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20 results on '"Akgün, Eyup"'

12. FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR–DOR Heteromer

Author

Akgün, Eyup, Lunzer, Mary M., Tian, Defeng, Ansonoff, Michael, Pintar, John, Bruce, Daniel, Hawkinson, Jon E., Wilcox, George L., and Portoghese, Philip S.

Abstract

This report describes the unique pharmacological profile of FBNTI, a potent DOR antagonist that acts as a MOR agonist via an allosteric mechanism. Binding of FBNTI to opioid receptors expressed in HEK 293 cells revealed a 190-fold greater affinity for DOR (Ki= 0.84 nM) over MOR (Ki= 160 nM). In mice, intrathecal FBNTI produced potent antinociception (ED50= 46.9 pmol/mouse), which was antagonized by selective MOR antagonists (CTOP, β-FNA). Autoantagonism of the MOR agonism by FBNTI was observed above the ED75dose, suggesting antagonism of activated MOR. That FBNTI is devoid of agonism in DOR knockout mice is consistent with allosteric activation of the MOR protomer via FBNTI bound to within a MOR–DOR heteromer. This proposed mechanism is supported by calcium mobilization assays, which indicate that FBNTI selectively activates the MOR–DOR heteromer and functionally antagonizes the MOR protomer at >ED75. The unprecedented mode of MOR activation by FBNTI may be responsible for the lack of tolerance after intrathecal (i.t.) administration. FBNTI was highly effective upon topical administration to the ipsolateral hind paw in the Hargreaves assay (EC50= 0.17 ± 0.08 μM) and without significant contralateral activity, suggesting a lack of systemic exposure.

Published
2021
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20. Targeting MOR-mGluR 5 heteromers reduces bone cancer pain by activating MOR and inhibiting mGluR5.

Author

Shueb SS, Erb SJ, Lunzer MM, Speltz R, Harding-Rose C, Akgün E, Simone DA, and Portoghese PS

Subjects
Animals, Bone Neoplasms drug therapy, Bone Neoplasms metabolism, Disease Models, Animal, Drug Administration Routes, Fibrosarcoma drug therapy, Fibrosarcoma metabolism, Hyperalgesia drug therapy, Ligands, Male, Mice, Mice, Inbred C3H, Morphine therapeutic use, Receptors, Kainic Acid administration & dosage, Receptors, Opioid, mu administration & dosage, Cancer Pain drug therapy, Cancer Pain metabolism, Receptors, Kainic Acid antagonists & inhibitors, Receptors, Opioid, mu agonists
Abstract

Pain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR 5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind paw Subcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesia, whose ED 50 was orders of magnitude lower than morphine. Moreover, the ED 50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or alter motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR 5 , and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain. This article is part of the Special Issue entitled 'New Vistas in Opioid Pharmacology'., (Copyright © 2019. Published by Elsevier Ltd.)

Published
2019
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