Linda A Rezmann-Vitti, Simon N S Louis, Tracy L Nero, Graham P Jackman, Curtis A Machida, William J Louis
Clinical Pharmacology and Therapeutics Unit, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, 3084 Victoria, Australia.
European journal of medicinal chemistry 2004 JulTo determine the role played by Tyr(356 (7.43)) in the rat beta(1)-adrenoceptor in binding the antagonists (+/-)cyanopindolol (4-[3-(t-butylamino]-3-(2'-cyano-indoloxy)-2-propanolol) and its iodinated analogue (+/-)[(125)Iodo]cyanopindolol (1-(t-butylamino]-3-(2'-cyano-3'-iodo-indoloxy)-2-propanolol), Tyr(356 (7.43)) was mutated to either Phe or Ala and binding affinities determined for wild type and mutant rat beta(1)-adrenoceptors. Our results indicate that Tyr(356 (7.43)) is important for (+/-)cyanopindolol, but not (+/-)[(125)Iodo]cyanopindolol, binding and that (+/-)cyanopindolol adopts a "reverse" binding orientation whereas (+/-)[(125)Iodo]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 beta(1)-adrenoceptor site-directed mutagenesis results are the first to support a "reverse" antagonist binding orientation and the involvement of Tyr(356 (7.43)) in this binding mode.
Linda A Rezmann-Vitti, Simon N S Louis, Tracy L Nero, Graham P Jackman, Curtis A Machida, William J Louis. Site-directed mutagenesis of the rat beta1-adrenoceptor. Involvement of Tyr356 (7.43) in (+/-)cyanopindolol but not (+/-)[125Iodo]cyanopindolol binding. European journal of medicinal chemistry. 2004 Jul;39(7):625-31
PMID: 15236843
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