CN114588143B - Pharmaceutical composition and application of compound as or in preparation of opioid receptor antagonist - Google Patents

Pharmaceutical composition and application of compound as or in preparation of opioid receptor antagonist Download PDF

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CN114588143B
CN114588143B CN202011404474.4A CN202011404474A CN114588143B CN 114588143 B CN114588143 B CN 114588143B CN 202011404474 A CN202011404474 A CN 202011404474A CN 114588143 B CN114588143 B CN 114588143B
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opioid receptor
opioid
kfb32
kfb18
kfb12
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CN114588143A (en
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梁鑫淼
侯滔
彭惺蓉
邱明华
张秀莉
周晗
王纪霞
徐芳芳
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Dalian Institute of Chemical Physics of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract

The invention relates to the discovery of four opioid receptor natural antagonists and application thereof, in particular to the discovery of phenolic acid compound acting targets in ganoderma lucidum plants, wherein the targets are Mu opioid receptors, and the opioid receptor antagonists are kfb10, kfb12, kfb18 and kfb32. In vitro cell experiments show that the compounds kfb10, kfb12, kfb18 and kfb32 have different degrees of antagonism on Mu opioid receptors. The current research shows that the opioid receptor is related to diseases such as pain, nervous system, respiratory system, gastrointestinal system, cancer and the like, and the opioid receptor antagonist can prevent and treat side effects generated by opioid medicines such as drug addiction, drug tolerance, respiratory depression, constipation and the like, and treat cancer. Therefore, the natural opioid receptor antagonist provides candidate compounds with definite action targets and novel structures for the drug development of the related diseases.

