Discovery of small molecule antagonists of TRPV1.
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.
Rami
Harshad K
HK
Neurology and GI CEDD, New Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. harshad.rami@gsk.com
Thompson
Mervyn
M
Wyman
Paul
P
Jerman
Jeffrey C
JC
Egerton
Julie
J
Brough
Stephen
S
Stevens
Alexander J
AJ
Randall
Andrew D
AD
Smart
Darren
D
Gunthorpe
Martin J
MJ
Davis
John B
JB
D000611:Aminobiphenyl Compounds / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D004594:Electrophysiology; D005453:Fluorescence; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007089:Image Enhancement; D018408:Patch-Clamp Techniques; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels
D000611:Aminobiphenyl Compounds; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin; D002118:Calcium