Development of biased/selective OP-NT hybrids for pain treatment

The application of opioid analgesics in moderate-to-severe pain is limited due to their several on-target side effects such as tolerance, dependence liability, and respiratory depression. With the advent of biased signaling in the field of pharmacology, it is now possible to obtain the desired analgesic effects of opioids through the activation of G-protein mediated signaling without activating the β-arrestin pathway (which is responsible for the aforementioned side effects). Targeting non-opioid signaling pathways involved in pain modulation, including neurotensin (NT) and its receptors (NTSR1 and NTSR2), is considered a promising approach in pain treatment with fewer side effects. Combining biased opioid and selective NT pharmacophores in a single entity could potentially increase the antinociceptive/adverse effect ratio in pain treatment. To increase the biased character of the opioid pharmacophore, the size of the aromatic system on position 3 and the length of the linker between the two pharmacophores were investigated. These modifications resulted in hybrid analogues with sub-nanomolar range binding affinity for the μ-opioid receptor and significantly reduced β-arrestin recruitment compared to DAMGO, which was used as a control. Furthermore, substitutions of Tyr and Ile in the native NT pharmacophore with (6-OH)Tic and Tle, respectively, increased the selectivity of the hybrid peptides towards NTS2R. Activation of NTS2R is associated with fewer side effects compared to NTS1R.