Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer

Abstract

The first bivalent ligand targeting the putative heterodimer of the mu opioid receptor and the chemokine receptor CXCR4.

Bivalent Ligand Aiming Putative Mu Opioid Receptor and Chemokine Receptor CXCR4 Dimers in Opioid Enhanced HIV-1 Entry

“…Finally, 8 and aminomethyl-substituted IT1t were coupled via EDCI/HOBt method to form the bivalent ligand 1a . The monovalent controls 2a and 3a were also synthesized following previously described procedure . By adopting similar synthetic routes, bivalent ligand S1b (Scheme S1) and its corresponding monovalent controls S2b and S3b were prepared accordingly.…”

“…selection of pharmacophores, choices of suitable attachment points of the spacer, and optimal length and chemical composition of the spacers . In our case, naltrexone (Figure ) was adopted as the MOR antagonist pharmacophore considering its previously successful application in studies of dimerization of opioid receptors, , and its desirable effects in treating opioid addiction in clinic. , Based on previous bivalent ligand studies, introduction different spacers to the C6-position of naltrexone appeared to not significantly influence its MOR affinity. ,,, Moreover, the docking pose of naltrexone in the inactive MOR indicated that the C6-position of naltrexone pointed toward the extracellular end of the transmembrane helix 5 (TM5) and TM6 (Figure a). Taken together, the C6-position of naltrexone was selected as the attachment point once transforming its carbonyl group to the 6β-amino group (Figures c).…”

“…In this regard, it would be invaluable to develop bivalent ligands targeting putative MOR-CXCR4 heterodimers and investigate their role in deleterious opioid and HIV interactions, which can exacerbate the infection, its pathologic consequences, and progression to AIDS. Our preliminary explorations revealed that a bivalent compound featuring both a MOR and a CXCR4 antagonist pharmacophore may preserve acceptable binding affinities and functional activities at both respective receptors . In this work, we report our most recent progress on development of a bivalent ligand targeting the putative MOR-CXCR4 heterodimer with the potential to effectively inhibit opioid enhanced HIV-1 invasion.…”

“…Numerous reports have pointed out that the spacer length of a bivalent ligand played critical roles in the binding to GPCR dimers while a spacer with a length between 16 and 22 atoms might be optimal for binding affinities. , In our current study, we incorporated an 18-atom spacer, two atoms shorter than our previously reported one . Meanwhile, to complementarily investigate how the spacer length affects activity, another bivalent ligand S1b bearing a longer spacer relative to the previously reported one was also synthesized.…”

“…All the synthesized compounds bearing the IT1t pharmacophore were then tested for binding affinity and functional activity at CXCR4 (Tables and S2). In the antibody binding assay with CXCR4-CHO cells, bivalent ligand 1a possessed substantially reduced binding affinity over CXCR4 (IC 50 = 3.6 ± 0.3 μM) while it was about 5 times more potent when compared to our previously reported bivalent ligand (IC 50 = 17.2 ± 2.7 μM) . A more significant reduction on the binding affinity of monovalent control 3a than 1a suggested that the spacer was not well tolerated in binding to CXCR4.…”