Description

Pharmaceutical composition and application of compound as or in preparation of opioid receptor antagonist
Technical Field
The invention belongs to the field of opioid receptor antagonists, and relates to the discovery of action targets of anti-stalk ganoderma lucidum phenolic acid compounds, in particular to kfb10, kfb12, kfb18 and kfb32 in phenolic acid compounds and corresponding pharmaceutically acceptable salt-forming compounds; the target is Mu opioid receptor; the application is the prevention and treatment of diseases such as opioid addiction, tolerance, respiratory depression, constipation, cancer and the like.
Background
Ganoderma lucidum is a fungus Chinese medicinal material and is various in variety, such as Ganoderma sinense, ganoderma lucidum, ganoderma sinense, ganoderma lucidum, and Ganoderma lucidum. The ganoderma lucidum contains rich chemical components, has complex and various structure types, has the effects of strengthening body resistance, prolonging life and the like, and has various pharmacological activities, such as enhancing immunity, protecting liver, improving sleep, reducing blood sugar and the like. In particular to a ganoderma lucidum (Ganoderma sinense) with the functions of benefiting joints, treating deafness, replenishing vital essence, protecting spirit, strengthening bones and muscles and prolonging life. However, most of the current research is focused on the cellular level, and little research is done on the action targets of pure compounds (Chen Yixiang, song, li Ting, etc. Ganoderma sinensis research progresses. Guangdong agricultural science 2011,38 (24): 36-39; hawk, wang Xinyu. Development of chemical composition of Ganoderma sinense. Bacterial composition research 2014,12 (04): 187-196+202+184; zhang Ruiting, zhou Tao, song Xiaoxiao, etc. the research progress of ganoderma lucidum active ingredient and its pharmacological action, anhui agricultural science 2018,46 (03): 18-19+22; zhou, F.J., nian, Y., yan, Y.M., et al, two New Classes of 1-Type Calcium Channel Inhibitors with New Chemical Scaffolds from Ganoderma cochlear. Organic letters 2015,17 (12): 3082-3085; dou, M., li, R.-t., and Cheng, Y., x.Minor Compounds from Fungus Ganoderma cochlear. Chinese medicinal acids 2016,8 (1): 85-88; wang, X.L., zhou, F.J., dou, M., et al, cochlearoids F-K: phenolic meroterpenoids from the fungus Ganoderma cochlear and their re σrotechanic activity. Biological & 4 letters 2016,26 (22): 5507-5512; wac.L., dou, M, luo, Q., et al, 466 Fixer 29, 93-93, 93.
Opioid receptors are a member of the superfamily of G protein-coupled receptors, mainly in central and peripheral neurons, and neuroendocrine (pituitary, adrenal), immune and ectodermal cells, expressed in mainly 4 subtypes: mu, kappa, delta, NOP. Research has shown that opioid receptors are associated with diseases such as pain, nervous system, respiratory system, gastrointestinal system, cancer, etc. At present, a great number of opioid analgesics have remarkable side effects, such as drug addiction, drug tolerance, respiratory depression, constipation and the like. And researches show that the opioid receptor antagonist has the effect of preventing and treating side effects of opioid analgesic drugs. There are studies reporting that the development of cancer at opioid receptors is closely related. Thus, new Opioid Receptor antagonists have been discovered to provide targeted therapies for Opioid-induced diseases, as well as cancer (Xiaolin, z., zheng, y., and Ruibin, s.research progress in drugs based on Opioid Receptor subtypes.chinese Journal of Pharmacology and toxicology.2017,31 (4): 346-351; yang Huan, bao Jingying, jiang Miaomiao, etc. analgesic effects of Opioid agonists and their target pathway studies have progressed, anhui medicine 2017,21 (02): 211-215; pan Chenling, meng Hao, wang Liangliang, et al, recent hot spot in Opioid Drug development, organic chemistry, 2018,38 (10): 2625-2632; zhu Lianghan, cui Zhiying, zhu Qihua, et al, opioid Receptor agonist research evolution, pharmaceutical evolution, 2018,42 (07): 537-543; trescot, a.m., datta, s., lee, m., et al, operational pharmaceutical, pain, 2008,11 (2): S133-S153; fes, y., he, x.z., yang, y.l., et al, current Research on Opioid Receptor function, current targets, 2012,13 (2): 230-246; singleton, p.a., mos, j., karp.d., et al, 15, A New Target for Cancer Therapy: cancer, 121 (16): 2681-2688;Stein,C.Opioid Receptors.Annual Review of Medicine.2016,67 (1): 433-passenger physico-2008, 11): S133-153; fest, fe, y., he, x.z., yang, y.2012, 13 (5).
At present, research on the action of kfb10, kfb12, kfb18 and kfb32 on Mu Opioid Receptor (MOR) in phenolic acid compounds in ganoderma atrovirens has not been reported.
Disclosure of Invention
The invention relates to the discovery of action targets of kfb10, kfb12, kfb18 and kfb32 in phenolic acid compounds and the application of the compounds, and aims to provide Mu opioid receptors as the action targets of the compounds kfb10, kfb12, kfb18 and kfb 32; and the second purpose is to provide the application range of the compounds in clinic.
The technical scheme of the invention is as follows:
the opioid receptor antagonists are compounds kfb10, kfb12, kfb18 and kfb32.
The chemical structures of the compounds kfb10, kfb12, kfb18 and kfb32 are as follows:
Figure SMS_1
the phenolic acid compound is applied to the preparation of medicines for preventing and/or treating opioid addiction, tolerance, respiratory depression, constipation, cancers and other diseases, wherein the phenolic acid compound is kfb10, kfb12, kfb18 and kfb32.
The invention has the beneficial effects that:
in vitro cell experiments show that the compounds of the invention are kfb10, kfb12, kfb18 and kfb32 which act on Mu opioid receptors, wherein the Mu opioid receptors are G protein coupled receptors, and the opioid receptors are related to diseases such as pain, nervous system, respiratory system, gastrointestinal system, cancer and the like, so that the clinical application range of the compounds can be widened according to the correlation of target points and the diseases.
Drawings
FIG. 1A shows the maximum DMR response of the compounds kfb10, kfb12, kfb18 and kfb32, and Loperamide in 60min on HEK293T-Mu cells;
FIG. 1B shows the maximum DMR response of Loperamide on HEK293T-Mu cells within 60min after pretreatment of HEK293T-Mu cells with the compounds kfb10, kfb12, kfb18 and kfb32, and Control (HBSS buffer with 0.1% DMSO) for 1 h.
FIG. 2A is a graph showing the maximum DMR response of Loperamide on HEK293T-Mu cells within 60min after pretreatment of HEK293T-Mu cells with different concentrations of the compound kfb32 for 1 h;
FIG. 2B is a DMR response dose curve of Loperamide on HEK293T-Mu cells after pretreatment of HEK293T-Mu cells with different concentrations of compounds kfb10, kfb12, kfb18 and kfb32 for 1 h.
Detailed Description
The invention will now be further illustrated with reference to examples, which are intended to be illustrative of the invention and not limiting.
Example 1: discovery of phenolic acid compounds kfb10, kfb12, kfb18 and kfb32 acting on opioid receptors
The compounds kfb10, kfb12, kfb18 and kfb32 were derived from the plant institute of kunming, academy of sciences of china. The stably transformed cell line (HEK 293T-Mu) highly expressing the humanized Mu opioid receptor is derived from university of California Europe division in the United states; loperamide (cat# 0840) was purchased from Tocres. Dimethyl sulfoxide (DMSO, cat# A503039-0250). HBSS buffer (Gibco, 14065056). The detection platform is Kang Ningdi third generation
Figure SMS_2
The signal detected by the imager is the wavelength shift caused by the Dynamic Mass Reset (DMR) of the cell.
HEK293T-Mu cells in logarithmic growth phase were seeded into
Figure SMS_3
In 384-well biosensor microplates, the volume of seeded cell suspension per well was 40 μl, and the number of cells seeded per well was 2.5X10 4 Next, 384-well plates were placed in a cell incubator (CO at 5% by volume concentration) 2 Culturing for 22-24h at 37 ℃ under the condition that the cell fusion degree reaches about 95 percent, and performing experiments.
First, 50. Mu.M of compounds kfb10, kfb12, kfb18 and kfb32, and 400nM of the Mu opioid receptor selective agonist Loperamide were added to HEK293T-Mu cells and tested for 1h, followed by a further test of Loperamide (400 nM) for 1h, and as shown in FIGS. 1A and 1B, compounds kfb10, kfb12, kfb18 and kfb32 inhibited the Loperamide DMR signals to varying degrees on HEK293T-Mu cells, indicating that they may have Mu opioid receptor antagonistic activity.
Example 2: verification of the action of phenolic acid compounds kfb10, kfb12, kfb18 and kfb32 on opioid receptors
HEK293T-Mu cells in logarithmic growth phase were seeded into
Figure SMS_4
In 384-well biosensor microplates, the volume of seeded cell suspension per well was 40 μl, and the number of cells seeded per well was 2.5X10 4 Next, 384-well plates were placed in a cell incubator (5% CO 2 Culturing at 37 ℃ for 22-24 hours, and carrying out experiments when the cell fusion degree reaches about 95%.
DMR antagonism detection: compound kfb10, kfb12, kfb18 and kfb32 at various final concentrations (400. Mu.M, 300. Mu.M, 200. Mu.M, 100. Mu.M, 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.13. Mu.M) were pre-treated HEK293T-Mu cells for 1h, respectively, followed by the addition of Mu opioid receptor selective agonist Loperamide (final concentration 400 nM) and monitoring continued for 1h, as shown in FIGS. 2A, 2B. Compounds kfb10, kfb12, kfb18 and kfb32 inhibit the DMR signal of the Mu opioid receptor selective agonist Loperamide to varying degrees and exhibit dose dependency, IC thereof 50 The values are 473.20 +/-127.44 mu M, 209.10 +/-38.46 mu M, 54.61 +/-11.43 mu M and 39.87 +/-8.70 mu M respectively, and the activity strengths are as follows: kfb32>kfb18>kfb12>kfb10. This demonstrates that compounds kfb10, kfb12, kfb18 and kfb32 have Mu opioid receptor antagonistic activity, which are Mu opioid receptor antagonists.
Pharmacological DMR experiments show that Mu opioid receptors are acting targets of the compounds kfb10, kfb12, kfb18 and kfb32. The current research shows that the opioid receptor is related to diseases such as pain, nervous system, respiratory system, gastrointestinal system, cancer and the like, and the clinical application range of the compound can be widened according to the relativity of the target point and the diseases.

