Kv1.3-Blocking 5-Phenylalkoxypsoralens: A New Class of Immunomodulators
- Julia Vennekamp,
- Heike Wulff,
- Christine Beeton,
- Peter A. Calabresi,
- Stephan Grissmer,
- Wolfram Hänsel and
- K. George Chandy
- 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.)
- 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
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.
Footnotes
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This work was supported by grants from the National Multiple Sclerosis Society (to K.G.C., P.A.C., and C.B.), the National Institutes of Health (MH59222), the Rockefeller Brothers Fund (to K.G.C.), the American Heart Association (to H.W.), the Deutsche Forschungsgemeinschaft (Gr848/8-2; to S.G.) and the Bundesministerium für Bildung und Forschung (iZKF Ulm, B7; to S.G.).
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J.V. and H.W. contributed equally to this work.
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Parts of this work have been presented previously at the Meeting of the German Pharmaceutical Society in Halle [Arch Pharm Pharm Med Chem 2001;334 (Suppl 2):C72], the Experimental Biology Meeting in San Diego (FASEB J 2003;17:A1051), and in the doctoral thesis of Julia Vennekamp [Vennekamp J (2002) Synthese und elektrophysiologische Testung hochwirksamer Psoralenderivate als nicht-peptidische Blocker des lymphozytären Kaliumkanals Kv1.3. thesis, University of Kiel, Germany].
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ABBREVIATIONS: TCM, central memory T cell subset; TEM, effector memory T cell subset; 5-MOP, 5-methoxysporalen; EAE, experimental autoimmune encephalomyelitis; MBP, myelin basic protein; MS, multiple sclerosis; Kv, voltage-gated K+ channel; ShK, Stichodactyla helianthus toxin; HERG, human ether-a-go-go-related gene; HPLC, high-performance liquid chromatography; PBMC, peripheral blood mononuclear cells; [3H]TdR, tritiated thymidine; WIN-17317-3, 1-benzyl-7-chloro-4-n-propylimino-1,4-dihydroquinoline hydrochloride; CP-339818, 1-benzyl-4-pentylimino-1,4-dihydroquinoline; UK-78282, 4-[(diphenylmethoxy)methyl]-1-[3-(4-methoxyphenyl)propyl]-piperidine.
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- Received November 21, 2003.
- Accepted February 24, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
