Bifunctional peptides possessing both neurokinin 1 receptor (NK1R) antagonist and opioid agonist properties have shown advantages over currently used opioid analgesic drugs (e.g. a potent analgesic effect in neuropathic pain states, suppression of tolerance).2 In this study, compact opioid agonist-NK1R antagonists were prepared, based on a constrained azepinone scaffold. By framework combination of an active in-house opioid tetrapeptide and a newly designed NK1R antagonist, a chimeric ligand with the desired dual activity, H-Dmt-D-Arg-Aba-Gly-NMe-3,5-(CF3)2Bn, was obtained.1 This compound underwent in vivo bio-evaluation. Because of its compact and constrained character this peptide did cross the blood-brain barrier (BBB) and was able to induce a potent antinociceptive response after systemic administration. Transport through the BBB represents a major hurdle for CNS drugs. Unfortunately, after repetitive administration and in analogy with morphine, tolerance did emerge. Hence, efforts were dedicated to improve both opioid and NK1 activity within this lead structure.
By structural modification of the lead structure, crucial features were identified for both activities. As such, the interpharmacophore distance was adapted by replacement of the glycine unit by a beta-alanine, a modification that resulted in a significant enhancement of opioid potency. A second modification that boosts the opioid potency is realized by a switch to D-Cit in position 2, whereas the removal of the amide N-methyl and trifluoromethyl groups reduce NK1R antagonism. Next, these compounds were tested in vivo. Upon comparison of in vivo and in vitro results, it became clear that the challenge herein does not only consist of finding high potency. One also has to consider the detrimental impact on BBB transport by subtle shifts in molecular flexibility.
In conclusion, this structure-activity study can be used to modulate the relative potency in the investigated ligands and shows the importance of flexibility in these hybrids.