86955-49-9Relevant articles and documents
Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands
Gaiser, Birgit I.,Danielsen, Mia,Marcher-R?rsted, Emil,R?pke J?rgensen, Kira,Wróbel, Tomasz M.,Frykman, Mikael,Johansson, Henrik,Br?uner-Osborne, Hans,Gloriam, David E.,Mathiesen, Jesper Mosolff,Sejer Pedersen, Daniel
, p. 7806 - 7839 (2019/09/07)
Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.
Calcium ionophores as cardiac stimulants. I. Diacids derived from dibenzo crown ethers
Ball,Cooper,Main
, p. 137 - 143 (2007/10/02)
A series of calcium chelating agents has been prepared based on carboxylic derivatives of open chain 18-Crown-6 analogues. Most of these are efficient calcium binding agents, many form lipophilic calcium complexes, and some of these are capable of releasing Ca2+ from liposomes by ionophore action. The best of these is 1,2-bis-[2-(1-carboxydecyloxy)phenoxy]ethane. This compound is cardiotonic in vitro but in the dog vasoconstriction it is the predominant biological effect.
β1-Selective Adrenoceptor Antagonists. 1. Synthesis and β-Adrenergic Blocking Activity of a Series of Binary (Aryloxy)propanolamines
Kierstead, R. W.,Faraone, A.,Mennona, F.,Mullin, J.,Guthrie, R. W.,et al.
, p. 1561 - 1569 (2007/10/02)
A series of binary (aryloxy)propanolamines has been prepared and examined in vitro and in vivo for β-adrenoreceptor blocking activity.These symmetrical compounds consist of two (S)-(phenyloxy)propanolamine pharmacophores coupled through alkylenedioxy or poly(oxyethylenedioxy) linking units of varying lengths.Examples of such binary compounds linked through the 2,2', 3,3', and 4,4' positions in the aromatic rings of the pharmacophores have been prepared.In vitro and in vivo test data indicate that the 2,2' compounds tend to be selective β2-adrenergic blocking agents, the 4,4' binaries tend to be selective β1-blocking agents, and those compounds with 3,3' linkages exhibit intermediate selectivities.One of the 4,4'-linked binary compounds, 4s, exhibited potent, cardioselective β-blockade in vivo, which was of short duration and was accompanied by a prolonged tachycardia.
