Disease relevance of RP 52028

• As increasing amounts of unlabeled PK 11195 were added to the radioactive ligand, the myocardial ligand concentration was proportional to myocardial regional perfusion up to quantities of 40 nmol/kg body weight [1].
• In vitro studies of surgically removed specimens of human glioma demonstrated little binding of Ro5-4864 but high levels of binding of another selective ligand, PK 11195 [2].
• In addition, prominent bundles of collagen fibers (fibrosis) were commonly found in livers of rats that had been treated with DDC or DDC and PK 11195 [3].
• We examined the biochemical and ultrastructural alterations in rat liver following experimentally induced acute hepatic porphyria, as well as the effects of the administration of a selective PBR ligand, PK 11195 [3].
• The increased binding of both ligands correlated to extent of neuronal loss, but only PK 11195 showed correlation to degree of gliosis [4].

Psychiatry related information on RP 52028

• Animal and human autoradiographic studies have shown increased in vitro binding of the peripheral benzodiazepine binding site antagonist PK 11195 in areas of microgliosis, including the temporal association cortex of patients with Alzheimer's disease [5].
• However, at 90 mg/kg PK 11195 also reduced social interaction, indicating an anxiogenic effect [6].

High impact information on RP 52028

• The chemotactic effects of benzodiazepine receptor agonists were blocked by the peripheral benzodiazepine receptor antagonist PK-11195, suggesting that these effects are mediated by the peripheral-type benzodiazepine receptor [7].
• We conclude that the PK 11195 manifests greater binding than Ro5-4864 to the peripheral-type benzodiazepine binding site on human gliomas and that human gliomas can be successfully imaged using [11C]PK 11195 and PET [2].
• High affinity binding of isoquinolines, such as PK 11195, is a conserved feature of peripheral-type benzodiazepine receptors (PBR) across species [8].
• The adrenocorticotropin (ACTH)-responsive Y-1 mouse adrenocortical cell line was used to compare the mechanisms by which ACTH and PK 11195 (a PBR ligand) stimulate steroidogenesis [9].
• These increases were accounted for by the expression of binding sites with approximate dissociation constants of 5 nM for PK 11195 and 8 nM for Ro5-4864, thereby distinguishing the expressed binding sites as being characteristic of the receptor from rat origin rather than of the host human-derived cell line [10].

Chemical compound and disease context of RP 52028

• Three novel peripheral-type benzodiazepine binding site (PBBS) ligands, NF 182, 213 and 262, along with the classically used PBBS ligands, PK 11195 and Ro5-4864, were found to inhibit, at micromolar concentrations and in dose-dependent manner, the proliferation of rat C6 glioma and human 1321N1 astrocytoma, without being cytotoxic [11].
• Pertussis toxin potentiates the antagonist effects of Ro 5-4864 and PK 11195 on carbachol-induced contractions, but cholera toxin does not affect them [12].
• Moreover, induced PBR protein expression in E. coli protoplasts caused an uptake of PPIX that could be completely inhibited by cholesterol and to a lesser extent inhibited by PK 11195 and Ro5-4864 [13].
• Attenuation of ammonia toxicity in mice by PK 11195 and pregnenolone sulfate [14].
• Ro 5-4864 potentiated whereas PK 11195 inhibited the myocardial ischemia produced by Bay K 8644 in the rat [15].

Biological context of RP 52028

• With 7-[(dimethylcarbamoyl)oxy]-6-(p-methoxyphenyl)pyrrolo[2,1- d][1,5]benzothiazepine (65), these were the most promising compounds with IC50s of respectively 9, 8, and 9 nM, under conditions where PK 11195 had an IC50 of 2 nM [16].
• PSC apoptosis was also induced by PK-11195, a ligand of the peripheral benzodiazepine receptor [17].
• In this same concentration range, PK 11195 and Ro 5-4864, in contrast to clonazepam, induced an accumulation of MCF-7 cells in both the G0-G1 and G2-M phases of the cell cycle [18].
• After cell exposure to PK 11195 or Ro5-4864 we evidenced typical alterations of apoptotic cell death such as DNA fragmentation and chromatin condensation assessed by flow cytometric and transmission electron microscopy (TEM) analysis, respectively [19].
• PBR knockdown by RNA inhibition did not affect the proliferation of either cell type and did not influence the inhibitory effect of PK 11195 and Ro5-4864 on cell growth [20].

