Radioligand dissociation measurements: potential interference of rebinding and allosteric mechanisms and physiological relevance of the biological model systems.

Georges Vauquelin, Isabelle Van Liefde

    Onderzoeksoutput: Articlepeer review

    23 Citaten (Scopus)

    Samenvatting

    Introduction
    In many situations, optimal drug therapy requires continuing, high levels of target occupancy and this notion has led pharmacologists to focus attention to the rate by which drug candidates dissociate from their target. To this end, radioligand dissociation experiments are often carried out on in vitro models such intact cells and membranes thereof but the interpretation of the collected data is sometimes ambiguous.
    Areas covered
    Pharmacodynamics is concerned about what the drug does to the target and, in this respect, allosteric modulation constitutes a quite novel, very promising research topic. The ability of unlabelled drugs to accelerate radioligand dissociation is often advocated to be a hallmark of such mechanism. Yet, the present computerized simulations reveal that competitive drugs produce the same effect by preventing hindered diffusion- and "forced proximity"-related rebinding of the radioligand. Hints are provided to discern among those mechanisms.
    Expert opinion
    A critical, but constructive appraisal of radioligand dissociation binding data leads to the viewpoint that, from a physiological perspective, dissociation from confluent target- expressing plated cells in naïve medium is likely to provide the most pertinent insight in that ligand's in vivo residence time.
    Originele taal-2English
    Pagina's (van-tot)583-595
    Aantal pagina's13
    TijdschriftExpert Opinion on Drug Discovery
    Volume7
    StatusPublished - 2012

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