| Autor: |
Hanson DC; Pfizer Inc., Central Research Division, Groton, Connecticut 06340, USA., Nguyen A, Mather RJ, Rauer H, Koch K, Burgess LE, Rizzi JP, Donovan CB, Bruns MJ, Canniff PC, Cunningham AC, Verdries KA, Mena E, Kath JC, Gutman GA, Cahalan MD, Grissmer S, Chandy KG |
| Jazyk: |
angličtina |
| Zdroj: |
British journal of pharmacology [Br J Pharmacol] 1999 Apr; Vol. 126 (8), pp. 1707-16. |
| DOI: |
10.1038/sj.bjp.0702480 |
| Abstrakt: |
1. UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high-throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 200 nM and 1:1 stoichiometry. A closely related compound, CP-190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at - 50 mV enhances the channel's sensitivity to UK-78,282. Decreasing the number of inactivated channels by exposure to approximately 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between tau(h) and IC50 values. 3. Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4. UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage-gated K+ channel, Kv1.4. 5. UK-78,282 effectively suppresses human T-lymphocyte activation. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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