Preparation and application of long-acting pain-easing peptide compounds acting on multiple target points
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A compound and multi-target technology, applied in the field of biochemistry, can solve problems such as short half-life and limited clinical use
Active Publication Date: 2021-03-09
LANZHOU UNIVERSITY
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For example, the above-mentioned chimeric peptides EN-9, BN-9, DN-9 and MCRT have short half-lives, and the effective analgesic action time is less than 90 minutes (Neuropharmacology, 2016, 108:364; Brit JPharmacol, 2016, 173:1864 ; J Med Chem,2016,59:10198; Regul Peptides,2012,179:23), which to some extent limits the clinical use of peptide drugs
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Embodiment 1
[0148] Embodiment 1, the synthetic method of compound HD-1
[0149] 1. Resin pretreatment: Pour 500mg of 2-Chlorotrityl-Chloride-Resin into a syringe, add 5ml of DCM and shake for 30min. After the resin is fully swollen, vacuum up the solvent, wash with DMF and drain the solvent.
[0150] 2. Remove the Fmoc protecting group: add 5ml of 20% hexahydropyridine / DMF solution to the resin that has been swollen and drained of solvent, shake for 15 minutes and then drain; add 5ml of DMF, wash for 1min and then drain; add 5ml of 20% hexahydropyridine The hydropyridine / DMF solution was shaken for 5 minutes and then drained, and repeated twice to completely remove the Fmoc group. Then, add 5ml DMF, oscillate for 1 min and then drain, repeat three times; add 5 ml DCM, shake for 1 min, then drain, repeat three times; add 1ml DMF for vibration, 1 min and then drain to wash hexahydropyridine. Finally, take part of the resin and carry out indene detection according to step 3. The solution tu...
Embodiment 2
[0156] Embodiment two, the synthetic method of compound HD-2
[0157] 1. Resin pretreatment: Add 500mg of Rink-Amide-Resin into the syringe, add 5ml of DCM and shake for 30 minutes to make the resin fully swell, then decompress and dry the solvent, wash with DMF and dry the solvent;
[0158] 2. Remove the Fmoc protecting group: same as 2 in Example 1;
[0159] 3. Indene inspection: same as 3 in Example 1;
[0160] 4. Condensation: 4 in the same embodiment one;
[0161] 5. Extension of the peptide chain: same as 5 in Example 1;
[0162] 6. N-terminal acetylation: After the peptide chain condensation is completely completed, follow the operation of the above step 2 to completely remove the Fmoc group of the last amino acid of the peptide resin. Then, shake and wash with 5ml DMF for 1min and then drain, repeat three times; wash with 5ml DCM for 1min and drain, repeat three times; add 5ml acetic anhydride / pyridinemixed solution (3:2), shake for 30-60min. Finally, drain the so...
Embodiment 3
[0165] Embodiment three, the synthetic method of compound HD-3
[0166] 1. Resin pretreatment: same as 1 in Example 1;
[0167] 2. Remove the Fmoc protecting group: same as 2 in Example 1;
[0168] 3. Indene inspection: same as 3 in Example 1;
[0169] 4. Condensation: 4 in the same embodiment one;
[0170] 5. Extension of the peptide chain: same as 5 in Example 1;
[0171] 6. N-terminal acetylation: same as 6 in Example 2;
[0172] 7. The peptide chain is cut from the resin: same as 6 in Example 1;
[0173] 8. Purification of crude peptide: same as 6 in Example 1.
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Abstract
The invention belongs to the field of biochemical technologies and particularly relates to a modification preparation method for multiple-target-point peptide compounds acting on an opium receptor anda neuropeptide FF receptor and application of the multiple-target-point peptide compounds. According to the method, a series of compounds are obtained through systematic peptide terminal modificationby taking a multiple-target-point chimeric peptide MCRT as a matrix, and two compounds with remarkable-improved pain-easing effects, i.e., HD-10 and HD-11 are screened out by using radiant-heat tail-flick acute pain mouse models. The compound HD-10 has the most excellent pain-easing effect and has the characteristics of high effect taking speed, long half life, high drug effect and the like. Preliminary pharmacological researches show that among the radiant-heat tail-flick acute pain mouse models, through lateral ventricle injection of the multiple-target-point peptide compound HD-10, highereffect taking speed and more durable and higher pain-easing activity are shown compared with morphine, and thus, the peptide compounds have a potential application value in clinical pain treatment.
Description
technical field [0001] The invention belongs to the field of biochemical technology, and relates to a class of multi-target peptide compounds acting on opioid receptors and neuropeptide FF receptors and a synthesis method thereof, and also relates to the use of the multi-target peptide compounds in the preparation of analgesic drugs in the application. Background technique [0002] Pain is a painful sensation resulting from actual or potential tissue damage, often accompanied by unpleasant emotions or cardiovascular and respiratory changes. Clinically, analgesic drugs are mainly divided into opioids, non-steroidals, anticonvulsants, and antidepressants. Among them, opioids are the most important analgesics for the clinical treatment of moderate to severe pain, which mainly produce analgesic effect by binding to central opioid receptors, and have a significant therapeutic effect on pain. However, the use of such drugs is usually accompanied by toxic side effects such as add...
Claims
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Application Information
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