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Application of NSC-156529 as T-type calcium channel antagonist

A calcium channel antagonist and calcium channel technology, applied in the field of NSC-156529 as a T-type calcium channel antagonist, can solve the problems of unrevealed and undisclosed analgesic effects of NSC-156529 compounds

Inactive Publication Date: 2019-09-20
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it does not reveal whether the NSC-156529 compound (see formula I), which has a completely different structure, has analgesic effect, nor does it reveal whether it acts on T-type calcium channels through the PKB / Akt pathway

Method used

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  • Application of NSC-156529 as T-type calcium channel antagonist
  • Application of NSC-156529 as T-type calcium channel antagonist
  • Application of NSC-156529 as T-type calcium channel antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: NSC-156529 can dose-dependently inhibit T-type calcium channel current in TG neurons

[0030] In this embodiment, the selected experimental materials are as follows:

[0031] ICR mice (18-22g) were provided by the Animal Center of Soochow University, animal certificate number: SYXK (Su) 2007-0035. NSC-156529 and electrophysiological reagents were purchased from Sigma.

[0032] The specific experimental plan is as follows:

[0033] Bilateral trigeminal ganglion (TG) of mice was collected by microsurgery, TG neurons were isolated acutely by enzymatic digestion, and the T-type calcium channel currents of small-diameter TG neurons were recorded by whole-cell patch clamp, and each group recorded 7- 9 cells.

[0034] When recording the T-type calcium channel current, the cell was clamped at -110mV, stimulated with a square wave to -40mV, and the stimulation time course was 40ms. The inner liquid of the recording electrode is: 110mM CsCl, 4mM MgATP, 0.3mM Na 2 ...

Embodiment 2

[0039] Example 2: NSC-156529 inhibits T-type calcium channel current independent of G protein and does not pass through the PKB / Akt pathway In this example, the selected experimental materials are as follows:

[0040] The G protein blocker GDP-β-S and the Akt kinase inhibitor Akt inhibitor III used in the experiment were purchased from Sigma, USA.

[0041] The specific experimental plan is as follows:

[0042] The method of acute cell separation is the same as above, the method of whole-cell patch clamp recording of T-type calcium channels and the components of the internal and external fluid of the electrodes are as described above. GDP-β-S and Akt inhibitor III block the signaling pathways mediated by G-protein and PDK1 / Akt, respectively, to detect whether NSC-156529 inhibits T-type calcium channels through the above pathways. Such as figure 2 As shown in A, 2C and 2B, 2D, the G-protein inhibitor GDP-β-S (1mM, figure 2 A, 2C) and Akt inhibitor III (10μM, figure 2 B, 2...

Embodiment 3

[0043] Example 3: NSC-156529 inhibits T-type calcium channel Cav3.1 and Cav3.2 subtypes, but has no effect on Cav3.3

[0044] In this embodiment, the selected experimental materials are as follows:

[0045] HEK293 cells were purchased from ATCC, USA; NSC-156529, transfection reagents and electrophysiological reagents were all purchased from Sigma.

[0046] The specific experimental plan is as follows:

[0047] Take a bottle of cultured cells, discard the culture medium, add 3ml of phosphate buffer saline to wash lightly twice, add about 1ml of 0.25% trypsin to digest, add DMEM culture medium after about 3-5 minutes, blow and beat, collect cells and centrifuge (1000 Turn / min) for 5 minutes, discard the supernatant, add about 5-10ml DMEM culture medium to suspend the cells. After slow blowing, passage to a 35mm petri dish covered with glass slides, and transfect after 24 hours. The classic calcium phosphate transfection method was used for cell transfection (transfection of C...

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Abstract

The invention discloses an application of a compound NSC-156529 in preparation of a T-type calcium channel antagonist. The compound inhibits the T-type calcium channel current in a dose-dependent manner through non-G-protein and non-Akt dependent ways. The T-type calcium channel antagonist drug containing the NSC-156529 structure can be constructed to be used for treating or preventing neuropsychiatric diseases (such as primary tremor, prosopalgia, cancer pain, schizophrenia, epilepsy, Parkinson's disease and depression) and reproductive diseases (such as varicocele infertility and sexual dysfunction) related to T-type calcium channel dysfunction.

Description

technical field [0001] The invention relates to the field of biochemistry, in particular to the application of NSC-156529 as a T-type calcium channel antagonist. Background technique [0002] Voltage-gated calcium channels can be divided into: high voltage-gated L-type (Cav1.1-1.4), P / Q-(Cav2.1), N-(Cav2.2), R-type (Cav2.3 ) and low-voltage-gated T-type calcium channels (Cav3.1-3.3). Among them, the low-voltage gated T-type calcium channel has unique electrophysiological characteristics: a very small depolarization can make the cell membrane quickly approach the resting membrane potential, thereby regulating neuronal excitability. Studies have shown that T-type calcium channels can be divided into three subtypes, Cav3.1, Cav3.2, and Cav3.3, and each subtype has obvious differences in channel characteristics such as voltage-dependent activation and inactivation. Different subtypes of T-type calcium channels have diverse functions and are involved in various physiological an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/381A61P25/00A61P25/18A61P25/04A61P25/16A61P25/24A61P25/08A61P15/10A61P15/00
CPCA61K31/381A61P25/00A61P25/18A61P25/04A61P25/16A61P25/24A61P25/08A61P15/10A61P15/00
Inventor 陶金张园钱志远孙玉芳蒋星红
Owner SUZHOU UNIV
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