Kv1.3 antagonists for use in the treatment of chronic and acute pain
The present patent application relates to the use of antagonists of delayed rectifier potassium (K + ) channels, more specifically Kv1.3 antagonists, as pharmaceutical agents in the treatment, prevention or reduction of both acute and chronic pain. The results and mode of action disclosed herein describe how Kv1.3 antagonists may act as analgesics through reduction of K + currents rather than their potentiation. With regard to their high efficacy in the treatment of pain, these compounds are highly selective for slow delayed rectifier voltage-activated potassium (K + ) currents. Such findings, together with those showing that nitenin, PSORA-4, PAP-1 and AM92016 hydrochloride act as K + channel blockers and by their effects on K + current inactivation profiles, also translate into an analgesic effect with reduced side effects. The results disclosed herein show that compounds that inhibit delayed rectifying Kv1.3 channels, such as the ones described herein, are a viable alternative to the already existing pharmaceutical compounds used in the treatment of pain, and specially, in chronic pain.
1 . An analgesic composition comprising a pharmacologically acceptable diluent or carrier and a therapeutically effective amount of one or more compounds that are antagonists of the slow delayed rectifier Kv1.3 channel, or pharmaceutical salts thereof, wherein the compound is an antagonist of the slow delayed rectifier Kv1.3 channel when the compound inhibits one or more slow delayed rectifier Kv1.3 channels, as evaluated by measuring the effect of the compound on slow delayed rectifier voltage-activated K+ currents recorded from small-diameter dorsal root neurons (DRG) neurons and/or small diameter trigeminal ganglia (TG) neurons; wherein one or more of the compounds have an affinity at least 2.5 times greater for the human Kvl1.3 channel than for any other human Kv1.1 channel, human Kv1.2 channel, human Kv1.4 channel, human Kv1.5 channel, human Kv1.6 channel, and human Kv1.7 channel, as measured by voltage clamp recordings of currents evoked by cells that express solely said channel; and wherein the compound is not AM92016 hydrochloride.
2 . The analgesic composition according to claim 1 , wherein one or more of the compounds is selected from nitenin, PSORA-4, PAP-1, their salts, and combinations thereof.
3 . A method of treating chronic pain or acute pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound that is an antagonist of the slow delayed rectifier Kv1.3 channel, or a pharmacologically acceptable salt thereof, wherein the compound is an antagonist of the slow delayed rectifier Kv1.3 channel when the compound inhibits one or more slow delayed rectifier Kv1.3 channels, as evaluated by measuring the effect of the compound on slow delayed rectifier voltage-activated K+ currents recorded from small-diameter dorsal root neurons (DRG) neurons and/or small diameter trigeminal ganglia (TG) neurons, wherein the compound is not AM92016 hydrochloride.
4 . The method of claim 3 , wherein said compound has an affinity at least 2.5 times greater for the human Kv1.3 channel than for any other human Kv1.1 channel, human Kv1.2 channel, human Kv1.4 channel, human Kv1.5 channel, human Kv1.6 channel, and human Kv1.7 channel, as measured by voltage clamp recordings of currents evoked by cells that express solely said channel.
5 . The method of claim 3 , wherein the compound is chosen from nitenin, PSORA-4, and PAP-1, their salts, and combinations thereof.
6 . The method of claim 5 , wherein the subject is a mammal.
7 . The method of any one of claims 3 to 6 , wherein the acute and chronic pain are chosen from neuropathic pain, nociceptive pain, psychogenic or somatogenic pain, diabetic neuropathic pain, post-herpetic pain, low-back pain, radiculopathy pain, musculoskeletal pain, post-operative and post-traumatic pain, phantom pain, surgical pain, wound associated pain, chemotherapy-induced peripheral neuropathic pain, short-term/acute or long-term/chronic inflammatory pain, rheumatic pain, arthritic pain, pain associated with osteoarthritis, myofascial pain, migraine, orofacial chronic pain, trigeminal neuralgia, pain associated with cancer, pain associated with fibromyalgia, hyperalgesia syndromes, pain associated with infections, HIV related pain, sprains and strains, hyperalgesia, somatogenic pain, psychogenic pain, heat induced pain, physical pain, nociceptive pain, rheumatic pain, headache, pelvic pain, myofascial, vascular pain, migraine wound, wound associated pain, arthritic pain, somatic visceral pain, phantom pain, radiculopathy, lumbar pain, visceral pain, bowel pain, bladder pain, and pain associated with osteoarthritis.
8 . The method of claim 6 , wherein the mammal is a human.