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

Opioid abuse and HIV/AIDS have been defined as synergistic epidemics. Opioids can accelerate HIV replication in the immune system by up-regulating the expression of HIV co-receptor CXCR4. Several hypotheses have been suggested as the mechanism of CXCR4 modulation by opioids through their activation on the mu opioid receptor (MOR). One hypothesis is the putative heterodimerization of the MOR and CXCR4 as a mechanism of cross-talk and subsequent exacerbation of HIV replication. Bivalent chemical probes can be powerful molecular tools to characterize protein–protein interactions, and modulate the function related to such interactions. Herein we report the design and synthesis of a novel bivalent probe to explore the putative MOR–CXCR4 dimerization and its potential pharmacological role in enhancing HIV progression. The developed bivalent probe was designed with two distinct pharmacophores linked through a spacer. One pharmacophore (naltrexone) will interact with the MOR and the other (IT1t) with the CXCR4. The overall synthetic routes to prepare the bivalent probe and its corresponding monovalent controls were comprised of 18–22 steps with acceptable yields. Preliminary biological evaluation showed that the bivalent probe preserved binding affinity and functional activity at both respective receptors, supporting the initial molecular design.