memory T cells. Because autoantigen-specific effector memory T cells contribute to the pathogenesis of T cell-mediated autoimmune diseases such as multiple sclerosis, Psora-4 and other Kv1.3 blockers may be useful as immunomodulators for the therapy of autoimmune disorders.

Original languageEnglish (US)
Pages (from-to)1364-1374
Number of pages11
JournalMolecular Pharmacology
Volume65
Issue number6
DOIs
StatePublished - Jun 2004

ASJC Scopus subject areas

  • Pharmacology

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    Vennekamp, J., Wulff, H., Beeton, C., Calabresi, P. A., Grissmer, S., Hänsel, W., & Chandy, K. G. (2004). Kv1.3-blocking 5-phenylalkoxypsoralens: A new class of immunomodulators. Molecular Pharmacology, 65(6), 1364-1374. https://doi.org/10.1124/mol.65.6.1364