Claims (3)

1. The application of the compound or the corresponding pharmaceutically acceptable salt of the compound in preparing medicines for treating respiratory depression caused by opioid and constipation caused by opioid is characterized in that: the compound is one of the following structures,
Figure QLYQS_1
，
the compound or the corresponding pharmaceutically acceptable salt thereof is used as an opioid receptor antagonist,
the opioid receptor is Mu opioid receptor.
2. The use according to claim 1, characterized in that: the medicament further comprises a pharmaceutically acceptable carrier and/or excipient.
3. The use according to claim 1, characterized in that: the compounds kfb10, kfb12, kfb18 and kfb32 are all derived from natural fungi ganoderma lucidum and are prepared from ganoderma lucidum.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042980A1 (en) * 2006-10-10 2009-02-12 Burnham Institute For Medical Research Neuroprotective compositions and methods
CN105213363A (en) * 2015-04-30 2016-01-06 中国科学院微生物研究所 The application of hydroquinone farnesyl compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090042980A1 (en) * 2006-10-10 2009-02-12 Burnham Institute For Medical Research Neuroprotective compositions and methods
CN105213363A (en) * 2015-04-30 2016-01-06 中国科学院微生物研究所 The application of hydroquinone farnesyl compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Cytotoxic and N-Acetyltransferase Inhibitory Meroterpenoids from Ganoderma cochlear;Li-Zhi Cheng等;《Molecules》;20180720;第1-10页 *
Isolation and identification of renoprotective substances from the mushroom Ganoderma lucidum;Qi Luo等;《Tetrahedron》;20141220;第840-845页 *

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