Methods and compositions for regulating imidazoline receptors

Abstract

The present invention relates to methods and compositions for regulating the activity of imidazoline receptors. In particular, the invention relates to pharmaceutical compositions comprising imidazoleacetic acid-ribotide (IAA-RP), imidazoleacetic acid-riboside (IAA-R) and its related congeners such as pros-linked ribotide and riboside. The invention is based on the discovery that IAA-RP and to a lesser extent IAA-P bind with a high affinity to imidazoline receptors. Antibodies to IAA-RP, IAA-R are additionally provided, as well as screening methods for identification of compounds that either promote or antagonize the activity of IAA-RP, IAA-R and its related congeners. The invention further relates to diagnostic and prognostic methods for detection of abnormalities in levels or activity of IAA-RP and IAA-R. The invention encompasses treatment of disorders related to the imidazoline system, including hypertension, glaucoma, psychiatric (e.g., depression), neurological (e.g., motor disorders, neurodegenerative disorders), diabetes and disorders related to platelet aggregation.

1 . A composition comprising imidazoleacetic acid-ribotide (IAA-RP) and a pharmaceutically acceptable carrier.  
     
     
         2 . A composition comprising imidazoleacetic acid-riboside (IAA-R) and a pharmaceutically acceptable carrier.  
     
     
         3 . A composition comprising one or mor congeners of imidazoleacetic acid-ribotide or imidazoleacetic acid-riboside and a pharmaceutically acceptable carrier.  
     
     
         4 . (Cancelled)  
     
     
         5 . (Cancelled)  
     
     
         6 . (Cancelled)  
     
     
         7 . An antibody which is capable of binding to an imidazoleacetic acid-ribotide or an imidazoleacetic acid-riboside.  
     
     
         8 . A method of diagnosing a disease or disorder characterized by an aberrant level of imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide in a subject, comprising measuring the level of imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide in a sample derived from the subject, in which an increase or decrease in the level of imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide, relative to the level of imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide found in an analogous sample derived from a subject not having the disease indicates the presence of the disease or disorder.  
     
     
         9 . The method of  claim 8  wherein the disease or disorder is hypertension.  
     
     
         10 . The method of  claim 8  wherein the disease or disorder is a psychiatric or neurological disorder.  
     
     
         11 . The method of  claim 8  wherein the disorder is a pancreatic disorder.  
     
     
         12 . A method for assaying for compounds that modulate the activity of imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide comprising: 
 (a) contacting a cell which expresses imidazoline receptors with imidazoleacetic acid-riboside or imidazoleacetic acid-ribotide in the presence of a test compound or a vehicle control; and    (b) determining whether the test compound decreases the level of imidazoline receptor activation as compared to those cells contacted with a vehicle control.    
     
     
         13 . The method of  claim 12 , wherein activation of the imidazoline receptor is assayed by measuring the level of arachidonic acid release.  
     
     
         14 . The method of  claim 12 , wherein activation of the imidazoline receptor is assayed by measuring the level of insulin secretion.  
     
     
         15 . The method of  claim 12 , wherein the activation of the imidazoline receptor is assayed by measuring the activation of K+/ATP channels.  
     
     
         16 . A method for identifying compounds that bind to an imidazoleacetic acid-ribotide or imidazoleacetic acid-riboside comprising: 
 (a) preparing a reaction mixture comprising an imidazoleacetic acid-ribotide or imidazoleacetic acid-riboside and a test compound under conditions and for time sufficient to allow the components of the mixture to interact and bind,    (b) identifying the bound test compound.