Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020
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Evaluation of Receptor Affinity, Analgesic Activity and Cytotoxicity of a Hybrid Peptide, AWL3020 Joanna Matalińska1 · Piotr F. J. Lipiński1 · Agnieszka Kotlarz2 · Piotr Kosson3 · Adriana Muchowska1 · Jolanta Dyniewicz1 Accepted: 11 February 2020 © The Author(s) 2020
Abstract In the present contribution we report design, synthesis and evaluation of receptor affinity, analgesic activity and cytotoxicity of a hybrid peptide, AWL3020. The peptide includes two pharmacophores, one of δ-opioid receptor (δOR) agonists and one of neurokinin-1 receptor (NK1R) antagonists. The design was motivated by the desire to obtain a compound with strong analgesic action and potential additional antiproliferative action. The compound displays high δOR affinity (IC50 = 29.5 nM). On the other hand, it has only poor affinity for the NK1R ( IC50 = 70.28 μM). The substance shows good analgesic action which is however weaker than that of morphine. Regarding the effect on proliferation, the compound exhibits no pro-proliferative action in the assayed range. In higher concentrations, it has also cytotoxic activity. This effect is however not selective. The strongest effect of AWL3020 was found for melanoma MeW164 cell line ( EC50 = 46.27 μM in reduction of cell numbers after a few days of incubation; EC50 = 37.78 μM in MTT assay). Keywords Cancer pain · Multitarget drugs · Neurokinin-1 receptor · Delta opioid receptor
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10989-020-10051-5) contains supplementary material, which is available to authorized users. * Joanna Matalińska [email protected] * Piotr F. J. Lipiński [email protected] Agnieszka Kotlarz [email protected] Piotr Kosson [email protected] Adriana Muchowska [email protected] Jolanta Dyniewicz [email protected] 1
Department of Neuropeptides, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02‑106 Warsaw, Poland
2
Maria Sklodowska-Curie Memorial Institute and Oncology Centre, 02‑781 Warsaw, Poland
3
Toxicology Research Laboratory, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02‑106 Warsaw, Poland
Various types of cancers are among the most important problems of modern medicine. Cancer is often difficult to treat and its progression is frequently accompanied by pain (Portenoy and Ahmed 2018). In particular, pain is most problematic in advanced stages of the disease. Pain seems to be a key factor contributing to the lowering of patients’ quality of lives. Current treatment of cancer pain relies mostly on opioids like morphine, fentanyl, buprenorphine, tramadol and others (Money and Garber 2018). Many ways of administrations are available for the opioids including oral, transdermal, transmucosal or via enteral tubes. Unfortunately, these therapies are far from ideal. In many cases, they lack enough efficacy in relieving pain and their prolonged use causes tolerance. The opioids can also have unpleasant or even life-threatening side-effec
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