Therapeutic compositions and methods relating to prolactin releasing peptide (PrRP)

Abstract

The invention provides a substantially pure Prolactin Releasing Peptide (PrRP) functional analog which suppresses absence seizures in a mammal, and related pharmaceutical compositions. The invention also provides a method of controlling absence seizures in a mammal, by administering to a mammal susceptible to absence seizures an effective amount of PrRP or a PrRP functional analog. Also provided are methods of identifying a compound that modulates AMPA receptor signaling in a mammal, by providing a compound that is a PrRP or PrRP functional analog, and determining the ability of the compound to modulate AMPA receptor signaling. The invention also provides methods of identifying a compound for controlling absence seizures in a mammal, by providing a compound that is a PrRP or PrRP functional analog, and determining the ability of the compound to control absence seizures in a mammal. Also provided are pharmaceutical compositions for controlling absence seizures in a mamma. The compositions and related methods contain a compound identified by the methods of the invention as a compound that modulates AMPA receptor signaling or as a compound that controls absence seizures.

What is claimed is:  
     
         1 . A substantially pure Prolactin Releasing Peptide (PrRP) functional analog, which suppresses absence seizures in a mammal.  
     
     
         2 . The PrRP functional analog of  claim 1 , which is a peptidomimetic of a peptide comprising the amino acid sequence set forth as SEQ ID NO: 23.  
     
     
         3 . A pharmaceutical composition, comprising the PrRP functional analog of  claim 1  and a pharmaceutically acceptable medium.  
     
     
         4 . The pharmaceutical composition of  claim 3 , further comprising a second compound which suppresses absence seizures.  
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein said second compound is selected from the group consisting of valproate, ethosuximade, flunarizine, trimethadione and lamotrigine.  
     
     
         6 . A pharmaceutical composition, comprising PrRP and a second compound which suppresses absence seizures.  
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said second compound is selected from the group consisting of valproate, ethosuximade, flunarizine, trimethadione and lamotrigine.  
     
     
         8 . A method of controlling absence seizures in a mammal, comprising administering to a mammal susceptible to absence seizures an effective amount of PrRP or a PrRP functional analog.  
     
     
         9 . The method of  claim 8 , wherein said PrRP comprises the amino acid sequence set forth as SEQ ID NO: 23.  
     
     
         10 . The method of  claim 8 , wherein said PrRP comprises the amino acid sequence set forth as SEQ ID NO: 18.  
     
     
         11 . The method of  claim 8 , wherein said PrRP comprises the amino acid sequence set forth as SEQ ID NO: 15.  
     
     
         12 . The method of  claim 8 , wherein said PrRP functional analog is a peptidomimetic of a peptide comprising the amino acid sequence set forth as SEQ ID NO: 23.  
     
     
         13 . The method of  claim 8 , further comprising administering to said mammal a second compound which suppresses absence seizures.  
     
     
         14 . The method of  claim 13 , wherein said second compound is selected from the group consisting of valproate, ethosuximade, flunarizine, trimethadione and lamotrigine.  
     
     
         15 . A method of identifying a compound that modulates AMPA receptor signaling in a mammal, comprising: 
 (a) providing a compound that is a PrRP or PrRP functional analog;    (b) determining the ability of said compound to modulate AMPA receptor signaling.    
     
     
         16 . The method of  claim 15 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes a predetermined signal, identifying a compound that promotes production of said predetermined signal, and providing said compound.  
     
     
         17 . The method of  claim 16 , wherein said predetermined signal is selected from the group consisting of calcium ion mobilization and arachadonic acid metabolite release.  
     
     
         18 . The method of  claim 16 , wherein said PrRP receptor is GPR10.  
     
     
         19 . The method of  claim 16 , wherein said one or more candidate compounds comprises greater than about 100 compounds.  
     
     
         20 . The method of  claim 15 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP binds said PrRP receptor, identifying a compound that binds said PrRP receptor, and providing said compound.  
     
     
         21 . The method of  claim 20 , wherein said PrRP receptor is GPR10.  
     
     
         22 . The method of  claim 20 , wherein said one or more candidate compounds comprises greater than about 100 compounds.  
     
     
         23 . The method of  claim 15 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes interaction of PrRP receptor with an AMPA receptor associated protein, identifying a compound that promotes said interaction, and providing said compound.  
     
     
         24 . The method of  claim 23 , wherein said AMPA receptor associated protein is selected from the group consisting of GRIP, GRIP2 and PICK1.  
     
     
         25 . The method of  claim 15 , wherein step (b) comprises contacting a thalamic preparation with said compound, and determining AMPA receptor mediated oscillatory activity in said preparation.  
     
     
         26 . The method of  claim 15 , wherein step (b) comprises contacting a cell with said compound, and determining AMPA receptor mediated currents in said cell.  
     
     
         27 . The method of  claim 15 , wherein step (b) comprises contacting a cell with said compound, and determining AMPA receptor mediated ion influx into said cell.  
     
     
         28 . The method of  claim 27 , wherein said ion influx is determined using an automated fluorometric assay.  
     
     
         29 . A pharmaceutical composition for controlling absence seizures in a mammal, comprising a compound identified by the method of  claim 15  as a compound that suppresses AMPA receptor signaling, and a pharmaceutically acceptable medium.  
     
     
         30 . A method of controlling absence seizures in a mammal, comprising administering to a mammal susceptible to absence seizures an effective amount of the pharmaceutical composition of  claim 29 .  
     
     
         31 . A method of identifying a compound for controlling absence seizures in a mammal, comprising: 
 (a) providing a compound that is a PrRP or PrRP functional analog;    (b) determining the ability of said compound to control absence seizures in a mammal.    
     
     
         32 . The method of  claim 31 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes a predetermined signal, identifying a compound that promotes production of said predetermined signal, and providing said compound.  
     
     
         33 . The method of  claim 32 , wherein said predetermined signal is selected from the group consisting of calcium ion mobilization and arachadonic acid metabolite release.  
     
     
         34 . The method of  claim 32 , wherein said PrRP receptor is GPR10.  
     
     
         35 . The method of  claim 32 , wherein said one or more candidate compounds comprises greater than about 100 compounds.  
     
     
         36 . The method of  claim 31 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP binds said PrRP receptor, identifying a compound that binds said PrRP receptor, and providing said compound.  
     
     
         37 . The method of  claim 36 , wherein said PrRP receptor is GPR10.  
     
     
         38 . The method of  claim 36 , wherein said one or more candidate compounds comprises greater than about 100 compounds.  
     
     
         39 . The method of  claim 31 , wherein step (a) comprises contacting a PrRP receptor with one or more candidate compounds under conditions wherein PrRP promotes interaction of PrRP receptor with an AMPA receptor associated protein, identifying a compound that promotes said interaction, and providing said compound.  
     
     
         40 . The method of  claim 39 , wherein said AMPA receptor associated protein is selected from the group consisting of GRIP, GRIP2 and PICK1.  
     
     
         41 . The method of  claim 31 , wherein step (b) comprises administering said compound to a mammal susceptible to absence seizures, and determining seizure activity in said mammal.  
     
     
         42 . The method of  claim 41 , wherein said compound is administered to a mammal selected from the group consisting of a human, a non-human primate, a rat and a mouse.  
     
     
         43 . A pharmaceutical composition for controlling absence seizures in a mammal, comprising a compound identified by the method of  claim 31  as a compound that controls absence seizures, and a pharmaceutically acceptable medium.  
     
     
         44 . A method of controlling absence seizures in a mammal, comprising administering to a mammal susceptible to absence seizures an effective amount of the pharmaceutical composition of  claim 43.