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.
Highlights
From the ancient use of the plant alkaloid morphine up until the discovery of modern medicine technologies, opioid receptor-targeting analgesics still occupy a prominent place in the management of acute or chronic pain
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 designed multiple ligands (DMLs)
To address the side effects associated with the long-term use of opioid agonists, the design of multifunctional ligands has emerged as a valuable strategy in the treatment of chronic pain
Summary
From the ancient use of the plant alkaloid morphine up until the discovery of modern medicine technologies, opioid receptor-targeting analgesics still occupy a prominent place in the management of acute or chronic pain. A first series of multifunctional opioid agonist–neurokinin NK2 or NK3 antagonist ligands were designed, synthesized, and evaluated in vitro in light of exploring new therapeutic pathways in pain and related disorders Reported for their high MOR binding affinity [23,24], the two putative opioid. Molecules 2021, 26, 5406 series of multifunctional opioid agonist–neurokinin NK2 or NK3 antagonist ligands3woef r1e5 designed, synthesized, and evaluated in vitro in light of exploring new therapeutic pathways in pain and related disorders Reported for their high MOR binding affinity [23,24], the two putative opioid agonist pharmacophores Dmt-DALDA and KGOP01 were covalaegnotnlyisltipnkheadrmtoacaopsehloercetisoDnmotf-pDeApLtiDdAic,apnsdeuKdGoO-pPe0p1twideirce, aconvdanleonnt-lypelipntkidedictNo aKs2ealencdtioNnKo3f ppehpatrimdiacc, oppsehuodreos-pSeBptLid-OicP, aNnKd-n1o, nS-BpeLp-OtidPiNc NKK-22, aannddNSKB3Lp-OhaPrNmKac-o3p(hFoigreusrSeB1LB-)O. In the NK3 radioligand binding assay, the parent NK3 pharmacophore SBL-OPNK-3 showed a slightly reduced affinity compared to the reference compound, while the corresponding hybrid ligand SBL-OPNK-9 presented again a 1.5-fold increase of its NK3 affinity and potency compared to the reference compound SB 222200
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