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Hormones as Immune Modulating Agents
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Beta-endorphin (β-END) is derived in the pituitary gland and in other tissues from the POMC peptide by enzymatic cleavage. The production and secretion of β-END in the pituitary gland are regulated by CRF and immune-derived cytokines, such as IL-1β and TNFα [164,165]. Beta-endorphin is also produced in lymphoid cells, especially those infiltrating inflamed tissues. There is evidence to suggest that opioids in general and β-END in particular exert an antiinflammatory effect and down-regulate the immune response [166,167], In vitro, both μ and κ opioid agonists exhibit immunosuppressive activity for antibody responses [168]. The κ opioid agonist agent U50.488H suppressed the production of IL-1 and TNFα by mouse perito-neal macrophages at 1 nM and IL-6 at 10 nM concentrations. This suppressive effect could be completely reversed by the κ-selective antagonist norbinaltorphimine [169].
An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease
Published in Expert Opinion on Pharmacotherapy, 2021
Zoe M. Lipman, Gil Yosipovitch
In preclinical studies, DFK exhibited full agonistic activity at the KOR receptor with an EC50 of 0.16 nm [38]. It showed no off-target activity on >94 other receptors, channels, and transporters while displaying ≥30,000-fold greater selectivity for KORs over MORs [38]. Its observed long action of duration is supported by a slow receptor off-rate of t1/2 of about 92 minutes. In animal models, IV-administered CR845 produced a norbinaltorphimine (nor‐BNI)-reversible long‐acting antinociception response of t½ of about 18 hours in a rat pancreatitis abdominal pain model (ED50 = 0.03 mg/kg IP at 60 min), mouse abdominal constriction test (ED50 = 0.07 mg/kg at 15 min), and rat model of neuropathic pain (tactile hypersensitivity) (ED50 = 0.38 mg/kg IV at 60 min). It also inhibited carrageenan‐induced hind paw edema in rats (ED50 ≈ 0.3 mg/kg IV at 3 h) and prevented hyperalgesia in a rat model of complete Freund’s adjuvant‐induced inflammatory pain (mechanical stimulus) (ED50 = 0.3 mg/kg IV at 60 min) [39]. In addition, it suppressed scratching behavior induced in mice by pruritogens (ED50 ≤ 0.08 mg/kg IV) and suppressed cytokine release in a mouse model of sepsis (ED50 ≈ 3 mg/kg SC) [39].
Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Justyna Piekielna-Ciesielska, Adriano Mollica, Stefano Pieretti, Jakub Fichna, Agata Szymaszkiewicz, Marta Zielińska, Radzisław Kordek, Anna Janecka
Anti-nociception was studied in the hot-plate test in mice after i.c.v. or i.v. administration of peptides. The results obtained in the dose-response studies after i.c.v. administration are shown in Figure 1(A). Both tested compounds showed dose-dependent anti-nociceptive activity, significantly stronger than that of endomorphin-2 (EM-2). The ED50 values (jumping response) for C-36 and F-81 were 57.78 and 17.27 ng, respectively, indicating that F-81 was approximately threefold more potent than C-36 (Figure 1(A)). In order to investigate if these peptides are able to cross the BBB, peripheral i.v. administration of the peptides was performed, and the results are reported in Figure 1(B). After i.v. administration at the dose of 20 mg/kg, only a negligible anti-nociceptive activity was observed for both compounds (Figure 1(B)). To characterize the involvement of opioid receptors in the anti-nociceptive action of analog F-81, co-administration studies with opioid receptor antagonists were performed. The anti-nociceptive effect of F-81 (10 ng/animal, i.c.v.) was blocked by β-funaltrexamine (β-FNA, 1 µg/animal), showing the involvement of the mu opioid receptors. The delta-opioid receptor antagonist, naltrindole (NTL, 1 µg/animal), and kappa-opioid receptor antagonist, norbinaltorphimine (nor-BNI, 5 µg/animal, i.c.v.), did not modify the anti-nociceptive action of F-81 (Figure 1(C)). Even though F-81 and C-36 showed significant kappa-affinity, the obtained results are in agreement with a generally accepted fact that the anti-nociceptive effects are mainly mediated by the mu opioid receptor32,38.
Can pharmacotherapy improve treatment outcomes in people with co-occurring major depressive and cocaine use disorders?
Published in Expert Opinion on Pharmacotherapy, 2021
Gustavo A. Angarita, Hasti Hadizadeh, Ignacio Cerdena, Marc N. Potenza
Similar to studies of D3R partial agonists or antagonists, there is a preclinical/clinical gap in KOR agents tested. One challenge relates to compounds’ half-lives; for example, nor-binaltorphimine has a long duration of action [111]. Some may act on other receptors, limiting use in some populations (e.g. LY2456302 may also antagonize MORs, limiting use in opioid-dependent groups)[112]. Clinically, proof-of-mechanism/target-engagement studies may provide support for further investigation [113]. Table 2 summarizes RCT findings, with some positive results for CUD and/or MDD.