Methods of regulating cannabinoid receptor activity-related disorders and diseases
Inventors
Wainer, Irving W. • Bernier, Michel • Paul, Rajib K.
Assignees
US Department of Health and Human Services
Publication Number
US-11389415-B2
Publication Date
2022-07-19
Expiration Date
2033-05-23
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Abstract
This disclosure concerns the discovery of the use of fenoterol analogues for regulating cannabinoid (CB) receptor activity-related disorders and disease, such as dysregulated CB receptors, including treating a disorder or disease, such as a glioblastoma, hepatocellular carcinoma, liver cancer, colon cancer, and/or lung cancer, which is associated with altered cannabinoid receptor activity. In one example, the method includes administering to a subject having or at risk of developing a disorder or disease regulated by CB receptor activity an effective amount of a fenoterol analogue to reduce one or more symptoms associated with the disorder or disease regulated by CB receptor activity.
Core Innovation
This disclosure concerns the discovery of the use of specific fenoterol analogues, such as (R,R′)-4′-methoxy-1-naphthylfenoterol (MNF) and related compounds, as modulators of cannabinoid (CB) receptor activity. These compounds have been found to regulate CB receptor activity-related disorders and diseases, including the treatment of tumors such as glioblastoma, hepatocellular carcinoma, liver cancer, colon cancer, and lung cancer that are associated with altered CB receptor activity or expression, particularly of the GPR55 cannabinoid receptor.
The inventors discovered that administration of these fenoterol analogues inhibits one or more signs or symptoms, such as tumor growth, associated with tumors expressing CB receptors. This is exemplified in their inhibition of cellular proliferation in cancer cell lines and reduction of tumor volume in in vivo models. The methods include administering an effective amount of a fenoterol analogue, characterized by specific chemical substituents and stereochemistry, to subjects having or at risk of developing disorders or diseases regulated by CB receptor activity, thereby reducing symptoms associated with such conditions.
The problem being addressed is the lack of effective treatments for various cancers, including brain and liver cancers, which involve dysregulated CB receptor activity. Cancer remains a leading cause of death with rising incidence, and many cancer types lack effective clinical treatments. This disclosure provides new therapeutic agents targeting CB receptor modulation, specifically GPR55, offering potential treatment avenues for these poorly managed malignancies.
Claims Coverage
The patent document presents one independent claim focusing on a method of detecting and treating liver or colon cancer using specified fenoterol analogues.
Method of detecting and treating liver or colon cancer by CB receptor activity identification and fenoterol analogue administration
A method comprising identifying a subject with liver or colon cancer tumors regulated by cannabinoid receptor (CB) activity; administering to the subject a therapeutically effective amount of optically active fenoterol analogues selected from 4′-methoxy-1-naphthylfenoterol (MNF), naphthylfenoterol (NF), ethyl-4′-methoxy-1-naphthylfenoterol (ethylMNF), 4′-amino-1-naphthylfenoterol (aminoNF), 4′-hydroxy-1-naphthylfenoterol (hydroxyNF), ethyl-naphthylfenoterol (ethylNF), or any combination thereof, to reduce tumor growth, metastasis, or both.
Utilization of GPR55 as CB receptor target
The CB receptor involved in the method is specified as GPR55, implicating this receptor subtype in the therapeutic mechanism.
Detection methods for tumors regulated by CB receptor activity
Detecting the liver or colon cancer tumor regulated by CB receptor activity by one or more of: altered CB expression or activity in a subject sample compared to non-tumor conditions; clinical signs such as vomiting or weight loss; diagnostic imaging including magnetic resonance imaging (MRI); histology; or combinations thereof.
Administration of specific isomers of fenoterol analogues
Administering the therapeutically effective amount of fenoterol analogue comprising optically active isomers chosen from the (R,R′) or (R,S′) stereoisomers of MNF or NF, or combinations thereof.
Pharmaceutical composition delivery and dosing
Administering the compound in a pharmaceutical composition with a pharmaceutically acceptable carrier, in oral or injectable dosage forms, with dosages from about 0.001 mg/kg to about 10 mg/kg orally and about 1 mg/kg to about 100 mg/kg parenterally.
Combination therapy with additional chemotherapeutic agents
Optionally administering additional chemotherapeutic agents before, during, or after administration of fenoterol analogues to improve therapeutic outcomes.
The claims focus on the therapeutic use of optically active fenoterol analogues, particularly those modulating GPR55 cannabinoid receptor activity, for detecting and treating liver and colon cancers. The inventive features include precise identification of subject tumors regulated by CB receptor activity and specific administration regimens of these compounds alone or in combination with chemotherapeutic agents, supporting a novel approach to managing these cancers.
Stated Advantages
Fenoterol analogues including MNF and NF can regulate cannabinoid receptor activity to inhibit tumor growth and proliferation associated with cancer types including glioblastoma, liver, lung, and colon cancers.
MNF demonstrates the ability to cross the blood-brain barrier, providing treatment potential for brain cancers.
The compounds show minimal off-target effects and limited central nervous system side effects relative to traditional cannabinoids.
The fenoterol analogues possess β2-AR agonist activity that may confer additional cardio-protective benefits while exerting anti-tumor effects via CB receptor modulation.
Documented Applications
Treatment of tumors or cancers associated with altered cannabinoid receptor activity, including glioblastoma, hepatocellular carcinoma, liver cancer, colon cancer, lung cancer, and brain cancers expressing CB receptors such as GPR55.
Use in treating metabolic disorders such as diabetes and obesity through regulation of CB receptor activity.
Treatment of inflammatory and neuropathic pain disorders, bone and muscle wasting diseases such as osteoarthritis and sarcopenia, central nervous system disorders including depression and anxiety, and age-related diseases such as Alzheimer's.
Pharmaceutical application of fenoterol analogues as chemotherapeutic agents alone or in combination with other therapeutic agents to inhibit tumor growth and metastasis.
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