Anatomical context of RP 52028

• In vivo, Ro5-4864 increased the initiation of regeneration after a sciatic nerve crush injury and the number of GAP-43-positive axons in the distal nerve while PK 11195 inhibited the enhanced growth produced by a preconditioning lesion [21].
• The subcellular distribution patterns of specific PK 11195 binding sites were unrelated to the distribution patterns of marker enzymes for plasma membranes, lysosomes, or endoplasmic reticulum [22].
• When DRG cells were preconditioned into an active growth state by a prior peripheral nerve injury Ro5-4864 augmented and PK 11195, a PBR antagonist, blocked the injury-induced increased outgrowth [21].
• Further differences between the binding of PK 11195 and Ro5-4864 in astrocytes were detected in the presence of ethanol which was more effective in inhibiting the binding of the latter [23].
• Inhibition studies in rats following intravenous pre-administration of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195, 1) showed high specific binding to PBR of [11C]4, [11C]5, and [11C]6 in heart, lung, kidney, adrenal gland, spleen, and brain [24].

Associations of RP 52028 with other chemical compounds

• The potency of PK 11195, Ro 5-4864, diazepam, flurazepam, chlordiazepoxide, Ro 15-1788, methyl-beta-carboline-3-carboxylate, and clonazepam to displace bound [3H]Ro 5-4864 from peripheral binding sites was similar in the membrane-bound and the soluble states [25].
• In contrast, compounds such as Ro 5-6900 and PK 11195, which bind with very high affinities to "peripheral-type" binding sites, are neither convulsants nor do they antagonize the convulsant actions of Ro 5-4864 [26].
• Moreover, photoirradiation increased PK 11195 drug ligand binding and reduced cholesterol binding capacity of proteoliposomes [27].
• The order of potency of several compounds as displacers at 25 degrees C (PK 11195 greater than RO5-4864 greater than diazepam greater than dipyridamole greater than clonazepam) demonstrates that [3H]PK 11195 binds to the peripheral-type benzodiazepine binding sites [28].
• The rank order of potency of the competitive inhibition of [3H]Ro5-4864 binding (Ro5-4864 = PK 11195 greater than diazepam = flunitrazepam much greater than clonazepam greater than Ro15-1788) is characteristic of the peripheral-type benzodiazepine binding site [29].

Gene context of RP 52028

• We have recently reported a significant decrease in the density of BZRP labeled by [3H] PK 11195 in the postmortem brain of chronic schizophrenics, suggesting that dysfunctions of the BZRP are involved in the pathophysiology of schizophrenia [30].
• Our studies show that PBR expression as measured by PK 11195 ligand binding and Western analysis is much higher in MA-10 cells than R2C cells [31].
• Moreover, PK-11195 delayed the [Ca2+]i rise induced by TTN but did not significantly affect its extent, and had no effect on the [Ca2+]i rise induced by ENP [32].
• In vitro inhibition of cellular immune responses by benzodiazepines and PK 11195. Effects on mitogen- and alloantigen-driven lymphocyte proliferation and on IL-1, IL-2 synthesis and IL-2 receptor expression [33].
• Binding of PK 11195 in both m- and p-fractions from AT-1 tumors, but only in m-fraction from ventral and dorsolateral prostate, was specific, saturable, and of high affinity [34].

Analytical, diagnostic and therapeutic context of RP 52028

• These results support the use of radiolabeled PK 11195 for clinical trials of imaging human gliomas by positron emission tomography [35].
• Moreover, PK 11195 and Ro5-4864 induced a decrease of DeltaPsi(m), as evidenced by JC-1 flow cytometry analysis [19].
• Whereas PK 11195 blocked the effect of FGIN-1-27 and partially blocked alpidem, it did not affect THDOC in both animal models of anxiety.(ABSTRACT TRUNCATED AT 250 WORDS)[36]
• The anxiolytic effects of intrahippocampal or intraseptal injection of pregnanolone were blocked by intracranial pretreatment with 20 ng of picrotoxin, but not by microinjection of 5 micrograms of flumazenil or 200 ng of PK 11195 [37].
• Scatchard analysis of saturation curves of [3H]PK 11195 binding to liver membranes of rats treated with lead alone or with both lead and PK 11195 showed and approximately two-fold decrease in receptor density in comparison with control groups [38].

References