title: Discovery of small molecule antagonists of TRPV1.
abstract: 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.
authors.affiliation: Neurology and GI CEDD, New Frontiers Science Park, GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, UK. harshad.rami@gsk.com
authors.forename: Harshad K
authors.initials: HK
authors.lastname: Rami
authors.forename: Mervyn
authors.initials: M
authors.lastname: Thompson
authors.forename: Paul
authors.initials: P
authors.lastname: Wyman
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Jerman
authors.forename: Julie
authors.initials: J
authors.lastname: Egerton
authors.forename: Stephen
authors.initials: S
authors.lastname: Brough
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Stevens
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Randall
authors.forename: Darren
authors.initials: D
authors.lastname: Smart
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Gunthorpe
authors.forename: John B
authors.initials: JB
authors.lastname: Davis
mesh_terms: 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
chemical_list: D000611:Aminobiphenyl Compounds; D011955:Receptors, Drug; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin; D002118:Calcium