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Novel hybrid compounds, opioid agonist+melanocortin 4 receptor antagonist, as efficient analgesics in mouse chronic constriction injury model of neuropathic pain

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dc.abstract.enWhen the nerve tissue is injured, endogenous agonist of melanocortin type 4 (MC4) receptor, α-MSH, exerts tonic pronociceptive action in the central nervous system, contributing to sustaining the neuropathic pain state and counteracting the analgesic effects of exogenous opioids. With the intent of enhancing opioid analgesia in neuropathy by blocking the MC4 activation, so-called parent compounds (opioid agonist, MC4 antagonist) were joined together using various linkers to create novel bifunctional hybrid compounds. Analgesic action of four hybrids was tested after intrathecal (i.t.) administration in mouse models of acute and neuropathic pain (chronic constriction injury model, CCI). Under nerve injury conditions, one of the hybrids, UW3, induced analgesia in 1500 times lower i.t. dose than the opioid parent (ED50: 0.0002 nmol for the hybrid, 0.3 nmol for the opioid parent) and in an over 16000 times lower dose than the MC4 parent (ED50: 3.33 nmol) as measured by the von Frey test. Two selected hybrids were tested for analgesic properties in CCI mice after intravenous (i.v.) and intraperitoneal (i.p.) administration. Opioid receptor antagonists and MC4 receptor agonists diminished the analgesic action of these two hybrids studied, though the extent of this effect differed between the hybrids; this suggests that linker is of key importance here. Further results indicate a significant advantage of hybrid compounds over the physical mixture of individual pharmacophores in their analgesic effect. All this evidence justifies the idea of synthesizing a bifunctional opioid agonist-linker-MC4 antagonist compound, as such structure may bring important benefits in neuropathic pain treatment.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorGątarz, Sandra
dc.contributor.authorMika, Joanna
dc.contributor.authorWitkowska, Ewa
dc.contributor.authorPrzewłocka, Barbara
dc.contributor.authorGodlewska, Magda
dc.contributor.authorOsiejuk, Jowita
dc.contributor.authorMakuch, Wioletta
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorStarnowska-Sokół, Joanna
dc.contributor.authorPiotrowska-Murzyn, Anna
dc.contributor.authorBogacka, Joanna
dc.date.accessioned2024-01-25T13:52:21Z
dc.date.available2024-01-25T13:52:21Z
dc.date.copyright2020-08-01
dc.date.issued2020
dc.description.accesstimeAT_PUBLICATION
dc.description.financePublikacja bezkosztowa
dc.description.versionFINAL_PUBLISHED
dc.description.volume178
dc.identifier.doi10.1016/J.NEUROPHARM.2020.108232
dc.identifier.issn0028-3908
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/113954
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/pii/S0028390820303002
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofNeuropharmacology
dc.relation.pages108232
dc.rightsCC-BY-NC-ND
dc.sciencecloudnosend
dc.subject.enNeuropathic pain
dc.subject.enSHU9119
dc.subject.enEnkephalin
dc.subject.enOpioids
dc.subject.enMelanocortin system
dc.subject.enBifunctional hybrid analgesics
dc.titleNovel hybrid compounds, opioid agonist+melanocortin 4 receptor antagonist, as efficient analgesics in mouse chronic constriction injury model of neuropathic pain
dc.typeJournalArticle
dspace.entity.typePublication