UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation

British Journal of Pharmacology

Volumn 126, Issue 8, 1999, Pages 1707-1716

  Hanson, Douglas C ^a   Nguyen, Angela ^b   Mather, Robert J ^a   Rauer, Heiko ^b   Koch, Kevin ^c   Burgess, Laurence E ^c   Rizzi, James P ^c   Donovan, Carol B ^a   Bruns, Matthew J ^a   Canniff, Paul C ^a   Cunningham, Ann C ^a   Verdries, Kimberly A ^a   Mena, Edward ^a   Kath, John C ^a   Gutman, George A ^d   Cahalan, Michael D ^b   Grissmer, Stephan ^e   Chandy, K George ^b,d  

^a PFIZER INC   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c AMGEN INC   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

^e UNIVERSITY OF ULM   (Germany)

Author keywords

Benzhydryl moiety; C type inactivation; Charybdotoxin; Immune suppression; Kv1.3; Piperidines; Potassium channels; T lymphocytes; Verapamil

Indexed keywords

4 [BENZYLMETHOXYMETHYL] 1 [3 (4 METHOXYPHENYL)PROPYL]PIPERIDINE; 4 [DIPHENYLMETHOXYMETHYL] 1 [3 (4 METHOXYPHENYL)PROPYL]PIPERIDINE; 4 BENZHYDRYLOXYMETHYL 1 [3 (4 METHOXYPHENYL)PROPYL]PIPERIDINE; 4 BENZYLOXYMETHYL 1 [3 (4 METHOXYPHENYL)PROPYL]PIPERIDINE; CHARYBDOTOXIN; PIPERIDINE DERIVATIVE; POTASSIUM CHANNEL; POTASSIUM CHANNEL BLOCKING AGENT; POTASSIUM ION; RUBIDIUM 86; TETRYLAMMONIUM; UNCLASSIFIED DRUG;

ANIMAL CELL; ARTICLE; CELL MEMBRANE POTENTIAL; CONTROLLED STUDY; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SELECTIVITY; HUMAN; HUMAN CELL; NONHUMAN; PRIORITY JOURNAL; RAT; T LYMPHOCYTE ACTIVATION;

ANIMALS; BENZHYDRYL COMPOUNDS; BINDING, COMPETITIVE; CATTLE; CHARYBDOTOXIN; COS CELLS; HELA CELLS; HUMANS; IMMUNOSUPPRESSIVE AGENTS; IODINE RADIOISOTOPES; ION CHANNEL GATING; LYMPHOCYTE ACTIVATION; MEMBRANE POTENTIALS; PIPERIDINES; POTASSIUM CHANNEL BLOCKERS; POTASSIUM CHANNELS; RATS; RATS, INBRED LEW; RUBIDIUM RADIOISOTOPES; T-LYMPHOCYTES; TETRAETHYLAMMONIUM;

EID: 0032903174     PISSN: 00071188     EISSN: None     Source Type: Journal    
DOI: 10.1038/sj.bjp.0702480     Document Type: Article

References (45)

