Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias
摘要:
Starting from the beta-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 Gas, while they only show weak or even no beta-arrestin-2 recruitment at both beta(1)- and beta(2)-AR Molecular dynamics simulations suggest that the difference in G protein efficacy and beta-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the beta(2)-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser(5.46) and Asn(6.55), and the aromatic head group of the ligands.
[EN] METHOD FOR PREPARING 2-ALKOXYPHENOXYETHANAMINES FROM 2-ALKOXYPHENOXYETHYLACETAMIDES [FR] PROCEDE DE PREPARATION DE 2-ALKOXYPHENOXYETHANAMINES A PARTIR DE 2-ALKOXYPHENOXYETHYLACETAMIDES
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. (C) 2010 Elsevier Ltd. All rights reserved.
METHOD FOR PREPARING 2-ALKOXYPHENOXYETHANAMINES FROM 2-ALKOXYPHENOXYETHYLACETAMIDES
申请人:MCM PHARMA GMBH
公开号:EP1506156A1
公开(公告)日:2005-02-16
PROCESS FOR THE PREPARATION OF CARVEDILOL AND ITS ENANTIOMERS
申请人:Trepat Guixer Elisenda
公开号:US20090005429A1
公开(公告)日:2009-01-01
The present invention relates to a process for the preparation of carvedilol as well as of the optically active R and S enantiomers thereof and of mixtures of these enantiomers and, more particularly, relates to an improved process for the preparation of carvedilol and its enantiomers characterized by the use of ethyl acetate as reaction solvent.