Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Center for Substance Abuse Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA.
Future Med Chem. 2021 Mar;13(6):551-573. doi: 10.4155/fmc-2020-0308. Epub 2021 Feb 16.
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.
七种混合作用κ阿片受体（KOR）/μ阿片受体（MOR）双靶点调节剂的调节和选择性机制进行了研究。分子建模结果表明，七种双靶点调节剂的“信息”部分与 KOR 和 MOR 的正位点具有相同的结合模式，而“地址”部分与 KOR 和 MOR 的变构位点的不同亚域结合。七种双靶点调节剂的“地址”部分与 KOR 和 MOR 的变构位点的不同亚域结合，可能对“信息”部分的结合亲和力和/或效力表现出可区分的变构调节作用。此外，七种双靶点调节剂中酚部分上的 3-羟基基团诱导对 KOR 的选择性，而不是 MOR。
