title: Novel state-dependent voltage-gated sodium channel modulators, based on marine alkaloids from Agelas sponges.
abstract: Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC₅₀ values in the lower micromolar range for the open-inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC₅₀ value of 8 μM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Hodnik
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašić
authors.forename: Lucija Peterlin
authors.initials: LP
authors.lastname: Mašič
authors.forename: Fiona
authors.initials: F
authors.lastname: Chan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Kirby
authors.forename: David J
authors.initials: DJ
authors.lastname: Madge
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D011758:Pyrroles; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C077211:clathrodin
keywords: Agelas; Clathrodin; DMF; DRG; Marine; N,N-dimethylformamide; O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate; Sodium channel modulator; TBTU; THF; VGSC; dorsal root ganglia; tetrahydrofuran; voltage-gated sodium channel