title: A golden approach to ion channel inhibition.
abstract: Drugs are often used in combination and, for pharmacologists, the manner of their interactions can cast light on drug mechanisms and biological processes. Here we provide simplified descriptions of commonly used analytical methods for analysing drug combinations and describe a new and practical experimental solution to address the mechanistic question: 'Do two channel-blocking drugs bind at the same site?' We define two simple mathematical models that describe the effects of two channel blockers acting simultaneously at either the same (Syntopic Model) or different (Allotopic Model) binding sites within a channel pore. We find that the optimum concentrations of two drugs for distinguishing between the two models are related to the mathematical Golden Ratio.
authors: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. Electronic address: gej1000@cam.ac.uk.
authors: Gavin E
authors: GE
authors: Jarvis
authors: Andrew J
authors: AJ
authors: Thompson
mesh_terms: D001665:Binding Sites; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008956:Models, Chemical; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism; D012702:Serotonin Antagonists / Q000737:chemistry / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C078730:serotonin 5 receptor
keywords: 5-HT(3)A receptors; Allotopic Model; Syntopic Model; channel blocking; synergism
references: Pharmacol Rev. 2003 Dec;55(4):597-606
references: 14657418
references: Science. 2010 Jan 8;327(5962):177-80
references: 20056884
references: Toxicol In Vitro. 2007 Aug;21(5):759-69
references: 17420112
references: J Gen Physiol. 1968 Feb;51(2):199-219
references: 5641635
references: Biometrics. 2010 Dec;66(4):1275-83
references: 20337630
references: J Physiol. 1980 Mar;300:89-103
references: 6247488
references: Br J Pharmacol Chemother. 1947 Sep;2(3):189-206
references: 20258355
references: Cancer Res. 2010 Jan 15;70(2):440-6
references: 20068163
references: Pharmacol Rev. 1995 Jun;47(2):331-85
references: 7568331
references: Am J Physiol Endocrinol Metab. 2013 Feb 1;304(3):E237-53
references: 23211518
references: Mol Pharmacol. 2011 Jul;80(1):183-90
references: 21505038
references: J Physiol. 1909 Dec 23;39(5):361-73
references: 16992989
references: Br J Pharmacol. 1998 Nov;125(5):924-47
references: 9846630
references: J Natl Cancer Inst. 1996 Jun 5;88(11):699-700
references: 8637018
references: J Membr Biol. 1979 Aug;48(4):357-64
references: 490630
references: PLoS Comput Biol. 2012;8(2):e1002389
references: 22359496
references: Bull Math Biol. 2008 Apr;70(3):643-53
references: 17994268
references: Proc Natl Acad Sci U S A. 2012 Oct 30;109(44):18102-7
references: 23077250
references: Ann Oncol. 2012 Aug;23(8):2161-2166
references: 22314859
references: Trends Pharmacol Sci. 1993 Apr;14(4):110-2
references: 8516953
references: Adv Enzyme Regul. 1984;22:27-55
references: 6382953
references: Pharmacol Ther. 2005 Apr;106(1):1-18
references: 15781119
references: Trends Pharmacol Sci. 2006 Mar;27(3):149-57
references: 16483674
references: Methods Mol Biol. 2004;259:29-46
references: 15250484
references: J Pharmacol Exp Ther. 2012 Jul;342(1):2-8
references: 22511201
references: Pharmacol Rev. 2002 Jun;54(2):323-74
references: 12037145
references: Neuropharmacology. 2011 Feb-Mar;60(2-3):488-95
references: 21059362