1. Aiyar, J., Nguyen, A., Chandy, K.G. & Grissmer, S. (1994). The P-region and S6 segment of Kv3.1 contribute to the formation of the potassium channel pore. Biophys. J., 67, 2261-2264.
2. Aiyar, J., Rizzi, J.P., Gutman, G.A. & Chandy, K.G. (1996). The signature sequence of voltage-gated potassium channels projects into the external vestibule. J. Biol. Chem., 271, 31013-31016.
3. + channel revealed by the NMR-derived structures of scorpion toxins. Neuron. 15, 1169-1181.
4. Burgess, L.E., Koch, K., Cooper, K., Biggers, M.S., Ramchandani, M., Smitrovich, J.H., Gilbert, E.J., Bruns, M.J., Mather, R.J., Donovan, C.B. & Hanson, D.C. (1997). The sar of UK-78,282: A novel blocker of human T cell Kv1.3 potassium channels. Biorganic Med. Chem. Lett., 7, 1047-1052.
5. Busch, A.E., Hurst, R.S., North, R.A., Adelman, J.P. & Kavanaugh, M.P. (1991). Current inactivation involves a histidine residue in the pore of the rat lymphocyte potassium channel RGK5. Biochem. Biophys. Res. Commun., 179, 1384-1390.
6. Cahalan, M.D. & Chandy, K.G. (1997). Ion channels in the immune system as targets for immunesuppression. Curr. Opin. Biotechnol., 8, 749-756.
7. Cahalan, M.D., Chandy, K.G., Decoursey, T.F., & Gupta, S. (1985). A voltage-gated potassium channel in human T lymphocytes. J. Physiol., 358, 197-237.
8. Chandy, K.G., Decoursey, T.E., Cahalan, M.D., McLaughlin, C. & Gupta, S. (1984). Voltage-gated potassium channels are required for human T lymphocyte activation. J. Exp. Med., 160, 369-385.
9. Chandy, K.G. & Gutman, G.A. (1995). Voltage-gated potassium channel genes. In Handbook of Receptors and Channels: Ligand and Voltage-gated Ion Channels, ed North, R.A., pp. 1-71. Boca Raton, FL: CRC Press, Inc.
10. Decoursey, T.E., Chandy, K.G., Gupta, S. & Cahalan, M.D. (1984). Voltage-gated potassium channels in human T lymphocytes: A role in mitogenesis? Nature, 307, 465-468.
11. + channel. J. Biol. Chem., 266, 3668-3674.
12. Fong, T.M., Cascieri, M.A., Yu, H., Bansal, A., Swain, C. & Strader, C.D. (1993). Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP-96345. Nature, 362, 350-353.
13. Freedman, B.D., Price, M.A. & Deutsch, C.J. (1992). Evidence for voltage modulation of IL-2 production in mitogen-stimulated human peripheral blood lymphocytes. J. Immunol., 149, 3784-3794.
14. + channels in human T-lymphocytes. Biophys. J., 55, 203-206.
15. Grissmer, S. & Cahalan. M.D. (1989b). Divalent ion trapping inside potassium channels of human T lymphocytes. J. Gen. Physiol., 93, 609-630.
16. + channel gene. Proc. Natl. Acad. Sci. U.S.A., 87, 9411-9415.
17. + channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines. Mol. Pharmacol., 45, 1227-1234.
18. + channels in human T lymphocytes. Mol. Pharm., 48, 98-104.
19. Ikeda, S.R., Soler, F., Zuhuke, R.D. & Lewis, D.L. (1992). Heterologous expression of the human potassium channel, Kv2.1, in clonal mammalian cells by direct cell injection. Pflueg. Arch. Eur. J. Physiol, 422, 201-203.
20. Jäger, H., Rauer, H., Nguyen, A.N., Aiyar, J., Chandy, K.G. & Grissmer, S. (1998). Regulation of mammalian Shaker-related potassium channels by extracellular potassium and pH: Evidence for non-conducting closed and non-conducting inactivated states. J. Physiol., 506, 291-301.
21. 22: A potent Kv1.3-specific immunosuppressive polypeptide. J. Biol. Chem., 273, 5851-5857.
22. Kath, J.C., Hanson, D.C. & Chandy, K.G. (1997). T lymphocyte potassium channel blockers. Ann. Reports in Med. Chem., 32, 181-190.
23. Knaus, H.G., McManus, O.B., Lee, S.H., Schmalhofer, W.A., Garcia-Calvo, M., Helms, L.M., Sanchez, M., Giangiacomo, K., Reuben, J.P., Smith, III A.B., Kaczorowski, G. & Garcia, M. (1994). Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry, 33, 5819-5828.
