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Dopamine transfer protein peptide inhibitor and its use

A transporter and inhibitor technology, applied in the field of pharmaceuticals, can solve problems such as lack of dopamine transporter

Inactive Publication Date: 2006-11-01
SHANGHAI BIOMODEL ORGANISM SCI & TECH DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In summary, since there is still a lack of satisfactory inhibitors of dopamine transporters, there is still an urgent need in this field to develop new inhibitors that effectively inhibit dopamine transporters

Method used

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  • Dopamine transfer protein peptide inhibitor and its use
  • Dopamine transfer protein peptide inhibitor and its use
  • Dopamine transfer protein peptide inhibitor and its use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1 Design of β-transition peptide

[0088] A variety of short peptides shown in Table 1 (peptides 1-9 have the sequence shown in SEQ ID NO:1-9 respectively) were designed and synthesized by conventional methods. Then use far ultraviolet circular dichroism to determine the secondary structure of the peptidomimetic. Methods as below:

[0089] The peptidomimetic was dissolved in 20 mmol potassium phosphate, 40 mmol sodium chloride, pH 7 solution containing 10% trifluoroethanol, and the peptide concentration was 0.4 mg / ml. The model of the circular dichrograph is Jasco J-715, and the test is carried out at 20℃, using standard parameters: wavelength is 190-250nm; sensitivity is 20mdeg; data collection interval is 0.1nm; scanning speed is 10nm / s; cumulative value 1; The response time is 0.25 seconds; the bandwidth is 1nm; the optical path is 0.1cm. The β-turn content in the peptidomimetic is positively correlated with the ellipticity at 218nm.

[0090] The result is figure...

Embodiment 2

[0096] Example 2 Structure-function relationship of peptidomimetic

[0097] In Table 1, peptides 1-4 clearly show that the β-turn is directly related to the activity of the peptidomimetic. Peptide 5 is designed on the basis of peptide 3 and has a similar secondary structure, but the activity is increased by more than 50 times. This is related to the improvement of the local structure which increases the binding force of the peptidomimetic and dopamine transporter, such as the removal of the basic L-lysine residue and the benzylation of the C-terminal L-threonine hydroxyl group. These changes Enhance the hydrophobicity of the molecule. The C-terminal L-glycine in peptide 5 is not necessary for the active structure, but is designed to facilitate solid phase synthesis. Peptides 7-9 show that the O-benzyl L-threonine in peptide 5 can be replaced by L-phenylalanine, L-tyrosine can be replaced by L-phenylalanine, and L-threonine can be Replaced by L-serine. These substitutions basically...

Embodiment 3

[0106] Example 3 Inhibition kinetics of peptidomimetic on dopamine transporter

[0107] The kinetic analysis of the peptidomimetic was performed on CHO cells stably expressing rat dopamine transporter. 1μM peptide 5 can inhibit 80% of the dopamine transporter activity, and after two washings, this inhibition can be completely reversed. Therefore, peptide 5 is a complete reversible inhibitor.

[0108] Saturation analysis experiments were also used to determine the properties of peptide 5 acting on dopamine transporters ( figure 2 ). When there is no inhibitor, the Km value of dopamine transporter for dopamine transport is 1.38±0.27μM, and the maximum transport speed Vmax is 1.27±0.13pmol / min.106cells; when there is 250nM peptide 5, the Km value is 2.41±0.35μM, Vmax It is 1.29±0.11pmol / min.106cells; when there is 600nM peptide 5, the Km value is 3.59±0.20μM, and the Vmax is 1.25±0.08pmol / min.106cells. It can be seen that peptide 5 only changes the Km value without changing the Vmax...

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Abstract

A dopamine transport protein mimic inhibitor and its use are disclosed. Specific acts on dopamine transport protein, competitive cocaine is located on combined site of dopamine transport protein and it penetrates blood-brain barrier to distribute in brain slowly. It can be used to treat neuropsychiatry and cocaine habituation and has long acting time.

Description

Technical field [0001] The invention relates to the field of pharmacology. More specifically, the present invention relates to a novel dopamine transporter peptidomimetic inhibitor and a pharmaceutical composition containing the inhibitor. The novel inhibitor of the present invention has a therapeutic effect on neuropsychiatric diseases related to dopamine transporters (especially cocaine addiction). Background technique [0002] Dopamine transporter is a good drug target. Some chemical drugs that have been successfully used to treat obesity, pediatric attention deficit disorder (ADHD), depression and Parkinson's disease are typical dopamine transporter inhibitors, such as the marketed Maindole (mazindol), ritalin, bupropion and brasofensine that entered clinical trials (Dutta, AK, Zhang, S., Kolhatkar, R. & Reith, MEDopamine transporter as target for drug development of cocaine dependence) medications. Eur. J. Pharmacol. 479, 93-106, 2003). [0003] [0004] Of particular conc...

Claims

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Application Information

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IPC IPC(8): C07K7/06A61K38/08A61P3/04A61P25/16A61P25/24A61P25/36A61P43/00C12N15/11
Inventor 费俭崔大敷丁金国
Owner SHANGHAI BIOMODEL ORGANISM SCI & TECH DEV
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