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Application of benzbromarone in the preparation of voltage-gated potassium channel kcnq agonists

A technology of benzbromarone and agonists, applied in the treatment and prevention of diseases, and the application field in the preparation of KCNQ agonists, which can solve the problems of reduced sensory sensitivity to noxious stimuli

Active Publication Date: 2019-03-08
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Third, mutations or gene knockouts of neural KCNQ channels lead to decreased sensory sensitivity to noxious stimuli in animals; in addition, in animal pain models, administration of KCNQ channel agonists and inhibitors reduces and induces (or increases) animal pain behaviors, respectively reaction

Method used

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  • Application of benzbromarone in the preparation of voltage-gated potassium channel kcnq agonists
  • Application of benzbromarone in the preparation of voltage-gated potassium channel kcnq agonists
  • Application of benzbromarone in the preparation of voltage-gated potassium channel kcnq agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 Benzbromarone Enhances KCNQ2 and KCNQ2 / Q3 Heteromeric Channel Current

[0067] 1.1 Cell culture and transfection

[0068] Chinese Hamster Ovary (CHO) (Cell Bank of Chinese Academy of Sciences) culture medium formula: 50 / 50DMEM / F-12 (Gibco), adding 10% fetal bovine serum (Fetal bovine serum, FBS) (Gibco, Australia) , 2 mM L-glutamine (Invitrogen).

[0069] In order to investigate the effect of benzbromarone on heterologously expressed KCNQ2 and KCNQ2 / Q3 channels, plasmids carrying KCNQ2 and KCNQ3 genes were expressed in CHO cells by means of lipofection.

[0070] Specifically: the expression of KCNQ2 homomeric channel and KCNQ2 / Q3 heteromeric channel, KCNQ2 plasmid was donated by Professor D. Makinnon of State University of New York, Stony Brook, and KCNQ3 plasmid was donated by University of Utah (University of Utah) Donated by Professor M.C.Sanguinetti of ), the base sequences of the plasmids were sequenced and proved by using the Megalign 7 (DNAStar) seque...

Embodiment 2

[0082] Example 2 Benzbromarone Enhances Endogenous KCNQ Current and Inhibits Action Potential Firing Frequency in Rat Dorsal Root Ganglion Neurons

[0083] In the peripheral sensory nervous system, the peripheral part of the primary sensory neurons that sense and transmit pain information is called nociceptors, which are unspecialized free nerve endings in morphology.

[0084] When the human body is stimulated by pain, the nerve impulses generated by the excitation of these pain receptors will be transmitted to the trigeminal or dorsal root nerve ganglia through the peripheral sensory nerve fibers, and then transmitted to the dorsal horn of the spinal cord after exchange, and then transmitted to the A central part of the brain that causes nociception and pain.

[0085] Primary afferent neurons are responsible for the sensation and afferent of the body's sensory system, including four specialized parts: peripheral nerve endings, axons, central terminals, and cell bodies. Studie...

Embodiment 3

[0097] Example 3 Benzbromarone Enhances Endogenous KCNQ Current and Inhibits Action Potential Firing Frequency in Rat Hippocampal Neurons

[0098] Epilepsy is a neurological disorder caused by sudden abnormal discharge of brain neurons, manifested as motor, sensory, conscious, mental, autonomic and other disorders. Because of the relatively clear structure and function of the hippocampus, hippocampal pyramidal neurons are a common target for electrophysiological testing of antiepileptic drugs.

[0099] 3.1 Isolation and culture of hippocampal neurons

[0100] The paired hippocampus of newborn 24-hour SD rats was acutely isolated, the meninges and cerebral microvessels were thoroughly removed in ice-bathed phosphate buffer, transferred into trypsin (2.5mg / ml, Type II-S, Sigma), and scissors crushed and digested at 37°C for 30 minutes. After completion, use an equal volume of growth medium (DMEM / F12 containing 10% fetal bovine serum, 1% penicillin and streptomycin, 2mM glutamine...

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Abstract

The invention provides an application of benzbromarone in preparation of KCNQ agonists; in addition, the invention also provides the application of the benzbromarone in preparation of drugs as the KCNQ agonists, wherein in the application, the KCNQ agonists can be used as a KCNQ2 agonist, a KCNQ2 / Q3 agonist, a KCNQ4 agonist and a KCNQ5 agonist. The benzbromarone is indicated to be capable of enhancing the KCNQ2, KCNQ2 / Q3, KCNQ4 and KCNQ5 current, enhancing endogenous KCNQ current, regulating hippocampal neuron resting membrane potential level and action potential frequency, and regulating dorsal root ganglion neuron resting membrane potential level and action potential frequency. Animal experiments indicate that the benzbromarone significantly relieves mice epileptic seizure induced by maximal electroshock, and significantly attenuates inflammatory pains induced by formalin, bradykinin and monosodium urate.

Description

technical field [0001] The present invention belongs to the field of medicines. Specifically, the present invention relates to the application of benzbromarone in the preparation of KCNQ agonists, wherein, in the above application, the KCNQ agonists can be KCNQ2 agonists, KCNQ2 / Q3 agonists, KCNQ4 Agonists and KCNQ5 agonists. In addition, the present invention also provides an application of benzbromarone in the preparation of drugs as KCNQ agonist and endogenous KCNQ current agonist, wherein, in the above application, the KCNQ agonist can be KCNQ2 agonist, KCNQ2 / Q3 agonists, KCNQ4 agonists, KCNQ5 agonists, or endogenous KCNQ current agonists. In addition, the present invention also relates to the application of benzbromarone in the treatment and prevention of diseases targeting KCNQ channels, such diseases include epilepsy, anxiety, hypertension, inflammatory pain, neuropathic pain and the like. Background technique [0002] Benzbromarone (Benzbromarone, as shown in the fo...

Claims

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Application Information

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IPC IPC(8): A61K31/343A61P25/08A61P25/22A61P9/12A61P29/00A61P25/04A61P11/06A61P27/16
Inventor 高召兵郑月明许海燕
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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