Publicaties

Bivalent ligands are increasingly important therapeutic agents. Although the naturally occurring antibodies prevail, it is becoming more common to combine different antibody fragments or even low molecular weight compounds to generate heterobivalent ligands. Those experience markedly increased affinity (i.e avidity) and target residence time when both pharmacophores can bind simultaneously to their target sites. This is because binding of one ...

In the past decades an increasing number of studies revealed that G protein-coupled receptors (GPCRs) are capable of forming dimers or even higher-ordered oligomers, which may modulate receptor function and act as potential drug targets. In this review, we briefly summarized the design strategy of bivalent GPCR ligands and mainly focused on how to use them to study and/or detect GPCP dimerization in vitro and in vivo. Bivalent ligands show ...

Bivalent ligands bear two target-binding pharmacophores. Their simultaneous binding increases their affinity (avidity) and residence time. They become "bitopic" when the pharmacophores exert allosteric modulation of each other's affinity and/or activity.
Present simulations reveal that positive cooperativity exacerbates these phenomena whereas negative cooperativity curtails them, irrespective of whether the association- or dissociation ...

In this study, we designed and synthesized heterobivalent ligands targeting heteromers consisting of the metabotropic glutamate 5 receptor (mGluR5) and the dopamine D-2 receptor (D2R). Bivalent ligand 22a with a linker consisting of 20 atoms showed 4-fold increase in affinity for cells coexpressing D2R and mGluR5 compared to cells solely expressing D2R. Likewise, the affinity of 22a for mGluR5 increased 2-fold in the coexpressing cells. ...

The investigations of the chemical system involving tetravalent uranium associated with trivalent lanthanides (La, Ce, Nd, Sm Er, Lu) and dipicolinic acid (H(2)dpa) led to the identification of six distinct types of heterometallic coordination complexes (I-VI). These compounds, obtained at room temperature from aqueous solution, have been characterized by single crystal X-ray diffraction. They consist of tris-chelated dipicolinate uranium ...

Employing two different alkyne-modified dopamine agonists to construct bivalent compounds via click chemistry resulted in the identification of a bivalent ligand (11c) for dopamine D-2 receptor homodimer, which, compared to its parent monomeric alkyne, showed a 16-fold higher binding affinity for the dopamine D-2 receptor and a 5-fold higher potency in a cAMP assay in HEK 293T cells stably expressing D2R. Molecular modeling revealed that 11c can ...

Bivalent ligands often display high affinity/avidity for- and long residence time at their target. Thereto responsible is the synergy that emanates from the simultaneous binding of their two pharmacophores to their respective target sites. Thermodynamic cycle models permit the most complete description of the binding process and thereto corresponding differential equation- based simulations link the "microscopic" rate constants that govern the ...