Stereoselective inhibition of the binding of [3H]PK 11195 to peripheral-type benzodiazepine binding sites by a quinolinepropanamide derivative

Dubroeucq, Marie-Christine; Bénavidès, J.; Doble, Adam; Guilloux, Francoise; Allam, D.; Vaucher, Nadine; Bertrand, Philìppe; Guérémy, C.; Renault, C.; Uzan, A.; Fur, G. Le

doi:10.1016/0014-2999(86)90776-4

Cited by 35 publications

(10 citation statements)

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“…3H-Ro 5-4864 and 3H-PK 11195 have been used to identify, characterize and localize the peripheral-type benzodiazepine receptors in the peripheral organs as well as in the central nervous system. [7][8][9][10][11][12] In the brain, high densities of peripheral-type benzodiazepine receptors have been observed in the choroid plexus, ependyma and olfactory bulb. 11,[13][14][15] Recently, high accumulations of 3H-PK 11195 in the transplanted glioma in the rat were reported.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of11C-PK 11195 forin vivo study of peripheral-type benzodiazepine receptors using position emission tomography

et al. 1989

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The biodistribution of 3H-PK 11195, an antagonist of the peripheral-type benzodiazepine receptors, was studied in mice. High accumulations of radioactivity in the heart, lung, spleen, kidney and adrenal were observed after intravenous injection of tracer amounts of 3H-PK 11195 into the mice. The radioactivity in the heart, lung, spleen, kidney and adrenal was significantly decreased by the coadministration of carrier PK 11195, which indicated that PK 11195 specifically binds to the receptors. No radioactive metabolites were observed in the heart, lung and brain 20 min after intravenous administration of 3H-PK 11195. The accumulation of 3H-PK 11195 in the lung was not affected by pretreatment with either alpha-methyl benzylamine or imipramine, suggesting that 3H-PK 11195 specifically binds to the receptors. The ratios of radioactivity of the kidney, adrenal and spleen to blood increased as a function of time, whereas that of the lung and heart rapidly reached to a steady state. 11C-PK 11195 was synthesized by the N-methylation of desmethyl precursor yielding more than 100 mCi with high specific activity (more than 1.4 Ci/mumol). The labeling and purification procedure was completed within 23 min after the end of bombardment (EOB). The 11C-PK 11195 solution for injection seems to have a high potential for the in vivo study of the peripheral-type benzodiazepine receptors in the living human by means of positron emission tomography (PET).

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Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of11C-PK 11195 forin vivo study of peripheral-type benzodiazepine receptors using position emission tomography

et al. 1989

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“…Nine ligands, exhibiting a range greater than four orders of magnitude in their affinities for PBRs, were examined for their potencies to inhibit 3H-labeled PK 11195 binding to Y--1 cells at 370C ( 14068 (25). Also at 37°C, benzodiazepines, 4'-chlorodiazepam, diazepam, and flunitrazepam showed a relatively low potency compared to PK 11195, which is in agreement with a report (26) that demonstrated that the binding of benzodiazepines to PBRs is a temperature-sensitive enthalpy-driven process.…”

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confidence: 99%

Mitochondrial benzodiazepine receptors regulate steroid biosynthesis.

Mukhin

Papadopoulos

Costa

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

192

110

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Recent observations on the steroid synthetic capability within the brain open the possibility that benzodiazepines may influence steroid synthesis in nervous tissue through interactions with peripheral-type benzodiazepine recognition sites, which are highly expressed in steroidogenic cells and associated with the outer mitochondrial membrane. To examine this possibility nine molecules that exhibit a greater than 10,000-fold difference in their affinities for peripheral-type benzodiazepine binding sites were tested for their effects on a well-established steroidogenic model system, the Y-1 mouse adrenal tumor cell line. 4'-Chlorodiazepam, PK 11195, and PK 14067 stimulated steroid production by 2-fold in Y-1 cells, whereas diazepam, flunitrazepam, zolpidem, and PK 14068 displayed a lower (1.2- to 1.5-fold) maximal stimulation. In contrast, clonazepam and flumazenil did not stimulate steroid synthesis. The potencies of these compounds to inhibit 3H-labeled PK 11195 binding to peripheral-type benzodiazepine recognition sites correlated (r = 0.985) with their potencies to stimulate steroid production. Similar findings were observed in bovine and rat adrenocortical cell preparations. These results suggest that ligands of the peripheral-type benzodiazepine recognition site acting on this mitochondrial receptor can enhance steroid production. This action may contribute specificity to the pharmacological profile of drugs preferentially acting on the benzodiazepine recognition site associated with the outer membrane of certain mitochondrial populations.

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“…Alternatively, qualitative differences may exist between the "anxiety states" induced by pharmacological manipulation of neuronal and non-neuronal benzodiazepine binding sites. The apparent analgesic efficacy of PK14068, a compound virtually inactive at both sites (Dubroeucq et al 1986), cannot be explained on the basis of currently available information (Doble, personal communication) and must therefore await further pharmacological characterization.…”

Section: Discussionmentioning

confidence: 98%

“…PKl1195, a isoquinoline carboxamide derivative, has very high selective affinity for non-neuronal sites with an ICso of 0.25-0.76 nM for inhibition of [aH]-Ro05-4864 binding in brain (LeFur et al 1983 a, b). Finally, the l-and d-enantiomers of N,N-diethyl-~-methyl-2-phenyl-4-quinolinepropanamide (PK14067 and PK14068, respectively) have recently been shown to stereospecifically bind to non-neuronal sites but to have only very low affinity for neuronal sites; ICso values of 8nM (PK14067) and 4000nM (PK14068) for the inhibition of [3H]-PKl1195 binding in brain have been reported (Dubroeucq et al 1986). …”

mentioning

confidence: 96%

Blockade of non-opioid analgesia in intruder mice by selective neuronal and non-neuronal benzodiazepine recognition site ligands

Rodgers

Randall

1988

Psychopharmacology

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In male mice, the biologically significant experience of social defeat is associated with an acute non-opioid form of analgesia. Recent studies have shown that this reaction is sensitive to certain benzodiazepine receptor ligands but is unaffected by others. The present experiments were designed to assess the possibility that activity at "non-neuronal" benzodiazepine binding sites might account for this unusual pharmacological profile. Our results show that defeat analgesia was blocked by clonazepam (0.06-3 mg/kg), Ro05-4864 (2.5-20 mg/kg), Ro05-5115 (20 mg/kg), PK11195 (5-20 mg/kg) and PK14067 (10-20 mg/kg). Furthermore, when given in combination, subthreshold doses of PK11195 (2.5 mg/kg) and clonazepam (0.03 mg/kg) totally prevented defeat analgesia. All of these effects were observed in the absence of intrinsic activity on basal nociception. Together with earlier findings, current data imply that inhibition of defeat analgesia by ligands for neuronal and/or non-neuronal benzodiazepine recognition sites is most probably unrelated to their activity at these sites. Alternative explanations for the overall patterns of results are considered.

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Stereoselective inhibition of the binding of [3H]PK 11195 to peripheral-type benzodiazepine binding sites by a quinolinepropanamide derivative

Cited by 35 publications

References 10 publications

Synthesis and evaluation of11C-PK 11195 forin vivo study of peripheral-type benzodiazepine receptors using position emission tomography

Synthesis and evaluation of11C-PK 11195 forin vivo study of peripheral-type benzodiazepine receptors using position emission tomography

Mitochondrial benzodiazepine receptors regulate steroid biosynthesis.

Blockade of non-opioid analgesia in intruder mice by selective neuronal and non-neuronal benzodiazepine recognition site ligands

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