8 results on '"Akgün, Eyup"'
Search Results
2. 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
- Full Text
- View/download PDF
3. Modulation of Cell Surface Expression of Nonactivated Cholecystokinin Receptors Using Bivalent Ligand-Induced Internalization.
- Author
-
Harikumar, Kaleeckal G., Akgün, Eyup, Portoghese, Philip S., and Miller, Laurence J.
- Abstract
CCK2 receptor antagonists potentiate pain relief by MOP receptor agonists. In an attempt to enhance this effect, we prepared bivalent ligands incorporating CCK2 receptor antagonist and MOP receptor agonist pharmacophores. Ligands with 16- to 22-atom spacers could simultaneously bind both receptors but provided no advantage in activity over individual ligands. We now examine the effect of these ligands on receptor internalization as a mechanism of receptor regulation. We prepared CHO cell lines expressing nonfluorescent halves (YN and YC) of yellow fluorescent protein attached to each receptor. Spatial approximation of constructs was needed to yield fluorescence. Monovalent MOP agonist 1 signaled normally and internalized the MOP receptor. Monovalent CCK2 antagonist 2 did not stimulate receptor internalization. In the dual receptor-bearing cells, bivalent ligands 3a−c capable of simultaneously binding both receptors resulted in cell surface fluorescence and internalization of the fluorescent complex in a time- and temperature-dependent manner. Bivalent ligand 4 with spacer too short to occupy both receptors simultaneously yielded no signal. Receptor tethering with appropriate bivalent ligands can down-regulate signaling by moving a nonactivated receptor into the endocytic pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
4. FBNTI, a DOR-Selective Antagonist That Allosterically Activates MOR within a MOR-DOR Heteromer.
- Author
-
Akgün E, Lunzer MM, Tian D, Ansonoff M, Pintar J, Bruce D, Hawkinson JE, Wilcox GL, and Portoghese PS
- Subjects
- Analgesics, Opioid chemistry, Animals, Calcium metabolism, HEK293 Cells, Humans, Injections, Spinal, Male, Mice, Mice, Inbred ICR, Mice, Knockout, Molecular Structure, Receptors, Opioid, delta genetics, Receptors, Opioid, delta metabolism, Analgesics, Opioid pharmacology, Receptors, Opioid, delta antagonists & inhibitors, Receptors, Opioid, mu agonists
- 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 ( K
i = 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 ED75 dose, 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
- Full Text
- View/download PDF
5. Heteromer Induction: An Approach to Unique Pharmacology?
- Author
-
Portoghese PS, Akgün E, and Lunzer MM
- Subjects
- Animals, Dose-Response Relationship, Drug, Humans, Ligands, Models, Chemical, Molecular Structure, Protein Binding drug effects, Receptor, Metabotropic Glutamate 5 chemistry, Receptor, Metabotropic Glutamate 5 metabolism, Receptors, Opioid, delta chemistry, Receptors, Opioid, mu chemistry, Structure-Activity Relationship, Analgesics, Opioid pharmacology, Protein Multimerization drug effects, Receptors, Opioid, delta agonists, Receptors, Opioid, mu agonists
- Abstract
It is proposed that two types of opioid receptor heteromers exist: a) those that are constitutive and b) those that are induced by bivalent ligands. Mu opioid agonists interact with constitutive MOR-DOR heteromer to mediate tolerance and dependence. Bivalent ligand, MDAN21, is devoid of these adverse effects by virtue of its DOR antagonist pharmacophore. We propose that bivalent ligands MMG22 and MCC22 induce colocalized receptors to form heteromers (MOR-mGluR5 and MOR-CCR5, respectively) that do not occur naturally, thereby promoting unique pharmacology. Heteromer induction with bivalent ligands offers a general approach to unique pharmacology that complements traditional SAR.
- Published
- 2017
- Full Text
- View/download PDF
6. Inhibition of Inflammatory and Neuropathic Pain by Targeting a Mu Opioid Receptor/Chemokine Receptor5 Heteromer (MOR-CCR5).
