title: Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist.
abstract: Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.
authors.affiliation: Neurology and GI-CEDD, New Frontiers Science Park, GlaxoSmithKline, Harlow, Essex, CM19 5AW, UK. martin_j_gunthorpe@gsk.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Gunthorpe
authors.forename: H K
authors.initials: HK
authors.lastname: Rami
authors.forename: J C
authors.initials: JC
authors.lastname: Jerman
authors.forename: D
authors.initials: D
authors.lastname: Smart
authors.forename: C H
authors.initials: CH
authors.lastname: Gill
authors.forename: E M
authors.initials: EM
authors.lastname: Soffin
authors.forename: S
authors.initials: S
authors.lastname: Luis Hannan
authors.forename: S C
authors.initials: SC
authors.lastname: Lappin
authors.forename: J
authors.initials: J
authors.lastname: Egerton
authors.forename: G D
authors.initials: GD
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Worby
authors.forename: L
authors.initials: L
authors.lastname: Howett
authors.forename: D
authors.initials: D
authors.lastname: Owen
authors.forename: S
authors.initials: S
authors.lastname: Nasir
authors.forename: C H
authors.initials: CH
authors.lastname: Davies
authors.forename: M
authors.initials: M
authors.lastname: Thompson
authors.forename: P A
authors.initials: PA
authors.lastname: Wyman
authors.forename: A D
authors.initials: AD
authors.lastname: Randall
authors.forename: J B
authors.initials: JB
authors.lastname: Davis
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000143:Acids / Q000494:pharmacology; D000813:Anilides / Q000737:chemistry / Q000494:pharmacology*; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002460:Cell Line; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D008564:Membrane Potentials / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D009479:Neuropeptides / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D000068797:Orexins; D018408:Patch-Clamp Techniques / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014966:Xanthenes / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000143:Acids; D000813:Anilides; D000814:Aniline Compounds; D002352:Carrier Proteins; D002934:Cinnamates; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D009479:Neuropeptides; D000068797:Orexins; D011955:Receptors, Drug; D017366:Serotonin Receptor Agonists; D014966:Xanthenes; C059715:Fluo-3; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium; D009638:Norepinephrine