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Exploring the putative mechanism of allosteric modulations by mixed-action kappa/mu opioid receptor bitopic modulators

    Huiqun Wang

    Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA

    ,
    Danni Cao

    Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA

    ,
    James C Gillespie

    Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA

    ,
    Rolando E Mendez

    Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA

    ,
    Dana E Selley

    Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA

    ,
    Lee-Yuan Liu-Chen

    Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA

    &
    Yan Zhang

    *Author for correspondence:

    E-mail Address: yzhang2@vcu.edu

    Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA

    Published Online:https://doi.org/10.4155/fmc-2020-0308

    The modulation and selectivity mechanisms of seven mixed-action kappa opioid receptor (KOR)/mu opioid receptor (MOR) bitopic modulators were explored. Molecular modeling results indicated that the ‘message’ moiety of seven bitopic modulators shared the same binding mode with the orthosteric site of the KOR and MOR, whereas the ‘address’ moiety bound with different subdomains of the allosteric site of the KOR and MOR. The ‘address’ moiety of seven bitopic modulators bound to different subdomains of the allosteric site of the KOR and MOR may exhibit distinguishable allosteric modulations to the binding affinity and/or efficacy of the ‘message’ moiety. Moreover, the 3-hydroxy group on the phenolic moiety of the seven bitopic modulators induced selectivity to the KOR over the MOR.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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