Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Para-n-benzene - sulfoxy-n containing doai – and said benzene...
Reexamination Certificate
1999-02-02
2001-09-18
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Para-n-benzene - sulfoxy-n containing doai, and said benzene...
C514S610000
Reexamination Certificate
active
06291442
ABSTRACT:
BACKGROUND OF THE INVENTION
Cells maintain concentration gradients of certain ions across their membranes. For example, cells have a lower sodium ion concentration and a higher potassium ion concentration inside the cell than that outside the cell. The concentration gradient of ions across the cell membrane and the selective permeability of the membrane results in the negative resting potential of the cell. Voltage-gated ion channels open in response to a perturbation of the resting potential of the cell and allow ions to flow into or out of the cell in the direction of lower concentration.
Voltage-gated ion channels are involved in many cellular processes. For example, nerve cells maintain a negative resting potential when not transmitting an electrical impulse. When an excitatory synaptic signal occurs, depolarization causes voltage-gated sodium channels to open. Since the concentration of sodium ions outside the cell is much higher than that inside the cell, positively charged sodium ions flow into the cell causing a further depolarization of the cell membrane. Voltage-gated potassium ion channels, for example, Shaker class Kv1.x-Kv4.x channels, also open in response to depolarization and are responsible for restoring the cell to its resting potential. Since the potassium ion concentration inside the cell is higher than that outside the cell, the positively charged potassium ions flow out of the cell and bring the cell back to its resting potential.
Because voltage-gated potassium ion channels are responsible for returning neurons to their resting potential, agents that prolong the length of time that the channel remains open, or potentiate channel activity, are expected to be useful in treating disorders characterized by abnormally high electrical activity, such as seizures and cardiac arrhythmias. However, for the majority of voltage-gated potassium ion channels, there are no known compounds that prolong the opening of the channel. Conversely, agents that decrease the length of time that the channel remains open, or inhibit channel activity, are expected to be useful in treating disorders that are characterized by loss of conductivity in neurons, such as multiple sclerosis or demyelination due to injury.
In addition, the activation of voltage-gated potassium ion channels is involved in mediating the immune response to an antigen. Therefore, inhibitors of these channels are expected to be therapeutically useful in suppressing graft rejection by inhibiting the immune response, and potentiators are expected to help stimulate immune response in cases where it is pathologically depressed.
SUMMARY OF THE INVENTION
Reported herein is the discovery of an allosteric receptor site located on the intracellular surface of Shaker class voltage-gated potassium ion channels that is distinct from the channel pore. Shaker class voltage-gated potassium ion channels include the Kv1.x-Kv4.x channels. It has now been discovered that this allosteric regulatory site is involved in regulating gating of the pore. A class of compounds has been identified that binds to this allosteric site and modulates the length of time the channel pore remains open. Based on these discoveries, novel methods of modulating the activity of Shaker class voltage-gated potassium ion channels and assays for determining which compounds are modulators of these ion channels are reported herein.
In one embodiment, the invention relates to methods of modulating the activity of Shaker class voltage-gated potassium ion channels in a subject by administering an agent that binds to the allosteric site. The allosteric site in Shaker class voltage-gated potassium ion channels Kv1.x-Kv4.x is located on the intracellular surface and specifically affects channel gating and not ion permeation.
In another embodiment, the invention relates to a method of modulating the activity of Shaker class voltage-gated potassium ion channels in a subject by administering a compound that binds to a site in the Shaker class voltage-gated
In structural formula I, X is —O—, —CO—, —S—, —SO— or —NH—.
Y is —(CH
2
)
n
—, or Y is absent. n is an integer from 0-2. When n=0, Y is a covalent bond.
Ring A is an unsubstituted aromatic group, or an aromatic group substituted with 1-5 substituents. Ring B is an aromatic group substituted with 1-5 substituents. Preferably, ring A and ring B are both phenyl, and R
1
is ortho or meta to “X”.
R
1
is —(CHR
2
)
n
CO
2
R
2
.
R
2
is a hydrogen or a lower alkyl group. Preferably, R
2
is a hydrogen.
In another embodiment, the invention relates to an assay for determining whether a compound modulates Shaker class voltage gated potassium ion channels.
Compounds of this invention have potential therapeutic advantages because they do not modulate voltage-gated potassium channels unconditionally. In the presence of modulators of this invention, voltage-gated potassium ion channels respond normally to membrane depolarization by opening the ion channel. But once the channel is opened, modulators will increase or decrease the length of time the channels remain opened, thereby increasing or decreasing the activity of the ion channel. Therefore, modulators should not affect the resting excitability of a cell. Even at concentrations where the allosteric receptor site is saturated, modulators do not disrupt the normal opening of the channels and do not cause the severe reduction in current associated with ion channel-blockers. Instead, they merely retard or speed the closing of the channel. Therefore, the use of modulators of this invention potentially provides a therapeutically safe method of regulating potassium ion channel activity with minimal disruption of normal cellular processes.
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Liu, Y., et al., “Dynamic Rearrangement of the Outer Mouth of a K+Channel during Gating,”Neuron 16:859-867 (1996).
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Armstutz, E.D. and Neumoyer, C.R., “Studies in the Sulfone Series. III. The Pr
Hamilton Brook Smith & Reynolds P.C.
The General Hospital Corporation
Weddington Kevin E.
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