Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Morphine, which acts through opioid receptors, is one of the most ecient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side eects, including analgesic tolerance, constipation, and dependence liability. The growing awareness that multifunctional ligands which simultaneously activate two or more targets may produce a more desirable drug profile than selectively targeted compounds has created an opportunity for a new approach to developing more eective medications. Here, in order to better understand the role of the neurokinin system in opioid-induced antinociception, we report the synthesis, structure–activity relationship, and pharmacological characterization of a series of hybrids combining opioid pharmacophores with either substance P (SP) fragments or neurokinin receptor (NK1) antagonist fragments. On the bases of the in vitro biological activities of the hybrids, two analogs, opioid agonist/NK1 antagonist Tyr-[d-Lys-Phe-Phe-Asp]-Asn-d-Trp-Phe-d-Trp-Leu-Nle-NH2 (2) and opioid agonist/NK1 agonist Tyr-[d-Lys-Phe-Phe-Asp]-Gln-Phe-Phe-Gly-Leu-Met-NH2 (4), were selected for in vivo tests. In the writhing test, both hybrids showed significant an antinociceptive eect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant dierences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.