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13. 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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25. Molecular Basis for Binding and Subtype Selectivity of 1,4-Benzodiazepine Antagonist Ligands of the Cholecystokinin Receptor

Author

Cawston, Erin E., primary, Lam, Polo C.H., additional, Harikumar, Kaleeckal G., additional, Dong, Maoqing, additional, Ball, Alicja M., additional, Augustine, Mary Lou, additional, Akgün, Eyup, additional, Portoghese, Philip S., additional, Orry, Andrew, additional, Abagyan, Ruben, additional, Sexton, Patrick M., additional, and Miller, Laurence J., additional

Published
2012
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37. BivalentLigands That Target μ Opioid (MOP)and Cannabinoid1 (CB1) Receptors Are Potent AnalgesicsDevoid of Tolerance.

Author

Le Naour, Morgan, Akgün, Eyup, Yekkirala, Ajay, Lunzer, Mary M., Powers, Mike D., Kalyuzhny, Alexander E., and Portoghese, Philip S.

Subjects
*LIGANDS (Biochemistry), *OPIOID peptides, *CENTRAL nervous system, *CELL culture, *MOLECULAR interactions, *IMMUNOFLUORESCENCE
Abstract

Given that μ opioid (MOP) andcanabinoid (CB1)receptors are colocalized in various regions of the central nervoussystem and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenousMOP-CB1in nociception and other pharmacologic effectshas been raised. As a first step in investigating this possibility,we have synthesized a series of bivalent ligands 1–5that contain both μ agonist and CB1antagonistpharmacophores for use as tools to study the functional interactionbetween MOP and CB1receptors in vivo. Immunofluorescentstudies on HEK293 cells coexpressing both receptors suggested 5(20-atom spacer) to be the only member of the series thatbridges the protomers of the heteromer. Antinociceptive testing inmice revealed 5to be the most potent member of the series.As neither a mixture of monovalent ligands 9+ 10nor bivalents 2–5producedtolerance in mice, MOR-CB1apparently is not an importanttarget for reducing tolerance. [ABSTRACT FROM AUTHOR]

Published
2013
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45. Zur Struktur von (Pyrazolinonyl)-(hydroxypyrazolylium)methanperchloraten NMR-, IR-spektroskopische Studien und Kristallstruktur / The Structure of (Pyrazohnonyl)-(hydroxypyrazolyhum)methaneperchlorates NMR, IR Spectroscopic Studies and Crystal Structure

Author

Burschka, Christian, Akgün, Eyup, and Pindur, Ulf

Abstract

The structures of 1a-1d were investigated by spectroscopic methods and in the case of la in addition by X-ray diffraction, 1a, vicarious for the compounds 1, is stabilized in solution and in the crystal by an intramolecular hydrogen bond in an eight-membered ring. The IR and NMR spectra show that 1 exhibit a symmetrical structure. In the case of 1 a the molecular structure is affected by unsymmetrical packing and electrostatic effects in the crystal and is therefore approximated best between the forms I and II.

Published
1983
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48. 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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49. Induced association of mu opioid (MOP) and type 2 cholecystokinin (CCK2) receptors by novel bivalent ligands.

Author

Zheng Y, Akgün E, Harikumar KG, Hopson J, Powers MD, Lunzer MM, Miller LJ, and Portoghese PS

Subjects
Animals, CHO Cells, COS Cells, Chlorocebus aethiops, Cricetinae, Cricetulus, Dimerization, Energy Transfer, Ligands, Magnetic Resonance Spectroscopy, Mice, Protein Binding, Receptor, Cholecystokinin B metabolism, Receptors, Opioid, mu metabolism
Abstract

Both mu-opioid (MOP) and type 2 cholecystokinin (CCK2) receptors are present in areas of the central nervous system that are involved in modulation of pain processing. We conducted bioluminescence resonance energy transfer (BRET) studies on COS cells coexpressing MOP and CCK2 receptors to determine whether receptor heterodimerization is involved in such modulation. These studies revealed the absence of constitutive or monovalent ligand-induced heterodimerization. Heterodimerization of MOP and CCK2 receptors therefore is unlikely to be responsible for the opposing effects between morphine and CCK in the CNS. However, association was induced, as indicated by a positive BRET signal, on exposure of the cells to bivalent ligands containing mu-opioid agonist and CCK2 receptor antagonist pharmacophores linked through spacers containing 16-22 atoms but not with a shorter (9-atom) spacer. These studies demonstrate for the first time that an appropriately designed bivalent ligand is capable of inducing association of G-protein-coupled receptors. The finding that opioid tolerance studies with these ligands in mice showed no correlation with the BRET data is consistent with the absence of association of MOP and CCK2 receptors in vivo.

Published
2009
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