Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics

Abstract

Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids.

Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects

“…Recently, several reports have investigated this question, − with a few of them describing the use of partial agonism as a conducive way to develop safer opioid analgesics. , In light of the above, the use of biased and/or partial agonists could be favorable to achieve beneficial side effect profiles. The second strategy to obtain safer analgesics consists in the development of hybrid or bifunctional compounds, acting at MOP and also at other opioid or nonopioid receptors known to be involved in the regulation of opioid-induced side effects. ,,,− Among the nonopioid receptors, neuropeptide FF1 and FF2 receptors (NPFFR1 and NPFFR2) contribute to opioid-induced adverse effects, including antinociceptive tolerance. Indeed, pharmacological blockade of NPFFR1/2 has been shown to suppress long-lasting opioid-induced hyperalgesia (OIH) and associated antinociceptive tolerance. − …”

Phylogenetic Analysis Provides Insight Into the Molecular Evolution of Nociception and Pain-Related Proteins

“…TACR1 is also named Neurokinin-1 (NK-1) receptor or substance-P receptor, which binds Substance P (SP)/neurokinin 1 (NK1). 12 A range of somatotopically directed pain-related behaviors are observed upon activation of spinal cord neurons that express TACR1 in the absence of noxious input. 13 TAC1 + spinal cord neurons are required for pain-related coping responses in mice.…”

Bifunctional Opioid-Neuropeptide FF Ligands as Analgesics with Reduced Side Effects

“…All of these side effects have an inevitable impact on the quality of life. To overcome this burden, the development of dual ligands, also called hybrids or bifunctional ligands, has increased over the past decade, more specifically by co-targeting opioid and non-opioid receptors involved in nocicaption [2,3]. Herein, the aim was to synthesize opioid-neuropeptide FF hybrids with selective G protein signaling over β-arrestin recruitment at the µ-opioid receptor (MOR).…”