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.
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.
The present invention relates to a process for preparing dithioesters in which a dithiocarboxylic acid and/or a dithiocarboxylic salt is reacted with a vinyl compound and/or an alkyl compound which includes a leaving group, the reaction being carried out in a biphasic system in which one of the phases comprises water and the weight ratio of the aqueous phase to the organic phase lies in the range from 95:5 to 5:95.
METHOD FOR PRODUCING A CARBOXYLIC ACID AMIDE FROM A CARBONYL COMPOUND AND HYDROCYANIC ACID
申请人:May Alexander
公开号:US20110306784A1
公开(公告)日:2011-12-15
The invention relates to a method for producing a carboxylic acid amide from a carbonyl compound and hydrocyanic acid, comprising the steps of A) reacting a carbonyl compound with hydrocyanic acid to produce a hydroxycarboxylic acid nitrile, B) hydrolysis of the hydroxycarboxylic acid nitrile obtained in step A) in the presence of a catalyst comprising manganese dioxide, wherein a molar excess of carbonyl compound is used in relation to the hydrocyanic acid to react the carbonyl compound with hydrocyanic acid according to step A), and the reaction mixture obtained in step A) is not purified by distillation before the hydrolysis according to step B) is carried out. The invention furthermore relates to a method for producing alkyl(meth)acrylates from polymers, moulding compounds and moulded bodies, wherein a method for producing a carboxylic acid amide from a carbonyl compound and hydrocyanic acid is carried out in accordance with the method described above.
[EN] CH-ACIDIC METHACRYLIC ESTERS FOR THE PREPARATION OF AQUEOUS POLYMER DISPERSIONS<br/>[FR] ESTERS MÉTHACRYLIQUES CH-ACIDES POUR LA PRÉPARATION DE DISPERSIONS POLYMÈRES AQUEUSES
申请人:EVONIK OPERATIONS GMBH
公开号:WO2020016037A1
公开(公告)日:2020-01-23
The present invention relates to CH-acidic methacrylic esters and also copolymers obtainable from CH-acidic methacrylic esters. Furthermore, the present invention relates to coating compositions comprising these copolymers.
RADICAL POLYMERISATION INITIATORS FOR LIGHT-CURABLE DENTAL MATERIALS
申请人:DENTSPLY SIRONA Inc.
公开号:US20170266081A1
公开(公告)日:2017-09-21
The invention provides a light-curable dental material comprising a polymerizable compound having at least one ethylenically unsaturated bond and a hexaaryl bisimidazole as a photopolymerisation initiator.
[DE] HOCHTRANSPARENTER KUNSTSTOFF FÜR OPTISCHE MATERIALIEN<br/>[EN] HIGHLY TRANSPARENT PLASTIC FOR OPTICAL MATERIALS<br/>[FR] PLASTIQUE HAUTEMENT TRANSPARENT POUR MATERIAUX OPTIQUES
申请人:ROEHM GMBH
公开号:WO2004041775A1
公开(公告)日:2004-05-21
Die vorliegende Erfindung betrifft Mischungen, die A) Verbindungen der Formel (I) und (II), worin R1 jeweils unabhängig voneinander Wasserstoff oder einen Methylrest, R2 jeweils unabhängig voneinander einen linearen oder verzweigten, aliphatischen oder cycloaliphatischen Rest oder einen substituierten oder unsubstituierten aromatischen oder heteroaromatischen Rest und m und n jeweils unabhängig voneinander eine ganze Zahl grösser gleich 0 mit m + n > 0 bedeuten, und B) mindestens ein von den Verbindungen der Formel (I) und (II) verschiedenes, ethylenisch ungesättigtes Monomer (A) enthalten. Weiterhin betrifft die vorliegende Erfindung auch Verfahren zur Polymerisation dieser Mischungen, die auf diese Weise erhältlichen hochtransparenten Polymere sowie deren Verwendung.