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Pharmaceutical Institute, University of Kiel, Kiel, Germany (J.V., W.H.); Department of Medical Pharmacology and Toxicology, University of California at Davis, Davis, California (H.W.); Department of Physiology and Biophysics, University of California at Irvine, Irvine, California (C.B., K.G.C.); Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland (P.A.C.); and Department of Applied Physiology, University of Ulm, Ulm, Germany (S.G.)
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.
Received November 21, 2003; accepted February 24, 2004.
Address correspondence to: K. George Chandy, Department of Physiology and Biophysics, Medical School, 346-D Med. Sci. I, University of California at Irvine, Irvine, CA 92697. E-mail: gchandy{at}uci.edu
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