Determination of drug–receptor residence times by radioligand binding and functional assays: experimental strategies and physiological relevance

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    Abstract

    Drug-receptor interactions were earlier quanti?ed in terms of af?nity and ef?cacy only but residence time has now also been recognized to affect clinical performance. Different approaches to measure drug binding kinetics are brie?y presented and critically evaluated with the help of simulations. Based on the antagonist's ability to reduce agonist-evoked responses, two main methods are used in functional assays. Radiolabelled drug binding to cell membranes constitutes an alternative approach and provides the most direct information. Yet, due to distinct binding properties and the occurrence of rebinding phenomena, intact cell binding studies are likely to be more relevant from a physiological perspective. Indirect information can also be obtained for unlabelled drugs based on their ability to compete with radioligands. Here, attention should be paid to reversible partitioning phenomena. A special matter of concern is that some experimental observations that are commonly interpreted in terms of allosteric interactions can equally well point to long residence time and/or rebinding.
    Original languageEnglish
    Pages (from-to)645-651
    Number of pages7
    JournalMedChemComm
    Volume3
    Publication statusPublished - 2012

    Keywords

    • residence time
    • binding kinetics
    • rebinding
    • radioligand
    • insurmountable antagonist
    • cell membranes

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