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

Abstract

Based 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.

• Authors: Ewa Witkowska, Magda Godlewska, Jowita Osiejuk, Sandra Gątarz, Beata Wileńska, Katarzyna Kosińska, Joanna Starnowska-Sokół, Anna Piotrowska, Piotr F J Lipiński, Joanna Matalińska, Jolanta Dyniewicz, Paweł K Halik, Ewa Gniazdowska, Barbara Przewlocka, Aleksandra Misicka
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 23 Issue 2 (Jan 08 2022) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 35054860 (Publication Type: Journal Article)

Chemical References

• Analgesics
• Melanocortins
• Peptidomimetics
• Receptors, Opioid, mu

Topics

• Amino Acid Sequence
• Analgesics
• Animals
• Binding Sites
• HEK293 Cells
• Humans
• Melanocortins (chemistry)
• Mice
• Models, Biological
• Neuralgia (drug therapy)
• Peptidomimetics (chemistry, pharmacology, therapeutic use)
• Receptors, Opioid, mu (chemistry, metabolism)