A bivalent ligand targeting the putative mu opioid receptor and chemokine receptor CCR5 heterodimer: binding affinity versus functional activities

Abstract

Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand 1 with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid-enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca2+ flux inhibition function activity of bivalent ligand 1 at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca2+ flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand 1 seemed to function more effectively by targeting specifically the putative MOR–CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR–CCR5 interaction during the progression of NeuroAIDS.

Oligomerization of GPCRs involved in endocrine regulation

“…, Rashid et al 2007, Gomes et al 2013); (iv) bind ligand(s) that differ (e.g. also at allosteric binding sites) (Durroux 2005); (v) bind artificial ligands that modify signaling pathways such as bivalent ligands (Shonberg et al 2011, Mohr et al 2013, Yuan et al 2013.…”

Beneficial properties of maraviroc on neuropathic pain development and opioid effectiveness in rats

“…Some in vitro studies have demonstrated that CCR5 and the mu-opioid receptor, both members of the GPCR family, may engage in cross-talk through dimerization (Chen et al, 2004;Yuan et al 2013). These results suggest that CCR5 might be involved in the development of opioid effectiveness, which, to the best of our knowledge, has not been studied in neuropathic pain.…”

Bivalent Ligands Targeting Chemokine Receptor Dimerization: Molecular Design and Functional Studies

“…Table 1 shows the results of both CCR5 and MOR radiobinding assays for selected compounds. Within the MOR binding assay, all of the compounds showed higher K i values than naltrexone ( 28 ) [75]. The bivalent compound 22 had a 70-fold loss in binding affinity to the MOR, whereas the monovalent compound 24 had a 13-fold loss in affinity.…”

“…The bivalent compound 22 had a 70-fold loss in binding affinity to the MOR, whereas the monovalent compound 24 had a 13-fold loss in affinity. The data for the CCR5 binding assay indicated that any substitution on maraviroc’s phenyl ring is detrimental; there was a clear trend of decreasing affinity with increasing size of the group at the 4-position [75]. Overall, there was about a 1000-fold loss of affinity seen for 22 compared to maraviroc [75].…”

“…The data for the CCR5 binding assay indicated that any substitution on maraviroc’s phenyl ring is detrimental; there was a clear trend of decreasing affinity with increasing size of the group at the 4-position [75]. Overall, there was about a 1000-fold loss of affinity seen for 22 compared to maraviroc [75]. However, it did still bind CCR5 at a nanomolar level, meaning that its affinity wasn’t completely abolished.…”