CN114588150B - Use of compounds as or in the preparation of opioid receptor antagonists and pharmaceutical compositions - Google Patents

Use of compounds as or in the preparation of opioid receptor antagonists and pharmaceutical compositions Download PDF

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CN114588150B
CN114588150B CN202011413848.9A CN202011413848A CN114588150B CN 114588150 B CN114588150 B CN 114588150B CN 202011413848 A CN202011413848 A CN 202011413848A CN 114588150 B CN114588150 B CN 114588150B
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opioid receptor
kct
opioid
compounds
compound
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CN114588150A (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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/286—Carthamus (distaff thistle)
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to a natural product Opioid receptor (OPR) antagonist and application thereof as a medicament, in particular to discovery of an alkaloid compound action target point in safflower seed plants, wherein the target point is Mu Opioid receptor, and the Opioid receptor antagonist is one or more than two of kct11, kct, kct and kct33 or compound derivatives and corresponding pharmaceutically acceptable salts thereof as active ingredients. In vitro cell experiments show that the compounds of the invention are antagonists of 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 drugs, such as drug addiction, drug tolerance, respiratory depression, constipation and the like, and treat cancer, so that a novel opioid receptor antagonist lead compound with definite action targets can be provided for the related diseases.

Description

Use of compounds as or in the preparation of opioid receptor antagonists and pharmaceutical compositions
Technical Field
The invention belongs to the field of opioid receptor antagonists, and relates to the discovery of an action target point of an alkaloid compound in safflower seeds, in particular to the discovery of action target points of kct11, kct12, kct17 and kct33 in the alkaloid compound. The alkaloid compounds are kct11, kct12, kct17, kct, derivatives 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
Safflower seed is the seed of the asteraceae plant safflower (Carthamus tinctorius l.), known as "western Ping Zi". The safflower seed oil has the effects of dredging channels and relieving pain, and activating blood and dissolving stasis, and is mainly used for treating amenorrhea due to blood stagnation, dysmenorrhea, arthralgia, traumatic blood stasis and swelling, macula and the like. Clinical and pharmacological studies show that safflower is beneficial to nervous system, cardiovascular and cerebrovascular and immune system, and has pharmacological activities of analgesia, anti-inflammatory, antibacterial, anti-tumor and anti-fatigue. However, most of the current research is focused on the cellular level, and little research is done on the target site of action of pure compounds (Yuan Qinqin, liu Wenying. Research on bioactive components and functional properties of safflower has progressed. Food industry science 2020,41 (03): 432-344;Sun LP,Shi FF,Wang K,et al.Antioxidant and Anti-Inflammatory Activities of Safflower (Carthamus tinctorius L.) Honey extract. FOODS.2020,9 (8): 1039-1054).
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 and 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 efficacy 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 target pathway research developments therefor 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, fe, 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., movement, j., karp.d., et al, temperature operation receiver: A New Target for Cancer Therapy.
At present, research on the action of kct, kct, kct, and kct33 in alkaloid compounds in safflower seeds on Mu Opioid Receptors (MOR) has not been reported.
Disclosure of Invention
The invention relates to the discovery of action targets of kct11, kct12, kct and kct33 in alkaloid compounds and application of the compounds, and aims to provide that the action targets of compounds kct11, kct12, kct17 and kct33 are Mu opioid receptors; 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 kct, kct12, kct17, and kct33.
The chemical structures of compounds kct11, kct, kct17 and kct33 are as follows:
Figure SMS_1
the alkaloid compounds are kct11, kct12, kct17 and kct, and are used for preparing medicines for preventing and/or treating opioid addiction, tolerance, respiratory depression, constipation, cancers and other diseases.
The invention has the beneficial effects that:
