The selective covalent tethering of ligands to a specific GPCR binding site has attracted considerable interest in structural biology, molecular pharmacology and drug design. We recently reported on a covalently binding noradrenaline analog (FAUC37) facilitating crystallization of the β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR<sup>H2.64C</sup>) in an active state. We herein present the stereospecific synthesis of covalently binding disulfide ligands based on the pharmacophores of adrenergic β<sub>1</sub>- and β<sub>2</sub> receptor antagonists. Radioligand depletion experiments revealed that the disulfide-functionalized ligands were able to rapidly form a covalent bond with a specific cysteine residue of the receptor mutants β<sub>1</sub>AR<sup>I2.64C</sup> and β<sub>2</sub>AR<sup>H2.64C</sup>. The propranolol derivative (S)-1a induced nearly complete irreversible blockage of the β<sub>2</sub>AR<sup>H2.64C</sup> within 30 min incubation. The CGP20712A-based ligand (S)-4 showed efficient covalent blocking of the β<sub>2</sub>AR<sup>H2.64C</sup> at very low concentrations. The analog (S)-5a revealed extraordinary covalent cross-linking at the β<sub>1</sub>AR<sup>I2.64C</sup> and β<sub>2</sub>AR<sup>H2.64C</sup> mutant while retaining a 41-fold selectivity for the β<sub>1</sub>AR wild type over β<sub>2</sub>AR. These compounds may serve as valuable molecular tools for studying β<sub>1</sub>/β<sub>2</sub> subtype selectivity or investigations on GPCR trafficking and dimerization.