title: Investigation of the structure activity relationship of flufenamic acid derivatives at the human TRESK channel K2P18.1.
abstract: TRESK (Twik RElated Spinal cord K+channel) is a member of the Twin Pore Domain potassium channel (K2P) family responsible for regulating neuronal excitability in dorsal root ganglion (DRG) and trigeminal (TG) neurons, peripheral neurons involved in pain transmission. As channel opening causes an outward K+current responsible for cell hyperpolarisation, TRESK represents a potentially interesting target for pain treatment. However, as no crystal structure exists for this protein, the mechanisms involved in the opening action of its ligands are still poorly understood, making the development of new potent and selective openers challenging. In this work we present a structure activity relationship (SAR) of the known TRESK opener flufenamic acid (FFA) and some derivatives, investigating the functional effects of chemical modifications to build a TRESK homology model to support the biological results. A plausible binding mode is proposed, providing the first predictive hypothesis of a human TRESK opener binding site.
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Aymeric
authors.initials: A
authors.lastname: Monteillier
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Loucif
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Omoto
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stevens
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Sergio
authors.initials: S
authors.lastname: Lainez
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Pierre-Philippe
authors.initials: PP
authors.lastname: Saintot
authors.affiliation: Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK.
authors.forename: Lishuang
authors.initials: L
authors.lastname: Cao
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer Neuroscience and Pain Research Unit, Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, UK. Electronic address: david@curadev.co.uk.
authors.forename: David C
authors.initials: DC
authors.lastname: Pryde
mesh_terms: D000818:Animals; D001665:Binding Sites; D005439:Flufenamic Acid / Q000737:chemistry* / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects; D015221:Potassium Channels / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C476574:KCNK18 protein, human; D015221:Potassium Channels; D005439:Flufenamic Acid
keywords: Channel; Fenamate; Opener; TRESK