87117-71-3Relevant academic research and scientific papers
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.
The Complexation of the Diquat Dication by Dibenzo-3n-crown-n Ethers
Colquhoun, Howard M.,Goodings, Eric P.,Maud, John M.,Stoddart, J. Fraser,Wolstenholme, John B.,Williams, David J.
, p. 607 - 624 (2007/10/02)
Spectrophotometric investigations of equimolar mixtures of diquat bis(hexafluorophosphate) (2) and a range of dibenzo-3n-crown-n ethers in acetonitrile reveal the existence of charge-transfer absorption bands at ca. λmax 400 nm.These absorptions are attributable to intermolecular ?-? charge transfer between the electron-rich catechol units of the dibenzo-crown ethers and the electron-deficient bipyridinium ring system of the diquat dication.The qualitative conclusion from these experiments, that the most stable 1:1 complex is formed between dibenzo-30-crown-10 (14) and diquat bis(hexafluorophosphate) (2), led to the isolation from dichloromethane methanol-n-heptane of red crystals of 2 suitable for X-ray crystallography.Although the crystal structure analysis revealed that there are two independent sets of 1:1 complexes (I and II) in the unit cell, the gross structural features of the two complexes are very similar.In addition to the paralell alignment of their three aromatic rings to accommodate the stabilising intermolecular ?-? charge-transfer interaction, there is probably some further host-guest stabilisation to be gained on account of favourable electrostatic interactions between the phenolic oxygen atoms in the host and the nitrogen atoms in the pyridinium rings of the guest.Moreover, there is some evidence for weak C-H...O hydrogen bonding involving principally H-6 and H-6' on the bipyridinium ring system of the guest and certain -CH2OCH2- oxygen atoms in the host.As evidenced by 1H n.m.r. spectroscopy in CD3COCD3, these non-covalent bonding interactions are probably responsible for the formation of stable and ordered 1:1 complexes with similar gross structural features in solution, at least in the cases where dibenzo-30-crown-10 (14), dibenzo-33-crown-11 (15), and dibenzo-36-crown-12 (16) are the hosts.Further evidence for the 1:1 stoicheiometry of these solution complexes, as well as for the complex involving dibenzo-27-crown-9 (13), has come from equilibrium constant measurements for the association between the dibenzo-3n-crown-n (n = 9-12) hosts (13)-(16) and diquat bis(hexafluorophosphate) (2) in acetone.A quantitative treatment of the charge-transfer absorption bands at 400 nm, which affords Ka values of 410, 17500, 10800, and 2000 M-1 for n = 9, 10, 11, and 12, respectively, provides convincing quantitative evidence for (a) 1:1 stoicheiometry and (b) the relative stabilities of the 1:1 complexes in solution.In the case of dibenzo-24-crown-8 (11), a complex of 2:1 (guest-host) stoicheiometry is believed to be formed in acetone with a Ka value of 385000 M-2, as shown by a successfull quantitative treatment of the charge-transfer absorption data by an independent method.
Neutral Ligands with Surfactant-Type Structure - Synthesis, Complexation, and Ion Transfer
Weber, Edwin
, p. 770 - 801 (2007/10/02)
New lipophilic neutral ligands which combine crown ether and podand characteristics with structural features of surfactants (cf. formulas 1-12, 16-26) were synthesized.Their complexation behaviour was studied, their solid-to-liquid and liquid-to-liquid phase transfer properties as well as their efficiency in ion transport across a liquid model membrane.Crystalline stoichiometric complexes of the cycles 2a-4a and of 3e with NaSCN, Ba(SCN)2, and BaI2 can be isolated.Among the noncyclic representatives a crystalline complex is obtained only from 11 with BaI2.The ligand 8d behaves in aqueous solution as a typical surfactant showing micelle formation and cloud point.
