Hybrid peptidomimetics for the use in neuropathicpain

Witkowska, Ewa; Osiejuk, Jowita; Godlewska, Magda; Gątarz, Sandra; Wileńska, Beata; Starnowska, Joanna; Piotrowska-Murzyn, Anna; Mika, Joanna; Przewłocka, Barbara; Misicka, Aleksandra

doi:10.17952/35eps.2018.273

Cited by 3 publications

(3 citation statements)

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“…In our efforts along this track, we designed and synthesized nine hybrid compounds [ 18 , 37 ]. Their evaluation as to the analgesic properties in rodent models of acute and neuropathic pain revealed substantial differences in the analgesic effects, depending on the linker type that was used to form a hybrid.…”

Section: Discussionmentioning

confidence: 99%

“…In our efforts along this track, based on our previous pharmacological experiments [ 16 , 17 ], we have designed, prepared, and evaluated for biological activity nine ( 1 – 9 , general structure presented in Figure 1 ) bifunctional hybrid peptidomimetics [ 18 ], which consist of an opioid agonist and a melanocortin-4 (MC4) receptor antagonist. Their exact structure comprises an opioid pharmacophoric fragment based on an enkephalin analog and a melanocortin-4 receptor antagonist fragment.…”

Section: Introductionmentioning

confidence: 99%

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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

Witkowska

Godlewska

Osiejuk

et al. 2022

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Witkowska

Godlewska

Osiejuk

et al. 2022

IJMS

Self Cite

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show abstract

“…The results of current studies were the basis for developing a new drug model consisting of 2 pharmacophores, namely, an antinociceptive opioid and an antagonist of the pronociceptive MC4 receptor, linked by specially designed various spacers. 77 We tested the analgesic properties and development of tolerance to 2 hybrids from a series of newly synthesized hybrids with an opioid (OP)-linker-MC4 structure, namely, UW3 and UW5 (which are protected by patent application no. PL422093/P31312PL00/AGR), in rat models of neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%