Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

Abstract

Morphine, which acts through opioid receptors, is one of the most efficient analgesics for the alleviation of severe pain. However, its usefulness is limited by serious side effects, 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 effective 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 effect in mice, while neither of them triggered the development of tolerance, nor did they produce constipation. No statistically significant differences in in vivo activity profiles were observed between opioid/NK1 agonist and opioid/NK1 antagonist hybrids.

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

“…Recently, Wtorek et al reported a series of hybrids based on a cyclic opioid peptide and linear peptide NK1 agonist/antagonist fragments [ 23 ]. One of these NK1R-antagonist-containing compounds was shown to be effective in acute pain model and not to trigger tolerance development.…”

“…The issue of gastrointestinal transit impairment was touched upon only a few times in the context of hybrid opioid/antitachykinin compounds. The aforementioned work by Wtorek et al demonstrated that their opioid/antitachykinin ligand did not produce constipation [ 23 ]. Earlier, Largent-Milnes et al reported that compound TY027 exerted no influence on gastrointestinal transit [ 37 ].…”

“…Their results are summarized and critically discussed in a review by Kleczkowska et al [ 20 ]. In a recent work, Wtorek et al [ 23 ] corroborated the rationale behind designing such hybrids, showing that a cyclic peptide opioid agonist/linear peptide NK1 antagonist has a significant antinociceptive effect but does not trigger tolerance development.…”

Antinociceptive and Cytotoxic Activity of Opioid Peptides with Hydrazone and Hydrazide Moieties at the C-Terminus

“…Yet another bivalent combination in which the hydrazide bridge found application was in hybrids of opioid agonist and neurokinin-1 receptor (NK1R) antagonists [27,28]. The rationale for preparing such multitarget compounds consisting of opioid sequences along with the pharmacophoric elements required for targeting some other receptors stems from the fact that simultaneous modulation of a few receptors involved in pain perception can provide analgesic compounds with enhanced efficacy and fewer side effects [29][30][31][32].…”

Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery

“…Increasing evidence on the heteromerization of native opioid receptors in discrete brain neuronal circuits with selective targeting of heteromers as a tool to modulate receptor activity, and multifunctional ligands, which simultaneously activate two or more targets to produce a more desirable drug profile, are emerging concepts for the development of novel therapeutic drugs and strategies, presented in the earlier cited report [2] and in two additional research articles [13,14].…”