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

NEUROPHARMACOLOGY

卷:178

Article

Starnowska-Sokol, Joanna¹  Piotrowska, Anna¹  Bogacka, Joanna¹  Makuch, Wioletta¹  Mika, Joanna¹  Witkowska, Ewa²  Godlewska, Magda²  Osiejuk, Jowita²  Gatarz, Sandra²  Misicka, Aleksandra²  Przewlocka, Barbara¹ 

[1] Polish Acad Sci, Maj Inst Pharmacol, Dept Pain Pharmacol, 12 Smetna St, PL-31343 Krakow, Poland

[2] Univ Warsaw, Fac Chem, Biol & Chem Res Ctr, Warsaw, Poland

关键词: Neuropathic pain;    SHU9119;    Enkephalin;    Opioids;    Melanocortin system;    Bifunctional hybrid analgesics;   

DOI  :  10.1016/j.neuropharm.2020.108232

来源: Elsevier

【 摘 要 】

When the nerve tissue is injured, endogenous agonist of melanocortin type 4 (MC4) receptor, alpha-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.

【 授权许可】

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