The clinical treatment of various pain states relis upon opioid analgesics. However, most of them produce – apart from strong antinociceptive effect – several side effects such as sedation, euphoria, constipation, and finally development of dependence and addiction 1-3 . One strategy to overcome these major side effects and to prolong the antinociceptive efficiency of the applied drugs involves the creation of multifunctional compounds, which contain hybridized structures 4,5 .
Neurotesin (NT)-induced antinociception is not mediated through the activation of the opioid system which makes it a potentially interesting target in pain research. Additionally, hybridizing neurotensin with an opioid element may result in a potent synergic antinociceptor 6 .
Herein, we would like to present the first hybrid compound containing both opioid and neurotensin pharmacophores, PK20. This chimera was shown to induce a long-lasting and time- and dose-dependent analgesic action when administered centrally (i.t) as well as peripherally (i.v.). The high antinociceptive effect of the investigated compound was proven by comparing the potency of PK20 injected at a much lower dose than morphine (0.02nM/rat vs. 3nM/rat, resp.). At a time-point of 60min post-injection, the administered dose of PK20 induced an almost equipotent antinociceptive effect to morphine, injected at the 150-fold higher dose 6 . Interestingly, the opioid-neurotensin chimera PK20 showed full agonism at both MOP receptor (pKi of 7.09 and EC50 of 79 nM) and neurotensin NTS1 receptor (pKi of 6.66 and EC50 of 217 nM,) when preforming the [35S]GTPγS binding assay 7 .
These results give hope that more efficient opioid analgesics are accessible through the combination of the agonism at opioid and NT receptors.