Methods for treating or preventing pain

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C514S233500, C514S332000, C514S336000, C514S337000, C514S338000, C514S339000, C514S340000

Reexamination Certificate

active

06326385

ABSTRACT:

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
Ion channels are cellular proteins that regulate the flow of ions, including calcium, potassium, sodium and chloride, into and out of cells. These channels are present in all human cells and affect such processes as nerve transmission, muscle contraction and cellular secretion. Among the ion channels, potassium channels are the most ubiquitous and diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. For example, the outward flow of potassium ions upon opening of these channels makes the interior of the cell more negative, counteracting depolarizing voltages applied to the cell. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP-sensitivity.
Potassium channels have now been associated with a number of physiological processes, including regulation of heartbeat, dilation of arteries, release of insulin, excitability of nerve cells, and regulation of renal electrolyte transport.
Potassium channels are made by alpha subunits that fall into at least 8 families, based on predicted structural and functional similarities (Wei et al.,
Neuropharmacology
35(7):805-829 (1997)). Three of these families (Kv, eag-related, and KQT) share a common motif of six transmembrane domains and are primarily gated by voltage. Two other families, CNG and SK/IK, also contain this motif but are gated by cyclic nucleotides and calcium, respectively. The three other families of potassium channel alpha subunits have distinct patterns of transmembrane domains. Slo family potassium channels, or BK channels, have seven transmembrane domains (Meera et al.,
Proc. Natl. Acad. Sci. U.S.A.
94(25):14066-71 (1997)) and are gated by both voltage and calcium or pH (Schreiber et al.,
J. Biol. Chem.
273:3509-16 (1998)). Another family, the inward rectifier potassium channels (Kir), belong to a structural family containing two transmembrane domains, and an eighth functionally diverse family (TP, or “two-pore”) contains two tandem repeats of this inward rectifier motif.
Potassium channels are typically formed by four alpha subunits, and can be homomeric (made of identical alpha subunits) or heteromeric (made of two or more distinct types of alpha subunits). In addition, potassium channels made from Kv, KQT and Slo or BK subunits have often been found to contain additional, structurally distinct auxiliary, or beta, subunits. These subunits do not form potassium channels themselves, but instead they act as auxiliary subunits to modify the functional properties of channels formed by alpha subunits. For example, the Kv beta subunits are cytoplasmic and are known to increase the surface expression of Kv channels and/or modify inactivation kinetics of the channel (Heinemann et al.,
J. Physiol.
493:625-633 (1996); Shi et al.,
Neuron
16(4):843-852 (1996)). In another example, the KQT family beta subunit, minK, primarily changes activation kinetics (Sanguinetti et al.,
Nature
384:80-83 (1996)).
Slo or BK potassium channels are large conductance potassium channels found in a wide variety of tissues, both in the central nervous system and periphery. They play a key role in the regulation of processes such as neuronal integration, muscular contraction and hormone secretion. They may also be involved in processes such as lymphocyte differentiation and cell proliferation, spermatocyte differentiation and sperm motility. Three alpha subunits of the Slo family have been cloned, i.e., Slo1, Slo2, and Slo3 (Butler et al.,
Science
261:221-224 (1993); Schreiber et al.,
J. Biol. Chem.,
273:3509-16 (1998); and Joiner et al.,
Nature Neurosci.
1: 462-469 (1998)). These Slo family members have been shown to be voltage and/or calcium gated, and/or regulated by intracellular pH.
Certain members of the Kv family of potassium channels were recently renamed (see Biervert et al.,
Science
279:403-406 (1998)). KvLQT1 was re-named KCNQ1, and the KvLQT1-related channels (KvLR1 and KvLR2) were renamed KCNQ2 and KCNQ3, respectively. More recently, a fourth member of the KCNQ subfamily was identified (KCNQ4) as a channel expressed in sensory outer hair cells (Kubisch et al.,
Cell
96(3):437-446 (1999)).
KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassium channels associated with benign familial neonatal convulsions (“BFNC”), a class of idiopathic generalized epilepsy (see Leppert et al.,
Nature
337:647-648 (1989); Yang et al.,
J. Biol. Chem.
273:19419-19423 (1998)). These channels have been linked to M-current channels (see Wang et al.,
Science
282:1890-1893 (1998)). The discovery and characterization of these channels and currents provides useful insights the physiologic and pathophysiologic roles of KCNQ-based currents. In addition, this discovery provides useful insights into how these voltage dependent (Kv) potassium channels function in different environments, and how they respond to various activation mechanisms.
In the present invention, we show, for the first time, that KCNQ2/3 channels and currents are expressed in dorsal root ganglion cells, indicating a possible role for these currents in pain processing. Furthermore, we show that a selective opener of KCNQ channels is analgesic in animal models of pain, and an anxiolytic in animal models of anxiety. The use of KCNQ channels as molecular targets for drugs to treat pain and anxiety, and the use of KCNQ modulators for the treatment of pain and anxiety is the subject of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to novel compounds and the use of such compounds in methods of treating pain and anxiety, by increasing ion flow in KCNQ channels and activating KCNQ currents by opening the channels.
In one aspect, the present invention relates to a method for reducing pain in a subject in need thereof by increasing ion flow through KCNQ potassium channels in a cell, the method comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound able to increase ion flow through KCNQ potassium channels, said composition administered to the subject in a potassium channel-opening amount, thereby reducing pain in the subject.
In another aspect, the present invention relates to a method for reducing anxiety in a subject in need thereof by increasing ion flow through KCNQ potassium channels in a cell, the method comprising the step of administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound able to increase ion flow through KCNQ potassium channels, said composition administered to the subject in a potassium channel-opening amount, thereby reducing anxiety in the subject.
In one embodiment, the potassium channel-opening amount is 0.1 mg/kg to 200 mg/kg. In another embodiment, the potassium-channel opening amount is 1 mg/kg to 150 mg/kg In another embodiment, the potassium channel-opening amount is 10 mg/kg to 100 mg/kg.
In one embodiment, the composition is administered orally, by injection, or after surgery.
In one embodiment, the pain is somatic pain, e.g., visceral pain or cutaneous pain, or pain caused by a burn, a bruise, an abrasion, a laceration, a broken bone, a torn ligament, a torn tendon, a torn muscle, a viral infection, a bacterial infection, a protozoal infection, a fungal infection, contact dermatitis, inflammation, or cancer. In another embodiment, the inflammation is caused by trauma, infection, surgery, burns, or diseases with an inflammatory component.
In one embodiment, the pain is neuropathic, e.g., caused by injury to the central or peripheral nervous system due to cancer, HIV infection, tissue trauma, infection, autoimmune disease, diabetes, arthritis, diabetic neuropathy, trigeminal neuralgia or

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