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

Starnowska-Sokół, Joanna; Piotrowska, Anna; Bogacka, Joanna; Makuch, Wioletta; Mika, Joanna; Witkowska, Ewa; Godlewska, Magda; Osiejuk, Jowita; Gątarz, Sandra; Misicka, Aleksandra; Przewłocka, Barbara

doi:10.1016/j.neuropharm.2020.108232

Cited by 14 publications

(19 citation statements)

References 72 publications

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“…Increasing evidence supports the excellent antinociceptive activity of bifunctional compounds in several animal models and indicates a significant advantage of compounds targeting more than one molecular target over the physical mixture of individual pharmacophores with respect to their analgesic effect (84)(85)(86). The benefits of this approach may arise from the simultaneous access to the two receptors at the same dose and, thus, the changing pharmacokinetics and pharmacodynamics, consequently leading to better analgesic effects.…”

Section: Discussionmentioning

confidence: 99%

Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy

et al. 2020

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Clinical management of neuropathic pain is unsatisfactory, mainly due to its resistance to the effects of available analgesics, including opioids. Converging evidence indicates the functional interactions between chemokine and opioid receptors and their influence on nociceptive processes. Recent studies highlight that the CC chemokine receptors type 2 (CCR2) and 5 (CCR5) seem to be of particular interest. Therefore, in this study, we investigated the effects of the dual CCR2/CCR5 antagonist, cenicriviroc, on pain-related behaviors, neuroimmune processes, and the efficacy of opioids in rats after chronic constriction injury (CCI) of the sciatic nerve. To define the mechanisms of action of cenicriviroc, we studied changes in the activation/influx of glial and immune cells and, simultaneously, the expression level of CCR2, CCR5, and important pronociceptive cytokines in the spinal cord and dorsal root ganglia (DRG). We demonstrated that repeated intrathecal injections of cenicriviroc, in a dose-dependent manner, alleviated hypersensitivity to mechanical and thermal stimuli in rats after sciatic nerve injury, as measured by von Frey and cold plate tests. Behavioral effects were associated with the beneficial impact of cenicriviroc on the activation/influx level of C1q/IBA-1-positive cells in the spinal cord and/or DRG and GFAP-positive cells in DRG. In parallel, administration of cenicriviroc decreased the expression of CCR2 in the spinal cord and CCR5 in DRG. Concomitantly, we observed that the level of important pronociceptive factors (e.g., IL-1beta, IL-6, IL-18, and CCL3) were increased in the lumbar spinal cord and/or DRG 7 days following injury, and cenicriviroc was able to prevent these changes. Additionally, repeated administration of this dual CCR2/CCR5 antagonist enhanced the analgesic effects of morphine and buprenorphine in neuropathic rats, which can be associated with the ability of cenicriviroc to prevent nerve injury-induced downregulation of all opioid receptors at the DRG level. Overall, our results suggest that pharmacological modulation based on the simultaneous blockade of CCR2 and CCR5 may serve as an innovative strategy for the treatment of neuropathic pain, as well as in combination with opioids.

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Section: Discussionmentioning

confidence: 99%

Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy

et al. 2020

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“…The preclinical tests in rodent models of NP performed by our group allowed to select the compounds characterized by the best analgesic profile under nerve injury conditions. Further authorial modifications to the compounds' structures, based on the preclinical evidence obtained, gave rise to the series of bifunctional ligands uniquely designed to treat neuropathic pain [94,95]. The basic studies on mice and rats subjected to sciatic nerve injury (CCI model) revealed that the linker type prominently influences the compound's properties in vivo, determining the intensity and duration of the final analgesic effect.…”

Section: Mop/dop Receptor Agonist-mc4 Receptor Antagonist Hybrids Promentioning

confidence: 99%

“…doses about hundred times lower than individual pharmacophores. The effect provided by single-target parent compounds, as well as their physical mix, was less pronounced and relatively short-lasting (Scheme 3) [94,95]. The unique property of the OP-MC4 receptor hybrid, as compared to other ideas of bivalent compounds proposed for neuropathic pain treatment, is that its analgesic functions result from the modulation of a single nociception-related system, as the hybrid simultaneously enhances and suppresses the effects of different products derived from the same prohormone.…”

Section: Mop/dop Receptor Agonist-mc4 Receptor Antagonist Hybrids Promentioning

confidence: 99%

“…The four graphs illustrate the antiallodynic effect (shown in a percentage of maximal possible effect; 100% = maximal analgesia) provided in a mouse chronic constriction injury (CCI) model by separate constituents (pharmacophores), physical mixture of two pharmacophores, and an opioid agonist-melanocortin type 4 (MC4) receptor antagonist hybrid compound. All compounds were administered intrathecally in an equivalent dose of 0.05 nM, and the hypersensitivity threshold was measured 30 and 90 min after injection[95].…”

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Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

Starnowska-Sokół

Przewłocka

2020

Molecules

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When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

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“…Working in the paradigm of multi-functional analgesics, researchers have investigated molecules designed by joining pharmacophores of various molecular targets and functional activities. The considered combinations are as diverse as MOR agonist/DOR agonist [6,7] MOR agonist/DOR antagonist [8,9], MOR agonist/cholecystokinin CCK2 receptor antagonist [10,11], MOR agonist/ neurotensin agonist [12,13], MOR agonist/ melanocortin-4 antagonist [14], MOR agonist/σ1-receptor antagonist [15,16], MOR agonist/voltage gated calcium channel (VGCC) blocker [17], MOR agonist/cannabinoid-1 receptors agonist [18] or MOR agonist/neuropeptide FF receptor agonist [19].…”

Section: Introductionmentioning

confidence: 99%

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

Matalińska

Lipiński

Kossoń

et al. 2020

IJMS

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AA3266 is a hybrid compound consisting of opioid receptor agonist and neurokinin-1 receptor (NK1R) antagonist pharmacophores. It was designed with the desire to have an analgesic molecule with improved properties and auxiliary anticancer activity. Previously, the compound was found to exhibit high affinity for μ- and δ-opioid receptors, while moderate binding to NK1R. In the presented contribution, we report on a deeper investigation of this hybrid. In vivo, we have established that AA3266 has potent antinociceptive activity in acute pain model, comparable to that of morphine. Desirably, with prolonged administration, our hybrid induces less tolerance than morphine does. AA3266, contrary to morphine, does not cause development of constipation, which is one of the main undesirable effects of opioid use. In vitro, we have confirmed relatively strong cytotoxic activity on a few selected cancer cell lines, similar to or greater than that of a reference NK1R antagonist, aprepitant. Importantly, our compound affects normal cells to smaller extent what makes our compound more selective against cancer cells. In silico methods, including molecular docking, molecular dynamics simulations and fragment molecular orbital calculations, have been used to investigate the interactions of AA3266 with MOR and NK1R. Insights from these will guide structural optimization of opioid/antitachykinin hybrid compounds.

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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

Cited by 14 publications

References 72 publications

Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy

Bidirectional Action of Cenicriviroc, a CCR2/CCR5 Antagonist, Results in Alleviation of Pain-Related Behaviors and Potentiation of Opioid Analgesia in Rats With Peripheral Neuropathy

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

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