- Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias
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Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gαs, while they only show weak or even no β-arrestin-2 recruitment at both β1- and β2-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the β2-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser5.46 and Asn6.55, and the aromatic head group of the ligands.
- Stanek, Markus,Picard, Louis-Philippe,Schmidt, Maximilian F.,Kaindl, Jonas M.,Hübner, Harald,Bouvier, Michel,Weikert, Dorothée,Gmeiner, Peter
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p. 5111 - 5131
(2019/05/28)
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- Design, synthesis, and pharmacological effects of structurally simple ligands for MT1 and MT2 melatonin receptors
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A series of phenoxyalkyl and phenylthioalkyl amides were prepared as melatoninergic ligands. Modulation of affinity of the newly synthesized compound by applying SARs around the terminal amide moiety, the alkyl chain, and the methoxy group on the aromatic ring provides compounds with nanomolar affinity for both melatonin receptor subtypes. Affinity towards MT1 and MT2 receptors were modulated also exploiting chirality. The investigation of intrinsic activity revealed that all the tested compounds behave as full or partial agonists.
- Carocci, Alessia,Catalano, Alessia,Lovece, Angelo,Lentini, Giovanni,Duranti, Andrea,Lucini, Valeria,Pannacci, Marilou,Scaglione, Francesco,Franchini, Carlo
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experimental part
p. 6496 - 6511
(2010/10/02)
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- METHOD FOR PREPARING 2-ALKOXYPHENOXYETHANAMINES FROM 2-ALKOXYPHENOXYETHYLACETAMIDES
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The present invention relates to a method for preparing 2-Alkoxyphenoxyethanamines and more particularly relates to the preparation of the new chemical entity 2-Alkoxyphenoxyethylacetamides, in particular as intermediates in said method. An industrial process for the synthesis of 2-Alkoxyphenoxyethanamines which is cheap and easy to perform, is a long felt need for those skilled in the art. The object of the present invention is therefore to provide a process for the industrial production of phenoxyethanamine which is cheap and easy to perform. This object is solved by the new chemical entity 2-Alkoxyphenoxyacetamide which is prepared by reacting an ortho substituted phenol with a 2-Alkyloxazoline. By hydrolysis of the acetamide with water in the presence of organic or mineral acids such as hydrochloric acid and/or sulfuric acid, the 2-Alkylphenoxyethanamine is obtained.
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Page/Page column 5
(2008/06/13)
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