Compositions and methods for treating g protein coupled receptor mediated conditions

Abstract

The present invention relates to cells and methods for detecting compounds that affect G protein coupled receptor mediated conditions. The invention also relates to methods for treating adverse drug reactions, autoimmune disorders, and pruritus.

1 . A method for screening for drug agents that modulate one or more MrgprX4 or MrgprX3 G protein coupled receptor-mediated conditions or disorders comprising:
 contacting one or more cells expressing an MrgprX4 or MrgprX3 G protein coupled receptor with a candidate drug agent; and   detecting a response of the one or more cells to thereby select the candidate drug agent for evaluation to modulate the G protein coupled receptor-mediated condition or disorder.   
     
     
         2 . The method of  claim 1  wherein a response of the cells is detected as activation of the G protein coupled receptor. 
     
     
         3 . The method of  claim 1  further comprising determining whether the candidate drug agent modulates the G protein coupled receptor-mediated condition or disorder. 
     
     
         4 . The method of  claim 1  wherein the MrgprX4 or MrgprX3 G protein coupled receptor-mediated condition is selected from adverse drug reactions, autoimmune disorders, multiple sclerosis, pain, pruritus, cholestatic pruritus, inflammation disorders, malignant transformations, skin disorders, and wound healing. 
     
     
         5 . The method of  claim 1  wherein the one or more cells are selected from immune cells, nerve cells, and skin cells. 
     
     
         6 - 8 . (canceled) 
     
     
         9 . The method of  claim 1  wherein:
 the detected response of the one or more cells is an increase in intracellular calcium; or 
 (ii) the detected response of the one or more cells is detected as activation of the G protein coupled receptor, wherein the activation is assessed by inositol phosphate detection. 
 
     
     
         10 . (canceled) 
     
     
         11 . A method of treating a G protein coupled receptor-mediated condition in a subject, the method comprising:
 administering an effective amount of an MrgprX3 antagonist and/or MrgprA6 antagonist to the subject, thereby treating the G protein coupled receptor-mediated condition.   
     
     
         12 . The method of  claim 11  wherein the G protein coupled receptor-mediated condition is selected from pain, pruritus, cholestatic pruritus, an inflammation disorder, a malignant transformation, a skin disorder, and/or wound healing. 
     
     
         13 . The method of  claim 11  wherein the antagonist comprises:
 (i) an antibody or fragment thereof, a binding protein, a polypeptide, or any combination thereof; or 
 (ii) a small molecule or a nucleic acid molecule. 
 
     
     
         14 - 26 . (canceled) 
     
     
         27 . A method for reducing the severity of an adverse drug reaction in a subject that is induced by administering a compound, the method comprising:
 administering the compound to a subject;   administering an MrgprA1 antagonist and/or MrgprX4 antagonist to the subject, thereby reducing the severity of an adverse drug reaction in the subject.   
     
     
         28 - 30 . (canceled) 
     
     
         31 . A pharmaceutical composition for the treatment of a G protein coupled receptor-mediated condition or disorder, the composition comprising an effective amount a MrpgrX4 or MrpgrX3 antagonist. 
     
     
         32 - 36 . (canceled) 
     
     
         37 . A kit comprising 1) a pharmaceutical composition of  claim 31  and 2) written instructions for treating the G protein coupled receptor condition or disorder, wherein the G protein coupled receptor condition or disorder is selected from adverse drug reactions, autoimmune disorders, multiple sclerosis, pain, pruritus, cholestatic pruritus, inflammation disorders, malignant transformations, skin disorders, and/or wound healing. 
     
     
         38 - 79 . (canceled)