Site-directed mutagenesis of the rat β1-adrenoceptor. Involvement of Tyr356 (7.43) in (+/-)cyanopindolol but not (+/-)[125Iodo]cyanopindolol binding

Linda A. Rezmann-Vitti, Simon N.S. Louis, Tracy L. Nero, Graham P. Jackman, Curtis A. Machida, William J. Louis

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


To determine the role played by Tyr356 (7.43) in the rat β1-adrenoceptor in binding the antagonists (+/-)cyanopindolol (4-[3-(t-butylamino]-3-(2′-cyano-indoloxy)-2-propanolol) and its iodinated analogue (+/-)[125Iodo]cyanopindolol (1-(t-butylamino]-3-(2′- cyano-3′-iodo-indoloxy)-2-propanolol), Tyr356 (7.43) was mutated to either Phe or Ala and binding affinities determined for wild type and mutant rat β1-adrenoceptors. Our results indicate that Tyr 356 (7.43) is important for (+/-)cyanopindolol, but not (+/-)[ 125Iodo]cyanopindolol, binding and that (+/-)cyanopindolol adopts a "reverse" binding orientation whereas (+/-)[125Iodo] cyanopindolol cannot be accommodated in this binding mode. We define a "reverse" antagonist binding mode as one where the aryloxy moiety interacts with residues on transmembrane helices 1, 2, 3 and 7. The β1-adrenoceptor site-directed mutagenesis results are the first to support a "reverse" antagonist binding orientation and the involvement of Tyr356 (7.43) in this binding mode.

Original languageEnglish (US)
Pages (from-to)625-631
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Issue number7
StatePublished - Jul 2004
Externally publishedYes


  • (+/-)-4-[3-(t-butylamino]-3-(2′-cyano-indoloxy)-2-propanolol
  • (+/-)[ Iodo]cyanopindolol
  • (+/-)[Iodo]cyanopindolol
  • (+/-)cyanopindolol
  • Molecular modelling
  • Mutagenesis
  • β-Adrenoceptor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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