in vitro cell experiments show that the compounds of the invention are kct11, kct12, kct17 and kct 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 targets and the diseases.
Drawings
FIG. 1A shows the maximum DMR response of compounds kct, kct, kct17 and kct33, and Loperamide over 60min on HEK293T-Mu cells;
FIG. 1B shows the maximum DMR response of Loperamide (400 nM) on HEK293T-Mu cells within 60min after pretreatment of HEK293T-Mu cells with compounds kct, kct, kct, 17 and kct33, and Control (HBSS buffer with 0.1% DMSO) for 1 h.
FIG. 2A is a graph showing the maximum DMR response of Loperamide (400 nM) on HEK293T-Mu cells for 60min after pretreatment of HEK293T-Mu cells with different concentrations of compound kct for 1 h;
FIG. 2B is a DMR response dose curve of Loperamide (400 nM) on HEK293T-Mu cells after pretreatment of HEK293T-Mu cells for 1h with different concentrations of compounds kct, kct12, kct, and kct33.
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 alkaloid compounds kct11, kct, kct17 and kct33 acting on opioid receptors
Compounds kct (N-P-Coumaroyl Serotonin/N-P-coumaroyl serotonin), kct, kct17 and kct (N-Cinnamoyl Serotonin/cinnamoyl serotonin) were derived from Kunming plant institute, national academy of sciences. 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 final concentrations of compounds kct, kct12, kct, and kct, respectively, and 400nM final concentration of the Mu opioid receptor selective agonist Loperamide were added to HEK293T-Mu cells for 1h, followed by further detection of Loperamide (400 nM) for 1h, and as a result, as shown in FIG. 1, compounds kct, kct, kct, and kct were able to inhibit the DMR signal of Loperamide to varying degrees on HEK293T-Mu cells, and the compounds themselves were devoid of or produced weaker DMR signals on HEK293T-Mu cells, indicating that they may have Mu opioid receptor antagonistic activity.
Example 2: verification of the action of alkaloid compounds kct11, kct12, kct17 and kct33 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 kct, kct12, kct17 and kct33 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) pre-treated HEK293T-Mu cells for 1h, followed by the addition of Mu opioid receptor selective agonist Loperamide (final 400 nM) and continued monitoring for 1h, results are shown in FIG. 2. Compounds kct, kct, kct17 and kct33 inhibit the DMR signal of the Mu opioid receptor selective agonist Loperamide to varying degrees and exhibit dose dependency, IC 50 The values are 146.10 +/-29.33 mu M, 264.70 +/-174.16 mu M, 20.83+/-2.73 mu M and 301.55 +/-44.87 mu M respectively, and the activity strengths are as follows: kct17 and 5217>kct11>kct12>kct33. This demonstrates that compounds kct, kct, 12, kct, 17 and kct33 have Mu opioid receptor antagonistic activity, which are Mu opioid receptor antagonists.
Pharmacological DMR experiments show that Mu opioid receptors are acting targets of compounds kct11, kct, kct17 and kct33. 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 kct, kct, kct17 and kct are all derived from natural Compositae plant safflower, and are prepared from safflower seeds.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023202A1 (en) * 1995-12-22 1997-07-03 STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON Subtype-selective nmda receptor ligands and the use thereof
CN101262866A (en) * 2005-09-14 2008-09-10 味之素株式会社 Hemodynamics improving agent
CN102046596A (en) * 2008-03-27 2011-05-04 格吕伦塔尔有限公司 Substituted cyclohexyldiamines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997023202A1 (en) * 1995-12-22 1997-07-03 STATE OF OREGON, acting by and through THE OREGON STATE BOARD OF HIGHER EDUCATION, acting for and on behalf of THE OREGON HEALTH SCIENCES UNIVERSITYA ND THE UNIVERSITY OF OREGON, EUGENE OREGON Subtype-selective nmda receptor ligands and the use thereof
CN101262866A (en) * 2005-09-14 2008-09-10 味之素株式会社 Hemodynamics improving agent
CN102046596A (en) * 2008-03-27 2011-05-04 格吕伦塔尔有限公司 Substituted cyclohexyldiamines

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Bioactive Indole Alkaloids from Croton echioides;Claudio R. Novello;《J. Braz. Chem. Soc.》;20161231;第2203-2209页 *
Multiple mechanisms involved in the inhibition of proinflammatory cytokine production from human monocytes by N-(p-coumaroyl)serotonin and its derivatives;Takemasa Takii等;《International Immunopharmacology》;20031231;第273-277页 *
Rare Hybrid Dimers with Anti-Acetylcholinesterase Activities from a Safflower (Carthamus tinctorius L.) Seed Oil Cake;Xing-Rong Peng等;《Journal of Agricultural and Food Chemistry》;20171010;第9453-9459页 *

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