Development of covalent antagonists for β1- and β2-adrenergic receptors |
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Authors: | Tobias Schwalbe Harald Huebner Peter Gmeiner |
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Institution: | Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, D-91058 Erlangen, Germany |
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Abstract: | 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 β2-adrenergic receptor (β2ARH2.64C) in an active state. We herein present the stereospecific synthesis of covalently binding disulfide ligands based on the pharmacophores of adrenergic β1- and β2 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 β1ARI2.64C and β2ARH2.64C. The propranolol derivative (S)-1a induced nearly complete irreversible blockage of the β2ARH2.64C within 30 min incubation. The CGP20712A-based ligand (S)-4 showed efficient covalent blocking of the β2ARH2.64C at very low concentrations. The analog (S)-5a revealed extraordinary covalent cross-linking at the β1ARI2.64C and β2ARH2.64C mutant while retaining a 41-fold selectivity for the β1AR wild type over β2AR. These compounds may serve as valuable molecular tools for studying β1/β2 subtype selectivity or investigations on GPCR trafficking and dimerization. |
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Keywords: | Corresponding author G protein-coupled receptor Beta blocker Covalent ligand Disulfide tethering Chemical probe |
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