Methods of treating liver disease
AssigneeMount Sinai School of Medicine
InventorsLakshmi A. Devi, Raphael Rozenfeld
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Abstract
Compounds and compositions useful for the treatment of liver diseases and methods of treating liver diseases are disclosed. The compounds of the invention specifically interact with heteromers of cannabinoid receptors as compared to monomers or homodimers. The invention also relates to methods of screening for compounds useful for the treatment of liver diseases and to methods of screening for diacylglycerol lipase inhibitors.
Claims46
An isolated monoclonal antibody which specifically binds to a type I cannabinoid receptor (CB1R)/angiotensin II receptor (AT1R) heteromer.
A method of treating a liver disease in a mammal, comprising administering to the mammal in need of such treatment an effective amount of a compound, that preferentially inhibits an activity of a type I cannabinoid receptor (CB1R)/angiotensin II receptor (AT1R) heteromer, as compared to a control receptor selected from the group consisting of CB1R monomer, CB1R homodimer, AT1R monomer, AT1R homodimer, and a combination thereof.
A method of treating a liver disease in a mammal, comprising administering to the mammal in need of such treatment an effective amount of a compound, that preferentially inhibits an activity of a type I cannabinoid receptor (CB1R)/adenosine 2a receptor (A2aR) heteromer, as compared to a control receptor selected from the group consisting of CB1R monomer, CB1R homodimer, A2aR monomer, and A2aR homodimer.
A method of screening for a candidate compound useful for the treatment of a liver disease, the method comprising:
- a) contacting the compound with a CB1R/A2aR heteromer, and with at least one control receptor selected from the group consisting of a CB1R monomer, a CB1R homodimer, an A2aR monomer, and an A2aR homodimer,
- b) measuring inhibition of an activity of the CB1R/A2aR heteromer and of the control receptor in the presence of the compound, and
- c) selecting the compound which preferentially inhibits the activity of the CB1R/A2aR heteromer as compared to the control receptor, as a candidate compound useful for the treatment of the liver disease.
A method of screening for a compound useful for the treatment of a liver disease, the method comprising:
- a) contacting the compound with a CB1R/AT1R heteromer, and with at least one control receptor selected from the group consisting of a CB1R monomer, a CB1R homodimer, an AT1R monomer, and an AT1R homodimer;
- b) measuring inhibition of an activity of the CB1R/AT1R heteromer and of the control receptor in the presence of the compound, and
- c) selecting the compound which preferentially inhibits the activity of the CB1R/AT1R heteromer as compared to the control receptor, as a candidate compound useful for the treatment of the liver disease.
A method of screening for a compound useful for the treatment of a liver disease, the method comprising:
- a) contacting the compound with a cell expressing a type I cannabinoid receptor (CB1R)/angiotensin II receptor (AT1R) heteromer, and with a control cell expressing CB1R alone or AT1R alone;
- b) measuring inhibition of endocannabinoid activity in the cell expressing CB1R/AT1R heteromer and in the control cell in the presence of the compound, and
- c) selecting the compound which preferentially inhibits endocannabinoid activity in the cell expressing the CB1R/AT1R heteromer as compared to the control cell, as the candidate compound useful for the treatment of the liver disease.
A method of screening for a compound useful for the treatment of a liver disease, the method comprising:
- a) contacting the compound with a cell expressing a type I cannabinoid receptor (CB1R)/adenosine 2a receptor (A2aR) heteromer, and with a control cell expressing CB1R alone or A2aR alone;
- b) measuring inhibition of endocannabinoid activity in the cell expressing CB1R/A2aR heteromer and in the control cell in the presence of the compound, and
- c) selecting the compound which preferentially inhibits endocannabinoid activity in the cell expressing the CB1R/A2aR heteromer as compared to the control cell, as the candidate compound useful for the treatment of the liver disease.
A method of screening for a compound useful for treating a liver disease, the method comprising:
- a) contacting the compound with a cell expressing a type I cannabinoid receptor (CB1R)/angiotensin II receptor (AT1R) heteromer, and with a control cell expressing CB1R alone or AT1R alone;
- b) measuring decrease in intracellular cAMP levels in the cell expressing CB1R/AT1R heteromer and in the control cell in the presence of the compound, and
- c) selecting the compound which causes a greater decrease in intracellular cAMP levels in the cell expressing the CB1R/AT1R heteromer as compared to the control cell, as the candidate compound useful for the treatment of the liver disease.
A method of screening for a diacylglycerol lipase (DAGL) inhibitor, the method comprising:
- a) contacting a compound with a cell expressing a type I cannabinoid receptor (CB1R) and a G-protein coupled receptor (GPCR), each receptor having a respective ligand, wherein the receptors are only capable of inducing ERK1/2 phosphorylation when the CB1R and the GPCR are co-stimulated by a ligand,
- b) measuring changes in ERK1/2 phosphorylation in the presence of the compound, and
- c) selecting the compound which causes a decrease in ERK1/2 phosphorylation as the DAGL inhibitor.
A method of measuring selective binding of a compound to CB1R/AT1R or CB1R/A2aR heteromer, the method comprising:
- a) providing a cell expressing CB1R/AT1R or CB1R/A2aR heteromer and a control cell expressing only CB1R, only AT1R, or only A2aR;
- b) contacting the cell expressing CB1R/AT1R or CB1R/A2aR heteromer and the control cell with Angiotensin II or A2aR agonist or the compound;
- c) adding a radioactive labeled Angiotensin II or A2aR agonist;
- and,
- d) measuring receptor-bound radioactivity.
An isolated monoclonal antibody which specifically binds to a type I cannabinoid receptor (CB1R)/adenosine 2a receptor (A2aR) heteromer.
Dependencies are inferred from the claim text.