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Bicyclic CB2 cannabinoid receptor ligands

A cyclic, dimethyl technology, applied in the field of α-pinene derivatives and pharmaceutical compositions thereof, can solve the problems of unknown therapeutic activity and the like

Inactive Publication Date: 2005-06-15
PHARMOS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the corresponding (+)α-pinene derivatives have not been synthesized and their therapeutic activity is unknown

Method used

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  • Bicyclic CB2 cannabinoid receptor ligands
  • Bicyclic CB2 cannabinoid receptor ligands
  • Bicyclic CB2 cannabinoid receptor ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0339] Binding affinity of CB1 and CB2 receptors.

[0340] Displacement from the CB1 receptor by detecting new compounds on the membrane [ 3 H] The ability of CP55940 to perform binding analysis of CB1, the membrane is derived from HEK-293 cells stably transfected with hCB1 (Perkin Elmer / NEN). Dilute the membrane in assay buffer (50mM Tris-HCl, 2.5mM EDTA, 5mM MgCl 2 , 1mg / ml BSA, pH=7.4) to get 500μg protein / ml. In the presence or absence of the bicyclic test compound, mix 50μl of the diluted membrane (25μg) with [ 3 H] CP55940 was incubated together in a total volume of 0.5 ml. The test compound was dissolved in DMSO and diluted in the assay buffer to obtain a final concentration of 0.1% solvent. Add the same amount of control sample as the medium. Non-specific binding was measured by adding 10 μM WIN 55212-2. After incubating at 30°C for 1.5 hours, the reaction was filtered through a Whatman 934A / H filter (pre-soaked with 0.1% polyethyleneimine (PEI)).

[0341] By detecting the...

Embodiment 2

[0357] Anti-inflammatory properties of bicyclic CB2 ligand in vitro.

[0358] The specific aspects of the inflammatory response cascade are achieved through cytokines such as tumor necrosis factor-α (TNF-α), IFN-γ, IL-2 and IL-1β, and such as COX-2 and PGE 2 Mediated by inflammatory mediators. Regulating the levels of these pro-inflammatory agents is very important for the severity of the final inflammatory outcome. These pro-inflammatory agents are also produced by activated cells of the immune system, and the purpose of this study is to test the effect of new bicyclic CB2 ligands on the secretion of these inflammatory agents from activated macrophages and T cells. The secretion level in various test groups was determined by ELISA analysis, and the inhibition level was calculated in comparison with the vehicle treatment group.

[0359] ELISA was used for protein quantification.

[0360] The quantification technique for a given protein in liquid samples, tissue culture supernatant...

Embodiment 3

[0378] The effect of the compound on gene expression.

[0379] The inhibitory activity shown by the effect of some bicyclic CB2 binding compounds on the secretion of inflammatory agents in cells activated by the immune system in vitro or in vivo may be related to the regulation of gene expression.

[0380] RNA preparation and real-time RT-PCR.

[0381] SV total RNA isolation system (Promega) was used to prepare total RNA. Cells or tissues are homogenized in lysis buffer. According to the instructions of the kit, the lysate was transferred to the RNA separation column, treated with DNAse, washed and eluted. The concentration of RNA was determined by GeneQuant II (Pharmacia-Amersham). Complementary DNA (cDNA) was synthesized from total RNA using SUPERSCRIPT II reverse transcriptase (LifeTechnologies). According to the kit instructions, combine 2μg of total RNA with oligonucleotides (dT) 15 The combination of primers, 0.5mM dNTP mix, 8 units of reverse transcriptase and other reactio...

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Abstract

The present invention relates to atypical cannabinoids, i.e. ligands of the peripheral cannabinoid receptor CB2, and pharmaceutical compositions thereof comprising novel (+) α-pinene derivatives as active ingredients, which are useful in the prophylaxis of and treatment of autoimmune diseases including but not limited to rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, type I diabetes, hepatitis, psoriasis and immune Associated disorders, including but not limited to tissue rejection in organ transplantation, malabsorption syndromes such as celiac disease, pulmonary diseases such as asthma and Sjögren's syndrome, inflammation including inflammatory bowel disease, including peripheral, visceral, neurological Sexual, inflammatory and associated pain, muscle spasms, cardiovascular disorders including arrhythmia, hypertension and myocardial ischemia, nervous system disorders including stroke, migraine and cluster headaches, including Parkinson's disease, Neurodegenerative diseases like Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, prion-related neurodegeneration, CNS poisoning, and certain types of cancer.

Description

Invention field [0001] The present invention relates to (+)α-pinene derivatives as peripheral cannabinoid receptor CB2 ligands and pharmaceutical compositions thereof, which can be used to prevent and treat autoimmune diseases and related disorders, inflammation, pain, muscle Spasticity, cardiovascular disorders, nervous system disorders, neurodegenerative diseases, CNS poisoning, and certain types of cancer. Background of the invention [0002] Cannabis preparations have long been regarded as therapeutic agents for the treatment of various diseases (Mechoulam, R. "Cannabinoids as Therapeutic Agents" CRC Press, Boca Raton, Fla., 1-19, 1986). Today, the natural active ingredient Δ 9 -Tetrahydrocannabinoid (Δ 9 -THC) Under the generic name Dronabinol, prescribed by doctors as an antiemetic and enhance appetite, it is mainly used for AIDS patients. However, until recently, clinically undesirable mental-influencing effects and therapeutically desirable effects, such as the difference...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/12A61K31/35C07C39/23C07C45/29C07C45/54C07C45/71C07C49/657C07C49/747C07C49/753C07C69/30C07C69/40C07C69/60C07C251/44C07C255/40C07F9/12
CPCA61K31/12A61K31/35C07C39/23C07C45/292C07C45/54C07C45/71C07C49/657C07C49/747C07C49/753C07C69/30C07C69/40C07C69/60C07C251/44C07C255/40C07F9/12C07C2602/42A61P1/00A61P1/16A61P11/00A61P11/06A61P17/06A61P19/02A61P21/00A61P21/04A61P25/00A61P25/04A61P25/06A61P25/14A61P25/28A61P29/00A61P35/00A61P37/02A61P43/00A61P9/00A61P9/06A61P9/10A61P9/12A61P3/10
Inventor 阿伦·加尔松乔治·芬克达利特·埃丝特·达尔纳伊姆·梅纳什阿耶莱特·努德尔曼奥里特·格林伯格阿维海.亚科万
Owner PHARMOS
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