UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation.
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.
Hanson
D C
DC
Pfizer Inc., Central Research Division, Groton, Connecticut 06340, USA.
Nguyen
A
A
Mather
R J
RJ
Rauer
H
H
Koch
K
K
Burgess
L E
LE
Rizzi
J P
JP
Donovan
C B
CB
Bruns
M J
MJ
Canniff
P C
PC
Cunningham
A C
AC
Verdries
K A
KA
Mena
E
E
Kath
J C
JC
Gutman
G A
GA
Cahalan
M D
MD
Grissmer
S
S
Chandy
K G
KG
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001667:Binding, Competitive; D019556:COS Cells; D002417:Cattle; D018999:Charybdotoxin / Q000378:metabolism / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007457:Iodine Radioisotopes; D015640:Ion Channel Gating / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D012414:Rubidium Radioisotopes; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019789:Tetraethylammonium / Q000378:metabolism / Q000494:pharmacology
C120256:4-(diphenylmethoxymethyl)-1-(3-(4-methoxyphenyl)propyl)piperidine; D001559:Benzhydryl Compounds; D007166:Immunosuppressive Agents; D007457:Iodine Radioisotopes; D010880:Piperidines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D018999:Charybdotoxin; D019789:Tetraethylammonium