Methods of regulating cannabinoid receptor activity-related disorders and diseases
Inventors
Wainer, Irving William • Bernier, Michel • Paul, Rajib Kumar
Assignees
US Department of Health and Human Services
Publication Number
US-10130593-B2
Publication Date
2018-11-20
Expiration Date
2033-05-23
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Abstract
This disclosure concerns the discovery of the use of fenoterol analogs 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 analog to reduce one or more symptoms associated with the disorder or disease regulated by CB receptor activity.
Core Innovation
This invention concerns methods of regulating cannabinoid (CB) receptor activity-related disorders and diseases by using specific fenoterol analogues for their modulatory effect on CB receptors. The composition includes administration of compounds such as (R,R′)-4′-methoxy-1-naphthylfenoterol (MNF), (R,S′)-MNF, (R,R′)-naphthylfenoterol (NF), and their analogs to treat disorders or diseases, including tumors, associated with altered CB receptor activity or expression, particularly the GPR55 cannabinoid receptor. The disclosed methods involve administering an effective amount of such fenoterol analogues to reduce one or more symptoms related to these disorders or diseases.
Cancer, especially brain and liver cancers such as glioblastoma and hepatocellular carcinoma, often lacks effective clinical treatments. There is a recognized need to develop therapies that can regulate tumor growth associated with dysregulated CB receptor activity. The invention identifies that specific fenoterol analogues acting as CB receptor modulators inhibit tumor growth and can be used therapeutically for treating such cancers and other CB receptor-related disorders.
The inventors discovered that MNF and related fenoterol analogues act as cannabinoid receptor regulators, notably as GPR55 activity modulators, inhibiting the growth of various tumor cells both in vitro and in vivo. The compounds cross the blood-brain barrier, have minimal off-target toxic effects, and show anti-proliferative and pro-apoptotic activity in cancer cell lines. These properties support their use as novel candidates for treating CB receptor-modulated diseases, including primary brain tumors and hepatocellular carcinoma.
Claims Coverage
The patent provides 12 inventive features centered on methods of inhibiting cell growth regulated by CB receptor activity using specific fenoterol analogues and pharmaceutical compositions thereof, focusing on colon and liver cancers as exemplary cell types.
Use of specific fenoterol analogues to inhibit cannabinoid receptor-regulated cancer cell growth
Methods for inhibiting growth of cells regulated by CB receptor activity by exposing cells to effective amounts of (R,R)-4′-methoxy-1-naphthylfenoterol (MNF), (R,S′)-MNF, (R,R′)-naphthylfenoterol (NF), (R,S′)—NF, or their combinations, or pharmaceutical compositions thereof.
Targeting hepatocellular carcinoma cells
The method specifically includes treatment of liver cancer cells identified as hepatocellular carcinoma cells regulated by CB receptor activity.
Pharmaceutical compositions comprising fenoterol analogues
Exposing cancer cells to fenoterol analogues via pharmaceutical compositions including pharmaceutically acceptable carriers.
Targeting GPR55 cannabinoid receptor
Wherein the CB receptor involved in the modulation is GPR55.
In vivo administration to subjects with CB receptor-regulated cancers
Administering fenoterol analogues to subjects identified with colon or liver cancers regulated by CB receptor activity, thereby reducing biological symptoms associated with the disease.
Reduction of symptoms including tumor growth and metastasis
The method achieves reduction of symptoms such as tumor growth inhibition, metastasis reduction, or combination thereof.
Therapeutic administration with additional chemotherapeutic agents
In some embodiments, combined administration of fenoterol analogues with other chemotherapeutic agents prior to, concurrent with, or subsequent to fenoterol analogue treatment.
Treatment of signs or symptoms associated with disease
Administration results in reduction of one or more signs or symptoms of colon or liver cancer diseases.
Preferred compounds for treatment
Compounds such as (R,R′)-MNF, (R,S′)-MNF, and (R,R′)—NF, or their combinations, are preferred for use in the methods.
The claims cover methods of treating cancers regulated by CB receptor activity, particularly colon and liver cancers, using specific fenoterol analogues including MNF and NF, administered alone or in pharmaceutical compositions, optionally in combination with other chemotherapeutic agents, with emphasis on targeting the GPR55 receptor variant.
Stated Advantages
Fenoterol analogues such as MNF effectively inhibit tumor growth including glioblastoma and hepatocellular carcinoma, cancers that lack effective treatment options.
These compounds cross the blood-brain barrier, allowing brain tumor treatment.
They have minimal off-target toxic effects and potential cardio-protective effects.
The ability to regulate CB receptor activity provides a new mechanism to treat CB receptor-modulated diseases.
Documented Applications
Treatment of cancers associated with altered CB receptor activity, including glioblastoma, hepatocellular carcinoma, liver cancer, colon cancer, and lung cancer.
Use in treating metabolic disorders such as diabetes and obesity through modulation of CB receptor activity.
Therapeutic applications in inflammatory and neuropathic pain disorders and diseases.
Use in central nervous system conditions such as depression and anxiety.
Administration in both in vitro and in vivo models for tumor growth inhibition and apoptosis induction.
Combined use with chemotherapeutic agents and anti-diabetic agents as adjuvant therapies.
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