24. Koo, G.C., Blake, J.T., Talento, A., Nguyen, M., Lin, S., Sirotina, A., Shah, K., Mulvany, K., Hora, D. Jr., Cunningham, P., Wunderler, D.L., McManus, O., Slaughter, R., Bugianesi, R., Felix, J., Garcia, M., Williamson, J., Kaczorowski, G., Sigal, N.H., Springer, M.S. & Feeney, W. (1997). Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo. J. Immunol., 158, 5120-5128.
25. Koschak, A., Bugianesi, R.M., Mitterdorfer, J., Kaczorowski, G.J., Garcia, M.L. & Knaus, H.G. (1998). Subunit composition of brain voltage-gated potassium channels determined by hongotoxin-1, a novel peptide derived from Centruroides limbatus venom. J. Biol. Chem., 273, 2639-2644.
26. + channels depolarize human T lymphocytes: Mechanism of the antiproliferative effect of charybdotoxin. Proc. Natl. Acad. Sci. U.S.A., 89, 10094-10098.
27. Levy, D.I. & Deutsch, C.J. (1996). Recovery from C-type inactivation is modulated by extracellular potassium. Biophys. J., 70, 798-805.
28. Lewis, R.S. & Cahalan, M.D. (1995). Potassium and calcium channels in lymphocytes. Annu. Rev. Immunol., 13, 623-653.
29. Lin, C.S., Boltz, R.C., Blake, J.T., Nguyen, M., Talento, A., Fischer, P.A., Springer, M.S., Sigal, N.H., Slaughter, R.S., Garcia, M.L., Kaczorowski, G.J. & Koo, G.C. (1993). Voltage-gated potassium channels regulate calcium-dependent pathways involved in human T lymphocyte activation. J. Exp. Med., 177, 637-645.
30. Liu, T., Jurman, M.E. & Yellen, G. (1996). Dynamic arrangement of the outer mouth of a K+ channel during gating. Neuron, 16, 859-867.
31. Lopez-Barneo, J., Hoshi, T., Heinemann, S.H. & Aldrich, R.W. (1993). Effects of external cations and mutations, in the pore region on C-type inactivation of Shaker potassium channels. Recept. Channels, 1, 61-71.
32. Nguyen, A., Kath, J.C., Hanson, D.C., Biggers, M.S., Canniff, P.C., Donovan, C.B., Mather, R.J., Bruns, M.J., Rauer, H., Aiyar, J., Lepple-Wienhues, A., Gutman, G.A., Grissmer, S., Cahalan, M.D. & Chandy, K.G. (1996). Novel nonpeptide agents potently block the C-type inactivated conformation of Kv1.3 and suppress T cell activation. Mol. Pharm., 50, 1672-1679.
33. + channels. Biophys. J., 69, 2449-2457.
34. + channel occurs by a cooperative mechanism. Biophys. J., 69, 896-903.
35. Price, M., Lee, S.C. & Deutsch, C.J. (1989). Charybdotoxin inhibits proliferation and interleukin 2 production in human peripheral blood lymphocytes. Proc. Natl. Acad. Sci. U.S.A., 86, 10171-10175.
36. Rader, R.K., Kahn, L.E., Anderson, G.D., Martin, C.L., Chinn, K.S. & Gregory, S.A. (1996). T cell activation is regulated by voltage-dependent and calcium-activated potassium channels. J. Immunol., 156, 1425-1430.
37. Rauer, H. & Grissmer, S. (1996). Evidence for an internal phenylakylamine action on the voltage-gated potassium channel Kv1.3. Mol. Pharm., 50, 1625-1634.
38. + channels. Mol. Pharm., 50, 1167-1177.
39. k(A) channels reopen during recovery from inactivation. Nature (Lond)., 17, 657-660.
40. Sabath, D.E., Monos, D.S., Lee, S.C., Deutsch, C. & Prystowsky, M.B. (1986). Cloned T-cell proliferation and synthesis of specific proteins are inhibited by quinine. Proc. Natl. Acad. Sci. U.S.A., 83, 4739-4743.
41. + channels in human and murine T-lymphocytes. J. Gen. Physiol., 93, 1061-1074.
42. + channel Kv1 subtypes in synaptic membranes from bovine brain. Biochemistry, 36, 8195-8201.
43. Spencer, R.H., Sokolov, Y., Li, H., Takenaka, B., Milici, A.J., Aiyar, J., Nguyen, A., Park, H., Jap, B.K., Hall, J.E., Gutman, G.A. & Chandy, K.G. (1997). Purification, visualization, and biophysical characterization of Kv1.3 tetramers. J. Biol. Chem., 272, 2389-2395.
44. Stühmer, W., Ruppersberg, J.P., Schroter, K.H., Sakmann, B., Stocker, M., Giese, K.P., Perschke, A., Baumann, A. & Pongs, O. (1989). Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain. EMBO J., 8, 3235-3244.
45. + channel gene, Kv1.4. J. Biol. Chem., 271, 15629-15634.