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

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 d..