De novo synthesis of modified saxitoxins for sodium ion channel study.
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.
Andresen
Brian M
BM
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
Du Bois
J
J
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*
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012530:Saxitoxin
J Physiol. 2007 Feb 15;579(Pt 1):1-14
17158175
Genome Biol. 2003;4(3):207
12620097
Nat Rev Neurosci. 2006 Jul;7(7):548-62
16791144
Biophys J. 2005 Jan;88(1):184-97
15475578
Biochemistry. 2000 Jul 18;39(28):8161-70
10889022
Chem Asian J. 2009 Feb 2;4(2):277-85
19040253
Biophys J. 2003 May;84(5):2999-3006
12719231
Toxicon. 2009 Mar 15;53(4):460-5
19708223
Nat Prod Rep. 2006 Apr;23(2):200-22
16572228
Pharmacol Rev. 2005 Dec;57(4):397-409
16382098
Biochem Biophys Res Commun. 1992 Apr 30;184(2):900-7
1315538
Trends Neurosci. 2001 Aug;24(8):473-8
11476887
J Biol Chem. 2007 Mar 16;282(11):8044-51
17237232
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8205-6
17488822
J Med Chem. 2001 Jan 18;44(2):115-37
11170622
Channels (Austin). 2008 Nov-Dec;2(6):407-12
19098433
Toxicon. 1995 Jun;33(6):723-37
7676464
J Mol Model. 2006 Sep;12(6):813-22
16508760
J Am Chem Soc. 2007 Aug 15;129(32):9964-75
17658800
Science. 1977 May 20;196(4292):883-5
404708
Biophys J. 2002 Aug;83(2):912-9
12124273