Schwalbe T, Hübner H, Gmeiner P (2019)
Publication Type: Journal article
Publication year: 2019
Book Volume: 27
Pages Range: 2959-2971
Journal Issue: 13
DOI: 10.1016/j.bmc.2019.05.034
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.
APA:
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. https://dx.doi.org/10.1016/j.bmc.2019.05.034
MLA:
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.
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