title: De novo synthesis of modified saxitoxins for sodium ion channel study.
abstract: Access to novel forms of (+)-saxitoxin (STX), a potent and selective inhibitor of voltage-gated Na(+) ion channels, has been made possible through de novo synthesis. Saxitoxin is believed to lodge in the outer mouth of the channel pore, thereby stoppering ion flux. Herein, we demonstrate that modification of the C13-carbamoyl unit can be accommodated in the binding site of the protein without significantly reducing ligand-receptor affinity. These discoveries have emboldened efforts to prepare photoaffinity-labeled and other unique forms of STX as pharmacological tools for interrogating both the molecular architecture and function of Na(+) channels. A synthetic plan that makes such compounds generally available is described.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Andresen
authors.forename: J
authors.initials: J
authors.lastname: Du Bois
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D008958:Models, Molecular; D016062:Porosity; D011487:Protein Conformation; D051381:Rats; D012530:Saxitoxin / Q000138:chemical synthesis* / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012530:Saxitoxin
references.citation: J Physiol. 2007 Feb 15;579(Pt 1):1-14
references.pmid: 17158175
references.citation: Genome Biol. 2003;4(3):207
references.pmid: 12620097
references.citation: Nat Rev Neurosci. 2006 Jul;7(7):548-62
references.pmid: 16791144
references.citation: Biophys J. 2005 Jan;88(1):184-97
references.pmid: 15475578
references.citation: Biochemistry. 2000 Jul 18;39(28):8161-70
references.pmid: 10889022
references.citation: Chem Asian J. 2009 Feb 2;4(2):277-85
references.pmid: 19040253
references.citation: Biophys J. 2003 May;84(5):2999-3006
references.pmid: 12719231
references.citation: Toxicon. 2009 Mar 15;53(4):460-5
references.pmid: 19708223
references.citation: Nat Prod Rep. 2006 Apr;23(2):200-22
references.pmid: 16572228
references.citation: Pharmacol Rev. 2005 Dec;57(4):397-409
references.pmid: 16382098
references.citation: Biochem Biophys Res Commun. 1992 Apr 30;184(2):900-7
references.pmid: 1315538
references.citation: Trends Neurosci. 2001 Aug;24(8):473-8
references.pmid: 11476887
references.citation: J Biol Chem. 2007 Mar 16;282(11):8044-51
references.pmid: 17237232
references.citation: Proc Natl Acad Sci U S A. 2007 May 15;104(20):8205-6
references.pmid: 17488822
references.citation: J Med Chem. 2001 Jan 18;44(2):115-37
references.pmid: 11170622
references.citation: Channels (Austin). 2008 Nov-Dec;2(6):407-12
references.pmid: 19098433
references.citation: Toxicon. 1995 Jun;33(6):723-37
references.pmid: 7676464
references.citation: J Mol Model. 2006 Sep;12(6):813-22
references.pmid: 16508760
references.citation: J Am Chem Soc. 2007 Aug 15;129(32):9964-75
references.pmid: 17658800
references.citation: Science. 1977 May 20;196(4292):883-5
references.pmid: 404708
references.citation: Biophys J. 2002 Aug;83(2):912-9
references.pmid: 12124273