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Research ArticleArticle

[125I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K+ Channel Opener: Characterization and Pharmacology of Binding

Rachel Davis-Taber, Eduardo J. Molinari, Robert J. Altenbach, Kristi L. Whiteaker, Char-Chang Shieh, Gary Rotert, Steven A. Buckner, John Malysz, Ivan Milicic, Jeffrey S. McDermott, Gary A. Gintant, Michael J. Coghlan, William A. Carroll, Victoria E. Scott and Murali Gopalakrishnan
Molecular Pharmacology July 2003, 64 (1) 143-153; DOI: https://doi.org/10.1124/mol.64.1.143
Rachel Davis-Taber
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Eduardo J. Molinari
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Robert J. Altenbach
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Kristi L. Whiteaker
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Char-Chang Shieh
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Gary Rotert
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Steven A. Buckner
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John Malysz
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Ivan Milicic
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Jeffrey S. McDermott
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Gary A. Gintant
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Michael J. Coghlan
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William A. Carroll
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Victoria E. Scott
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Murali Gopalakrishnan
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Abstract

Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihydropyridine KATP channel opener, [125I]A-312110 [(9R)-9-(4-fluoro-3-125iodophenyl)-2,3,5,9-tetrahydro-4H-pyrano[3,4-b]thieno[2,3-e]pyridin-8(7H)-one-1,1-dioxide]. Binding of [125I]A-312110 to guinea pig cardiac (KD = 5.8 nM) and urinary bladder (KD = 4.9 nM) membranes were of high affinity, saturable, and to a single set of binding sites. Displacement of [125I]A-312110 by structurally diverse potassium channel openers (KCOs) indicated a similar rank order of potency in both guinea pig cardiac and bladder membranes (Ki, heart): A-312110 (4.3 nM) > N-cyano-N′-(1,1-dimethylpropyl)-N″-3-pyridylguanidine (P1075) > (-)-N-(2-ethoxyphenyl)-N′-(1,2,3-trimethylpropyl)-2-nitroethene-1,1-diamine (Bay X 9228) > pinacidil > (-)-cromakalim > N-(4-benzoyl phenyl)-3,3,3-trifluro-2-hydroxy-2-methylpropionamine (ZD6169) > 9-(3-cyanophenyl)-3,4,6,7,9,10-hexahydro-1,8-(2H,5H)-acridinedione (ZM244085) ≫ diazoxide (16.7 μM). Displacement by KATP channel blockers, the sulfonylurea glyburide, and the cyanoguanidine N-[1-(3-chlorophenyl)cyclobutyl]-N′-cyano-N″-3-pyridinyl-guanidine (PNU-99963) were biphasic in the heart but monophasic in bladder with about a 100- to 500-fold difference in Ki values between high- and low-affinity sites. Good correlations were observed between cardiac or bladder-binding affinities of KCOs with functional activation as assessed by their respective potencies to either suppress action potential duration (APD) in Purkinje fibers or to relax electrical field-stimulated bladder contractions. Collectively, these results demonstrate that [125I]A-312110 binds with high affinity and has an improved activity profile compared with other radiolabeled KCOs. [125I]A-312110 is a useful tool for investigation of the molecular and functional properties of the KATP channel complex and for the identification, in a high throughput manner, of both novel channel blockers and openers that interact with cardiac/smooth muscle-type KATP channels.

  • Received December 27, 2002.
  • Accepted April 7, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 64 (1)
Molecular Pharmacology
Vol. 64, Issue 1
1 Jul 2003
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Research ArticleArticle

[125I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K+ Channel Opener: Characterization and Pharmacology of Binding

Rachel Davis-Taber, Eduardo J. Molinari, Robert J. Altenbach, Kristi L. Whiteaker, Char-Chang Shieh, Gary Rotert, Steven A. Buckner, John Malysz, Ivan Milicic, Jeffrey S. McDermott, Gary A. Gintant, Michael J. Coghlan, William A. Carroll, Victoria E. Scott and Murali Gopalakrishnan
Molecular Pharmacology July 1, 2003, 64 (1) 143-153; DOI: https://doi.org/10.1124/mol.64.1.143

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Research ArticleArticle

[125I]A-312110, a Novel High-Affinity 1,4-Dihydropyridine ATP-sensitive K+ Channel Opener: Characterization and Pharmacology of Binding

Rachel Davis-Taber, Eduardo J. Molinari, Robert J. Altenbach, Kristi L. Whiteaker, Char-Chang Shieh, Gary Rotert, Steven A. Buckner, John Malysz, Ivan Milicic, Jeffrey S. McDermott, Gary A. Gintant, Michael J. Coghlan, William A. Carroll, Victoria E. Scott and Murali Gopalakrishnan
Molecular Pharmacology July 1, 2003, 64 (1) 143-153; DOI: https://doi.org/10.1124/mol.64.1.143
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