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 Machida, William J. Louis

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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
Volume39
Issue number7
DOIs
StatePublished - Jul 2004

Fingerprint

Mutagenesis
Site-Directed Mutagenesis
Adrenergic Receptors
Rats
Propranolol
cyanopindolol

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Site-directed mutagenesis of the rat β1-adrenoceptor. Involvement of Tyr356 (7.43) in (+/-)cyanopindolol but not (+/-)[125Iodo]cyanopindolol binding. / Rezmann-Vitti, Linda A.; Louis, Simon N S; Nero, Tracy L.; Jackman, Graham P.; Machida, Curtis; Louis, William J.

In: European Journal of Medicinal Chemistry, Vol. 39, No. 7, 07.2004, p. 625-631.

Research output: Contribution to journalArticle

Rezmann-Vitti, Linda A. ; Louis, Simon N S ; Nero, Tracy L. ; Jackman, Graham P. ; Machida, Curtis ; Louis, William J. / Site-directed mutagenesis of the rat β1-adrenoceptor. Involvement of Tyr356 (7.43) in (+/-)cyanopindolol but not (+/-)[125Iodo]cyanopindolol binding. In: European Journal of Medicinal Chemistry. 2004 ; Vol. 39, No. 7. pp. 625-631.
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abstract = "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.",
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AU - Rezmann-Vitti, Linda A.

AU - Louis, Simon N S

AU - Nero, Tracy L.

AU - Jackman, Graham P.

AU - Machida, Curtis

AU - Louis, William J.

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AB - 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.

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