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Relevant academic research and scientific papers

Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

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.

USE OF NATURAL PRODUCTS AND RELATED SYNTHETIC COMPOUNDS FOR THE TREATMENT OF CARDIOVASCULAR DISEASE

Use of a compound of formula (I), wherein Ar is an aromatic ring system comprising one or more optionally substituted phenyl rings optionally linked to or fused with one or more other optionally substituted phenyl rings or one or more 5 or 6-membered, optionally substituted heterocyclic rings wherein the heteroatom is oxygen; and wherein the ring system comprises 1-4 phenyl rings and wherein Ar can be linked to another Ar via a group X wherein the Ar is independently selected; where X is optionally substituted C1-20alkylene, C1-20alkenylene or C2-20alkynylene; R is hydrogen; C1-12alkenyl , C2-20alkynyl, C2-20alkanoyl, C2-20alkynoyl, each of which can be optionally substituted; R1 is independently selected and is hydrogen; optionally substituted C1-12alkyl , C2-12alkenyl, C2-2oalkynyl; ?COOR'?NR'R', halogen, ?OR', ?COR', ?CONRR', =O , ?SR', ?SO3R'. ?SO2NR'R', ?SOR', ?SO2R', ?NO2, ?CN, glycoside, silyl; where R' is independently hydrogen; alkyl, alkenyl or alkynyl each optionally substituted; and where two groups R1 can be joined; wherein the optional substituents are one or more independently selected from C1-10alkyl, C2-10alkenyl, C2-10alkynyl; ?COOR"? NR"R", halogen, OR", ?COR", ?CONR"R", ?SR", =O , ?SO3R", ?SO2NR"R", ?SOR", ?S2", ?NO2 , ?CN: wherein R" is independently hydrogen, alkyl. alkenyl, or alkynyl; n=1, 2 or 3; m=1 , 2, 3 or 4; or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for inhibiting the action of Ca2+ -ATPase enzymes. Certain compounds of formula (I) and 8-lavandulyl flavone pharmaceutical formulations are new.