In vivo immunomodulating activity of PK 1195, a structurally unrelated ligand for “peripheral” benzodiazepine binding sites — I. Potentiation in mice of the humoral response to sheep red blood cells

doi:10.1016/0192-0561(86)90021-4

International Journal of Immunopharmacology

Volume 8, Issue 7, 1986, Pages 825-828

International Journa...

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Abstract

PK 11195, an isoquinoline carboxamide compound with the highest affinity for the peripheral type benzodiazepine binding site has been shown to enhance the humoral response of mice to sheep red blood cells, a T cell dependent antigen. The compound was active when administered i.p. 1 day following immunization. The active doses ranged from 10 ng to 1 mg/kg. Such an immunomodulating activity might be related to the presence of peripheral type benzodiazepine binding sites, previously detected on the macrophage.

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Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair
2008, Pharmacology and Therapeutics
For over 15 years, the peripheral benzodiazepine receptor (PBR), recently named translocator protein 18 kDa (TSPO) has been studied as a biomarker of reactive gliosis and inflammation associated with a variety of neuropathological conditions. Early studies documented that in the brain parenchyma, TSPO is exclusively localized in glial cells. Under normal physiological conditions, TSPO levels are low in the brain neuropil but they markedly increase at sites of brain injury and inflammation making it uniquely suited for assessing active gliosis. This research has generated significant efforts from multiple research groups throughout the world to apply TSPO as a marker of “active” brain pathology using in vivo imaging modalities such as Positron Emission Tomography (PET) in experimental animals and humans. Further, in the last few years, there has been an increased interest in understanding the molecular and cellular function(s) of TSPO in glial cells. The latest evidence suggests that TSPO may not only serve as a biomarker of active brain disease but also the use of TSPO-specific ligands may have therapeutic implications in brain injury and repair. This review presents an overview of the history and function of TSPO focusing on studies related to its use as a sensor of active brain disease in experimental animals and in human studies.
Strategy for improved [11C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [11C]DAA1106
2007, Nuclear Medicine and Biology
The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [¹¹C]DAA1106 ([¹¹C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs.
A four-step synthetic route was devised to prepare DAA1123, the precursor for [¹¹C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [¹¹C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [¹¹C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [¹¹C]CH₃I trapped. Evaluation of [¹¹C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry.
The standard solution method produced 2.6–5.2 GBq (n=19) of [¹¹C]DAA1106, whilst the captive solvent method produced 1.6–6.3 GBq (n=10) of [¹¹C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/μmol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [¹¹C]DAA1106. In vivo microPET [¹¹C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 μmol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry.
A robust, high yielding captive solvent method of [¹¹C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.
Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands
2004, Bioorganic and Medicinal Chemistry
Citation Excerpt :
cDNA encoding PBR has been cloned from humans,16 bovines,17 rats18 and mice.19 PBR plays roles in cell proliferation,20 steroidogenesis,21 calcium flow,22 cellular respiration,23 cellular immunity,24 and malignancy.25 As endogenous ligands for peripheral benzodiazepine receptors (PBRs), anthraline, diazepam-binding inhibitor (DBI) and proptoporphyrin IV have been reported.
Since the peripheral benzodiazepine receptor (PBR) has been primarily found as a high-affinity binding site for diazepam in rat kidney, numerous studies of it have been performed. However, the physiological role and functions of PBR have not been fully elucidated. Currently, we presented the pharmacological profile of two high and selective PBR ligands, N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl)acetamide (7-096, DAA1106) (PBR: IC₅₀=0.28 nM) and N-(4-chloro-2-phenoxyphenyl)-N-(2-isopropoxybenzyl)acetamide (7-099, DAA1097) (PBR: IC₅₀=0.92 nM). The compounds are aryloxyanilide derivatives, and identified with known PBR ligands such as benzodiazepine (1, Ro5-4864), isoquinoline (2, PK11195), imidazopyridine (3, Alpidem), and indole (5, FGIN-1-27) derivatives. The aryloxyanilide derivatives, which have been derived by opening the diazepine ring of 1, are a novel class as PBR ligands and have exhibited high and selective affinity for peripheral benzodiazepine receptors (PBRs). These novel derivatives would be useful for exploring the functions of PBR. In this paper, the design, synthesis and structure–affinity relationships of aryloxyanilide derivatives are described.
Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: Evidence from activated microglial cells in vitro
2003, Neurobiology of Disease
Increased binding of a ligand for the peripheral benzodiazepine binding receptor is currently used in PET studies as an in vivo measurement of inflammation in diseases like multiple sclerosis and Alzheimer's disease. Although peripheral-type benzodiazepin receptors (PBRs) are abundant in many cell types and expressed in the CNS physiologically only at low levels, previous reports suggest that after experimental lesions in animal models and in human neurodegenerative/-inflammatory diseases upregulated PBR expression with increased binding of its ligand PK11195 is confined mainly to activated microglia in vivo/in situ. Because the functional role of the PBR is unknown, we confirm by immunohistochemistry and PCR (I) that this receptor is expressed on microglia in vitro and (II) that benzodiazepines modulate proliferation of microglial cells and the release of the inflammatory molecules nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) in cell culture supernatants of primary rat microglia. Compared to lipopolysaccharide-activated controls the release of NO was markedly decreased in cultures treated with benzodiazepines (clonazepam, midazolam, diazepam) and the PBR ligand PK11195. Moreover, release of TNF-α and proliferation was significantly inhibited in the benzodiazepine-treated groups. These findings link the in vivo data of elevated PBR levels in neurodegenerative/-inflammatory diseases to a functional role and opens up possible therapeutic intervention targeting the PBR in microglia.
Involvement of the peripheral benzodiazepine receptor in the development of rheumatoid arthritis in Mrl/lpr mice
2002, European Journal of Pharmacology
In this study, the effects of different peripheral benzodiazepine receptor ligands: PK 11195 [1-(2-chloro-phenyl)-N-methyl-N-(1-methylpropyl)-1-isoquinoline carboxamide], Ro5-4864 [7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one] and the newly described SSR 180575 (7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridozine[4,5-b] indole-1-acetamide) were analysed on the progression and severity of rheumatoid arthritis in vivo in the Mrl/lpr mice model, following chronic treatment (at 3 mg/kg, i.p. for 30 days). We found that peripheral benzodiazepine receptor ligands have significant beneficial therapeutic action on the development of spontaneous rheumatoid arthritis-like signs. Concomitantly, we mapped immunoreactive peripheral benzodiazepine receptor in inflamed tissues, and we observed that in addition to the infiltrated leukocytes, peripheral benzodiazepine receptor was expressed in synovial membranes, at the cartilage pannus junction and in chondrocytes. Interestingly, we observed that peripheral benzodiazepine receptor expression in chondrocytes was reduced when Mrl/lpr mice developed the pathology and restored upon peripheral benzodiazepine receptor ligand treatment. Altogether, our data provide further evidence of a role played by peripheral benzodiazepine receptor in the regulation of inflammation processes and support new therapeutic applications for specific potent peripheral benzodiazepine receptor ligands.
Binding of [3H]CB 34, a selective ligand for peripheral benzodiazepine receptors, to rat brain membranes
2001, European Journal of Pharmacology
The 2-phenyl-imidazo[1,2-a]pyridine derivative CB 34 is a ligand for peripheral benzodiazepine receptors. The binding of [³H]CB 34 to rat cerebrocortical membranes was characterized. Specific binding was rapid, reversible, saturable and of high affinity. Kinetic analysis yielded association and dissociation rate constants of 0.2×10⁸ M⁻¹ min⁻¹ and 0.29 min⁻¹, respectively. Saturation binding experiments revealed a single class of binding sites with a total binding capacity of 188±8 fmol/mg protein and an apparent dissociation constant of 0.19±0.02 nM. Specific [³H]CB 34 binding was inhibited by ligands selective for peripheral benzodiazepine receptors, whereas, with the exception of flunitrazepam and diazepam, ligands for central benzodiazepine receptors were inactive. Of the brain regions examined, the density of the [³H]CB 34-binding sites was greatest in the hypothalamus and lowest in the cerebral cortex. [³H]CB 34 is thus a potent and selective ligand for peripheral benzodiazepine receptors and should be proven useful for studies of the roles of these receptors.

