Low dosage serotonin 5-ht2a receptor agonist to suppress inflammation

Abstract

Activation of 5-HT 2A receptors using agonists at surprisingly low concentrations was shown to potently inhibit TNF-α-induced inflammation in multiple cell types. Significantly, proinflammatory markers were also inhibited by the agonist, (R)-DOI, even many hours after treatment with TNF-α. With the exception of a few natural toxins, no current drugs or small molecule therapeutics demonstrate a comparable potency for any physiological effect. TNF-α and TNF-α receptor mediated inflammatory pathways have been strongly implicated in a number of diseases, including atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, depression, schizophrenia, and Alzheimer's disease. Importantly, because (R)-DOI can significantly inhibit the effects of TNF-α many hours after the administration of TNF-α, potential therapies could be aimed not only at preventing inflammation, but also treating inflammatory injury that has already occurred or is ongoing.

We claim: 
     
         1 . A method for the treatment of an inflammatory disorder in a mammal, said method comprising administering to a mammal in need of such treatment an therapeutically effective amount of a 5-HT 2A  receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 
     
     
         2 . The method of  claim 1 , wherein the 5-HT 2A  receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 
     
     
         3 . The method of  claim 1 , wherein the 5-HT 2A  receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 
     
     
         4 . The method of  claim 3 , wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 
     
     
         5 . The method of  claim 3 , wherein the ((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 
     
     
         6 . The method of  claim 3 , wherein the (((R)-DOI) is administered in an amount in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 
     
     
         7 . The method of  claim 1 , wherein the inflammatory disorder is associated with a disease selected from the group consisting of atherosclerosis, asthma, rheumatoid arthritis, psoriasis, type II diabetes, irritable bowel syndrome, Crohn's disease, septicemia, depression, schizophrenia, and Alzheimer's disease. 
     
     
         8 . The method of  claim 1 , additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs. 
     
     
         9 . A method to reduce the expression of the intracellular adhesion molecule 1 (ICAM-1) gene associated with stimulation of the tumor necrosis factor-alpha receptor in a mammal, said method comprising administering to a mammal in need of such reduction an therapeutically effective amount of a 5-HT 2A  receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 
     
     
         10 . A pharmaceutical composition which comprises a dose of a 5-HT 2A  receptor agonist in an amount no greater than that required to result in a body fluid concentration no greater than 5 nM in a pharmaceutically acceptable carrier. 
     
     
         11 . The composition of  claim 10 , wherein the 5-HT 2A  receptor agonist is selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), and (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az) 
     
     
         12 . The composition of  claim 10 , wherein the 5-HT 2A  receptor agonist is (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI). 
     
     
         13 . The composition of  claim 12 , wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 1 nM. 
     
     
         14 . The composition of  claim 12 , wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 50 pM. 
     
     
         15 . The composition of  claim 12 , wherein the ((R)-DOI) is in an amount no greater than that required to result in a body fluid concentration no greater than 20 pM. 
     
     
         16 . The composition of  claim 9 , additionally comprising administering one or more compounds selected from the group consisting of DOI, (R)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ((R)-DOI), (4-Bromo-3,6 dimethoxybenzocyclobuten-1-yl) methylamine (2C-BCB), (2'S,4'S)-(+)-9,10-Didehydro-6-methylergoline-8β-(trans-2,4-dimethylazetidide)(LA-SS-Az), lysergic acid diethylamide (LSD), and known anti-inflammatory drugs.