Chimeric receptors and methods for identifying compounds active at metabotropic glutamate receptors and the use of such compounds in the treatment of neurological disorders and diseases

Abstract

The present invention provides chimeric receptors. The chimeric receptors comprise at least one region homologous to a region of a metabotropic glutamate receptor and at least one region homologous to a region of a calcium receptor. The invention also includes methods of preparing such chimeric receptors, and methods of using such receptors to identify and characterize compounds which modulate the activity of metabotropic glutamate receptors or calcium receptors. The invention also relates to compounds and methods for modulating metabotropic glutamate receptor activity and binding to metabotropic glutamate receptors. Modulation of metabotropic glutamate receptor activity can be used for different purposes such as treating neurological disorders and diseases, inducing an analgesic effect, cognition enhancement, and inducing a muscle-relaxant effect.

What is claimed is:  
     
         1 . A method of screening for a compound that binds to a metabotropic glutamate receptor or a calcium receptor, comprising the steps of: 
 a. preparing a nucleic acid sequence encoding a fragment of a receptor,    b. inserting said sequence into a replicable expression vector capable of expressing said fragment in a host cell,    c. transforming a host cell with the vector of (b),    d. recovering the fragment from said host cell,    e. introducing said fragment and said compound into an acceptable medium, and    f. monitoring the binding of the compound to the fragment by physically detectable means.    
     
     
         2 . The method of  claim 1 , wherein said receptor is a metabotropic glutamate receptor.  
     
     
         3 . The method of  claim 2 , wherein said fragment comprises an extracellular domain of said metabotropic glutamate receptor.  
     
     
         4 . The method of  claim 2 , wherein said fragment comprises a seven transmembrane domain of said metabotropic glutamate receptor.  
     
     
         5 . The method of  claim 2  wherein said fragment comprises a seven transmembrane domain and a cytoplasmic tail domain of a metabotropic glutamate receptor.  
     
     
         6 . The method of  claim 1  wherein said receptor is a calcium receptor.  
     
     
         7 . The method of  claim 6  wherein said fragment comprises an extracellular domain of said calcium receptor.  
     
     
         8 . The method of  claim 6  wherein said fragment comprises a seven transmembrane domain of said calcium receptor.  
     
     
         9 . The method of  claim 6  wherein said fragment comprises a seven transmembrane domain and a cytoplasmic tail domain of said calcium receptor.  
     
     
         10 . A method of screening for a compound that binds to or modulates a metabotropic glutamate receptor or a calcium receptor, comprising the steps of: 
 a. preparing a nucleic acid sequence encoding a fragment of a receptor,    b. inserting said sequence into a replicable expression vector capable of expressing said fragment in a host cell,    c. transforming a host cell with the vector of (b),    d. introducing said transformed host cell and said compound into an acceptable medium, and    e. monitoring the effect of said compound on said host cell.    
     
     
         11 . The method of  claim 10 , wherein said fragment comprises the seven transmembrane domain and cytoplasmic tail domain of a metabotropic glutamate receptor.  
     
     
         12 . The method of  claim 10 , wherein said fragment comprises the seven transmembrane domain and cytoplasmic tail domain of a calcium receptor.  
     
     
         13 . A method of screening for a compound that binds to or modulates a receptor, comprising the steps of: 
 a. preparing a nucleic acid sequence encoding a first fragment comprising a fragment of a first receptor,    b. inserting the sequence into a replicable expression vector capable of expressing said first fragment in a host cell,    c. transforming a host cell with the vector of (b),    d. recovering the first fragment from the host cell,    e. preparing a nucleic acid sequence encoding a second fragment comprising a fragment of a second receptor,    f. inserting the sequence of (e) into a replicable expression vector capable of expressing said second fragment in a host cell,    g. transforming a host cell with the vector of (f),    h. recovering the second fragment from the host cell of (g), and    i. introducing said first fragment and said second fragment and said compound into an acceptable medium, and    j. monitoring the binding and/or modulation of the compound by physically detectable means.    
     
     
         14 . The method of  claim 13 , wherein said first fragment comprises the extracellular domain of a metabotropic glutamate receptor, and said second fragment comprises the seven transmembrane domain and the cytoplasmic tail domain of a calcium receptor.  
     
     
         15 . The method of  claim 13 , wherein said first fragment comprises the extracellular domain and the seven transmembrane domain of a metabotropic glutamate receptor, and said second fragment comprises the cytoplasmic tail domain of a calcium receptor.  
     
     
         16 . The method of  claim 13  whereinsaid first fragment comprises the extracellular domain of a calcium receptor, and said second fragment comprises the seven transmembrane domain and the cytoplasmic tail domain of a metabotropic glutamate receptor.  
     
     
         17 . The method of  claim 13  wherein said first fragment comprises the extracellular domain of a calcium receptor, andsaid second fragment comprises the seven transmembrane domain of a metabotropic glutamate receptor and the cytoplasmic tail domain of a calcium receptor.