- Author
-
Akgün E, Javed MI, Lunzer MM, Powers MD, Sham YY, Watanabe Y, and Portoghese PS
- Subjects
- Animals, Chronic Disease, HEK293 Cells, Humans, Inflammation drug therapy, Inflammation immunology, Male, Mice, Models, Molecular, Molecular Targeted Therapy, Neuralgia immunology, Receptors, Opioid, mu immunology, Analgesics chemistry, Analgesics therapeutic use, CCR5 Receptor Antagonists chemistry, CCR5 Receptor Antagonists therapeutic use, Neuralgia drug therapy, Receptors, CCR5 immunology, Receptors, Opioid, mu agonists
- Abstract
Chemokine release promotes cross-talk between opioid and chemokine receptors that in part leads to reduced efficacy of morphine in the treatment of chronic pain. On the basis of the possibility that a MOR-CCR5 heteromer is involved in such cross-talk, we have synthesized bivalent ligands (MCC series) that contain mu opioid agonist and CCR5 antagonist pharmacophores linked through homologous spacers (14-24 atoms). When tested on lipopolysaccharide-inflamed mice, a member of the series (MCC22; 3e) with a 22-atom spacer exhibited profound antinociception (i.t. ED50 = 0.0146 pmol/mouse) that was 2000× greater than morphine. Moreover, MCC22 was ~3500× more potent than a mixture of mu agonist and CCR5 antagonist monovalent ligands. These data strongly suggest that MCC22 acts by bridging the protomers of a MOR-CCR5 heteromer having a TM5,6 interface. Molecular simulation studies are consistent with such bridging. This study supports the MOR-CCR5 heteromer as a novel target for the treatment of chronic pain., Competing Interests: Notes “The authors declare no competing financial interest.”
- Published
- 2015
- Full Text
- View/download PDF
7. Synthesis and in vitro characterization of radioiodinatable benzodiazepines selective for type 1 and type 2 cholecystokinin receptors.
- Author
-
Akgün E, Körner M, Gao F, Harikumar KG, Waser B, Reubi JC, Portoghese PS, and Miller LJ
- Subjects
- Animals, Autoradiography, Benzodiazepines chemistry, Benzodiazepines pharmacology, Binding Sites, CHO Cells, Calcium metabolism, Cricetinae, Cricetulus, Gallbladder diagnostic imaging, Gallbladder metabolism, Gastrointestinal Stromal Tumors diagnostic imaging, Gastrointestinal Stromal Tumors metabolism, Humans, Iodine Radioisotopes, Leiomyoma diagnostic imaging, Leiomyoma metabolism, Ligands, Meningioma diagnostic imaging, Meningioma metabolism, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacology, Radioligand Assay, Radionuclide Imaging, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacology, Receptor, Cholecystokinin A metabolism, Receptor, Cholecystokinin B metabolism, Stereoisomerism, Thyroid Neoplasms diagnostic imaging, Thyroid Neoplasms metabolism, Benzodiazepines chemical synthesis, Phenylurea Compounds chemical synthesis, Radiopharmaceuticals chemical synthesis, Receptor, Cholecystokinin A antagonists & inhibitors, Receptor, Cholecystokinin B antagonists & inhibitors
- Abstract
Radiolabeled antagonists of specific peptide receptors identify a higher number of receptor binding sites than agonists and may thus be preferable for in vivo tumor targeting. In this study, two novel radioiodinated 1,4-benzodiazepines, (S)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (9) and (R)-1-(3-iodophenyl)-3-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (7), were developed. They were characterized in vitro as high affinity selective antagonists at cholecystokinin types 1 and 2 (CCK(1) and CCK(2)) receptors using receptor binding, calcium mobilization, and internalization studies. Their binding to human tumor tissues was assessed with in vitro receptor autoradiography and compared with an established peptidic CCK agonist radioligand. The (125)I-labeled CCK(1) receptor-selective compound 9 often revealed a substantially higher amount of CCK(1) receptor binding sites in tumors than the agonist (125)I-CCK. Conversely, the radioiodinated CCK(2) receptor-selective compound 7 showed generally weaker tumor binding than (125)I-CCK. In conclusion, compound 9 is an excellent radioiodinated nonpeptidic antagonist ligand for direct and selective labeling of CCK(1) receptors in vitro. Moreover, it represents a suitable candidate to test antagonist binding to CCK(1) receptor-expressing tumors in vivo.
- Published
- 2009
- Full Text
- View/download PDF
8. 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
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.