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Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

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dc.abstract.enBased on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorPrzewłocka, Barbara
dc.contributor.authorMisicka-Kęsik, Aleksandra
dc.contributor.authorGniazdowska, Ewa
dc.contributor.authorHalik, Paweł K.
dc.contributor.authorDyniewicz, Jolanta
dc.contributor.authorMatalińska, Joanna
dc.contributor.authorLipiński, Piotr
dc.contributor.authorPiotrowska, Anna
dc.contributor.authorStarnowska-Sokół, Joanna
dc.contributor.authorKosińska, Katarzyna
dc.contributor.authorWileńska, Beata
dc.contributor.authorGątarz, Sandra
dc.contributor.authorOsiejuk, Jowita
dc.contributor.authorGodlewska, Magda
dc.contributor.authorWitkowska, Ewa
dc.date.accessioned2024-01-24T18:36:14Z
dc.date.available2024-01-24T18:36:14Z
dc.date.copyright2022-01-08
dc.date.issued2022
dc.description.accesstimeAT_PUBLICATION
dc.description.financeŚrodki finansowe, o których mowa w art. 365 pkt. 2 ustawy
dc.description.number2
dc.description.versionFINAL_PUBLISHED
dc.description.volume23
dc.identifier.doi10.3390/IJMS23020674
dc.identifier.issn1422-0067
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/102285
dc.identifier.weblinkhttps://www.mdpi.com/1422-0067/23/2/674/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofInternational Journal of Molecular Sciences
dc.relation.pages674
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.enneuropathic pain
dc.subject.enpeptidomimetics
dc.subject.enopioids
dc.subject.enMC4 antagonist
dc.subject.enlinkers
dc.subject.endual target molecules
dc.subject.enmedicinal chemistry
dc.subject.endrug discovery
dc.subject.enrational design
dc.titleBifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores
dc.typeJournalArticle
dspace.entity.typePublication