Discovery of small molecule antagonists of TRPV1.
Rami HK., Thompson M., Wyman P., Jerman JC., Egerton J., Brough S., Stevens AJ., Randall AD., Smart D., Gunthorpe MJ., Davis JB.
Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca(2+) based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.