Development of covalent antagonists for beta 1-and beta 2-adrenergic receptors

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Details zur Publikation

Autorinnen und Autoren: Schwalbe T, Hübner H, Gmeiner P
Zeitschrift: Bioorganic & Medicinal Chemistry
Jahr der Veröffentlichung: 2019
Band: 27
Heftnummer: 13
Seitenbereich: 2959-2971
ISSN: 0968-0896


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 beta 2-adrenergic receptor (beta 2ARH2.64C) in an active state. We herein present the stereospecific synthesis of covalently binding disulfide ligands based on the pharmacophores of adrenergic beta 1-and beta 2 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 beta 1ARI2.64C and beta 2ARH2.64C. The propranolol derivative (S)-1a induced nearly complete irreversible blockage of the beta 2ARH2.64C within 30 min incubation. The CGP20712A-based ligand (S)-4 showed efficient covalent blocking of the beta 2ARH2.64C at very low concentrations. The analog (S)-5a revealed extraordinary covalent cross-linking at the beta 1ARI2.64C and beta 2ARH2.64C mutant while retaining a 41-fold selectivity for the beta 1AR wild type over beta 2AR. These compounds may serve as valuable molecular tools for studying beta 1/beta 2 subtype selectivity or investigations on GPCR trafficking and dimerization.

FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Schwalbe, Tobias
Lehrstuhl für Pharmazeutische Chemie


Schwalbe, T., Hübner, H., & Gmeiner, P. (2019). Development of covalent antagonists for beta 1-and beta 2-adrenergic receptors. Bioorganic & Medicinal Chemistry, 27(13), 2959-2971.

Schwalbe, Tobias, Harald Hübner, and Peter Gmeiner. "Development of covalent antagonists for beta 1-and beta 2-adrenergic receptors." Bioorganic & Medicinal Chemistry 27.13 (2019): 2959-2971.


Zuletzt aktualisiert 2019-24-06 um 08:23