Poster Presentation 10th Australian Peptide Conference 2013

PK20, a novel enzymatically stable hybrid compound that induces antinociceptive responses by bearing a full agonist activity at both opioid and neurotensin receptors (#126)

Patrycja Kleczkowska 1 , Engin Bojnik 2 , Piotr Kosson 1 , Emmanuel Hermans 3 , Isabelle Van den Eynde 4 , Dirk Tourwé 4 , Andrzej W Lipkowski 1
  1. Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, POL, Poland
  2. Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
  3. Laboratory of Neuropharmacology, Université Catholique de Louvain, Brussels, Belgium
  4. Department of Organic Chemistry, Vrije Universiteit Brussel , Brussels, Belgium

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.

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  6. Kleczkowska P, Kosson P, Ballet S, et al. PK20, a new opioid neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects. Mol Pain 2010; 6: 86.
  7. Kleczkowska P, Bojnik E, Lesniak A, et al. Identification of Dmt-D-Lys-Phe-Phe-OH as a highly antinociceptive tetrapeptide metabolite of the opioid-neurotensin hybrid peptide PK20. Pharmacol Rep 2012 (in review).