Template associated NPY Y2-receptor agonists

Abstract

The present invention is directed to agonists of neuropeptide Y (NPY) or PYY that are formed by combining these peptides or a portion of these peptides with a template that promotes biologically active folds. Typically, templates consist of cyclized peptides containing one or more naphthyl ring structures. The agonists may be used in the treatment of diseases and conditions known to be responsive to NPY or PYY and, particularly in the treatment of asthma, rhinitis, and bronchitis.

What is claimed is:  
     
         1 . An agonist of neuropeptide Y (NPY) comprising: 
 (a) a template comprising a cyclized peptide 3 to 10 amino acids in length, wherein at least two residues in said cyclized peptide are joined by a naphthyl ring; and    (b) at least one linear peptide between 12 and 37 amino acids in length covalently bound to said template, wherein said linear peptide has a C-terminal sequence selected from the group consisting of: RHYTNLITRQRY, (SEQ ID NO:3); and RHYLNLVTRQRY (SEQ ID NO:4); and wherein the C-terminal tyrosine of said linear peptide is amidated.    
     
     
         2 . The agonist of  claim 1 , wherein said template has the structure:  
       
         
           
           
               
               
           
         
       
       and wherein said linear peptide is attached to said template at either or both of the lysine residues.  
     
     
         3 . The agonist of  claim 2 , wherein said C-terminal sequence of said linear peptide is preceded at the N terminal end by between 1 and 24 residues of amino acids 1-24 of NPY, said sequence being: YPSKPDNPGEDAPAEDMARYYSAL, (SEQ ID NO:5).  
     
     
         4 . The agonist of  claim 3 , wherein said linear peptide has the sequence: YSALRHYINLITRQRY, (SEQ ID NO:6).  
     
     
         5 . The agonist of  claim 3 , wherein said linear peptide further comprises an aminooxy acetylated glycine at its N terminus.  
     
     
         6 . The agonist of  claim 3 , wherein said linear peptide is bound to said template by an oxime bond.  
     
     
         7 . The agonist of  claim 6 , wherein said agonist is TASP-V.  
     
     
         8 . The agonist of  claim 2 , wherein said C-terminal sequence of said linear peptide is preceded at the N terminal end by between 1 and 24 residues of amino acids 1-24 of PYY, said sequence being: YPIKPEAPGEDASPEELNRYYASL (SEQ ID NO:7).  
     
     
         9 . The agonist of  claim 8 , wherein said linear peptide has the sequence: YASLRHYLNLVTRQRY (SEQ ID NO:8).  
     
     
         10 . The agonist of  claim 9 , wherein said linear peptide further comprises an aminooxy acetylated glycine at its N terminus.  
     
     
         11 . The agonist of  claim 9 , wherein said linear peptide is bound to said template by an oxime bond.  
     
     
         12 . The agonist of  claim 6 , wherein said agonist is TASP-V2.  
     
     
         13 . A pharmaceutical composition comprising the agonist of  claim 1 .  
     
     
         14 . A method of reducing airway resistance in a patient suffering from a bronchial disease or condition, comprising administering a therapeutic agent selected from the group consisting of: NPY, PYY, an agonist of NPY or an agonist of PYY.  
     
     
         15 . The method of  claim 14 , wherein said patient is administered either NPY or PYY.  
     
     
         16 . The method of  claim 14 , wherein said patient is administered either: 
 a) an agonist that is a peptide comprising the sequence of amino acids 25-36 of NPY; or    b) an agonist that is a peptide comprising the sequence of amino acids 25-36 of PYY.    
     
     
         17 . The method of  claim 16 , wherein said agonist is either TASP-V or TASP-V2.  
     
     
         18 . The method of  claim 14 , wherein said therapeutic agent is in a pharmaceutical composition administered by inhalation and said therapeutic agent is administered at a dose of between 1 and 100 μg.  
     
     
         19 . The method of  claim 14 , wherein said bronchial disease or condition is asthma.  
     
     
         20 . The method of  claim 14 , wherein said bronchial disease or condition is bronchitis.  
     
     
         21 . In a method for treating a disease or condition that is responsive to NPY or PYY, the improvement comprising administering the agonist of  claim 1  at a unit dose of between 1 and 100 μg.  
     
     
         22 . The improvement of  claim 21 , wherein said agonist comprises the template:  
       
         
           
           
               
               
           
         
       
       and wherein the peptide bound to said template: 
 a) comprises a sequence selected from the group consisting of: amino acids 25-36 of NPY (SEQ ID NO:3); and amino acids 25-36 of PYY (SEQ ID NO:4);  
 b) further comprises 0-24 residues a sequence selected from the group consisting of:  
 amino acids 1-24 of NPY (SEQ ID NO:5); and amino acids 1-24 of PYY (SEQ ID NO:7).  
 
     
     
         23 . The improvement of  claim 22 , wherein said agonist is either TASP-V or TASP-V2.  
     
     
         24 . The improvement of  claim 21 , wherein said disease or condition is selected from the group consisting of: laryngitis, chronic rhinosinusitis, oedema, inflammation, anxiety, congestive heart failure, cardiomyopathy, coronary artery disease, diminished cardiac vagal activity, hypertension, Alzheimer's Disease, epilepsy, ischemia, angina, myocardial infarction, AIDS and diseases characterized by a decreased immune responsiveness.  
     
     
         25 . The improvement of  claim 21 , wherein said agonist is administered to increase body weight or as an antihistamine.