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International Journal of Immunopharmacology

Abstract

References (20)

Opposite effects of an agonist Ro 5-4864 and an antagonist PK 11195 of the peripheral type benzodiazepine binding sites on audiogenic seizures on DBA/2 J mice

Life Sci.

Suppression of humoral and cellular immunity in normal mice by diazepam

Immun. Lett.

The anxiogenic action of Ro 5-4864 is reversed by phenytoin

Neurosci. Lett.

Adverse influence of diazepam upon resistance to Klebsiella pneumoniae infection in mice

Toxicol. Lett.

Peripheral benzodiazepine binding sites: Effect of PK 11195 1-(2-chlorophenyl)-N-methyl-(1-methylpropyl)-3 isoquinoleine

Life Sci.

Peripheral benzodiazepine binding sites: effect of PK 11195 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide — I. In vitro studies

Life Sci.

The benzodiazepine receptor functional complexity

TIPS

Electrophysiological and pharmacological evidence that perpheral type benzodiazepine receptors are coupled to calcium channels in the heart

Life Sci.

Interactions of benzodiazepines with mouse macrophages

Eur. J. Pharmac.

Properties of benzodiazepine binding sites in peripheral tissues

Cited by (28)

Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair

Strategy for improved [<sup>11</sup>C]DAA1106 radiosynthesis and in vivo peripheral benzodiazepine receptor imaging using microPET, evaluation of [<sup>11</sup>C]DAA1106

Design, synthesis and structure-affinity relationships of aryloxyanilide derivatives as novel peripheral benzodiazepine receptor ligands

Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: Evidence from activated microglial cells in vitro

Involvement of the peripheral benzodiazepine receptor in the development of rheumatoid arthritis in Mrl/lpr mice

Binding of [<sup>3</sup>H]CB 34, a selective ligand for peripheral benzodiazepine receptors, to rat brain membranes

ImmunotoxicologyIn vivo immunomodulating activity of PK 1195, a structurally unrelated ligand for “peripheral” benzodiazepine binding sites — I. Potentiation in mice of the humoral response to sheep red blood cells

Abstract

Life Sci.

Immun. Lett.

Neurosci. Lett.

Toxicol. Lett.

Life Sci.

Life Sci.

TIPS

Life Sci.

Eur. J. Pharmac.

Properties of benzodiazepine binding sites in peripheral tissues

Immunotoxicology
In vivo immunomodulating activity of PK 1195, a structurally unrelated ligand for “peripheral” benzodiazepine binding sites — I. Potentiation in mice of the humoral response to sheep red blood cells