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1.
The effect of GABA on in vitro binding of two novel non-benzodiazepines, PK 8165 and CGS 8216, to benzodiazepine receptors in the rat brain 总被引:1,自引:0,他引:1
The effect of gamma-aminobutyric acid (GABA) on the binding of PK 8165, a quinoline derivative, and CGS 8216, a pyrazoloquinoline, was assessed in two different regions of the rat brain. PK 8165, a compound with reported anxiolytic properties, inhibited [3H]-propyl beta-carboline-3-carboxylate labeled receptors in the cerebellum with an IC50 of 844 nM and 370 nM in the absence and presence of micro M GABA, respectively. GABA (100 micro M) was less effective in the cerebral cortex, decreasing the IC50 value from 280 to 197 nM. In saturation isotherm studies with [3H]-CGS 8216, a benzodiazepine receptor antagonist, GABA (100 micro M) induced a small but significant reduction in the apparent affinity of [3H]-CGS 8216 for benzodiazepine receptors in the cerebral cortex but the Bmax was unchanged. 相似文献
2.
M Mestre T Carriot G Néliat A Uzan C Renault M C Dubroeucq C Guérémy A Doble G Le Fur 《Life sciences》1986,39(4):329-339
In a partially depolarized guinea pig papillary muscle preparation, BAY K8644 stimulated voltage-operated calcium channels, promoting slow action potentials; this effect was dose-dependent over a concentration range of 3 X 10(-7) M to 3 X 10(-6) M. Isoproterenol and histamine also induced slow action potentials by stimulating beta or H2 receptors, respectively. PK 11195, the antagonist of peripheral type benzodiazepine receptors, inhibited the effect of BAY K8644, but not those of histamine or isoproterenol. Moreover, PK 11195 "dose-dependently" antagonized the ability of RO5-4864 to inhibit the slow action potentials elicited by barium chloride. Thus, in the heart, PK 11195, an antagonist of peripheral type benzodiazepine receptors, can modulate voltage-operated calcium channels when they are activated directly, but not when they are activated by stimulation of neurotransmitter receptors. 相似文献
3.
Park SY Cho N Chang I Chung JH Min YK Lee MK Kim KW Kim SJ Lee MS 《Apoptosis : an international journal on programmed cell death》2005,10(3):537-544
Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A,{ a blocker of mitochondrial permeability transition pore}. Caspase inhibitors further inhibited MIN6N8 cell death. PK11195 induced dissipation of mitochondrial potential and cytochrome c translocation to cytoplasm. PK11195 induced an increase in cytoplasmic [Ca2 +], which was reversed by cyclosporin A. Rhod-2 staining showed decreased mitochondrial [Ca2 +] after PK11195 treatment. PK11195 potentiated glucose-induced insulin secretion probably due to the increased cytoplasmic [Ca2 +]. Calpain was activated following Ca2 + release, and calpain inhibitors attenuated death of insulinoma cells by PK11195. These results suggest that PK11195 induces mitochondrial potential loss, cytochrome c translocation, increased insulin secretion in conjunction with an increase in cytoplasmic [Ca2 +] and calpain activation, which collectively leads to apoptosis of insulinoma cells. 相似文献
4.
Intraperitoneal administration of 5 mg/kg zopiclone a cyclopyrolone acting on the central benzodiazepine receptors was found to produce significant reduction of total lipids, total cholesterol and triglyceride in rats randered hyperlipidemic by intraperitoneal injection of Triton W-1339. Blood glucose level was also reduced. Flumazenil (10 mg/kg) potentiated the hypoglicemic effect of zopiclone but had no additional effect on serum lipids. PK 11195 (25 mg/kg) antagonized the hypolipidemic effects of zopiclone. In conclusion: 1. The central benzodiazepine receptors are not involved in the hypolipidemic activity of zopiclone. 2. The peripheral type benzodiazepine receptors are partly responsible, for the hypolipidemic activity of this cyclopirrolone. 3. The changes of blood glucose level induced by these drugs does not seem to be related to benzodiazepine receptors. 相似文献
5.
Opposite effects of two ligands for peripheral type benzodiazepine binding sites, PK 11195 and RO5-4864, in a conflict situation in the rat 总被引:7,自引:0,他引:7
J Mizoule A Gauthier A Uzan C Renault M C Dubroeucq C Guérémy G Le Fur 《Life sciences》1985,36(11):1059-1068
The effects of two drugs acting at the peripheral type benzodiazepine binding sites, PK 11195 and RO5-4864, were examined in shock-induced suppression of drinking in rats. These two compounds have opposite effects : RO5-4864 (3.1-1205 mg/kg i.p.) enhanced whereas PK 11195 (25-50 mg/kg i.p.) decreased the punished responding, and PK 11195 (6.25 mg/kg, a dose which did not alter the punished responding) blocked the proconflict action of RO5-4864 (6.25 and 12.5 mg/kg). The effects of RO5-4864 and PK 11195 were not antagonized by RO15-1788, a selective antagonist of the central benzodiazepine site. In addition, PK 11195 (6.25 mg/kg) did not reverse the proconflict effect of two beta-carbolines : beta-CEE and FG 7142. AS picrotoxin did not change the punished responding, these data imply that the effects of RO5-4864 and PK 11195 on the one hand and those of chlordiazepoxide and beta-carbolines on the other hand are differentially mediated and suggest that the peripheral type benzodiazepine binding sites are involved in this conflict model. 相似文献
6.
3H-Diazepam binding to a total particulate fraction of rat forebrain is enhanced by (+)-etomidate and GABA, but not by (?)-etomidate. The enhancement of 3H-diazepam binding by (+)-etomidate was due to a two-fold increase in binding affinity, the maximal number of sites remained unchanged. The degree of stimulation with (+)-etomidate was higher than that obtained with GABA. THIP did not stimulate 3H-diazepam binding to forebrain, and did not reverse the enhanced binding seen with (+)-etomidate or GABA. In a synaptosomal membrane preparation of rat cerebellum, unlike (+)-etomidate, GABA and muscimol produced a marked stimulation of 3H-diazepam binding. (+)-Etomidate did not inhibit 3-muscimol binding to GABA receptors, nor did it activate or inhibit other receptor binding assays. The effects of (+)-etomidate on the benzodiazepine binding are different from those of gabamimetic drugs. It is proposed that like barbiturates, (+)-etomidate may affect benzodiazepine binding by interaction with the chloride ionophore which is coupled to the GABA-receptor. 相似文献
7.
Nancy C. Lan Jie-Sheng Chen Deborah Johnson † Kelvin W. Gee 《Journal of neurochemistry》1995,64(2):684-688
Abstract: The interactions of the atypical benzodiazepine 4'-chlorodiazepam (Ro 5-4864) with functionally expressed human GABAA receptor cDNAs were determined. Cotransfection of human α2 , β1 , and γ2 subunits was capable of reconstituting a 4'-chlorodiazepam recognition site as revealed by a dose-dependent potentiation of t -[35 S]butylbicyclophosphorothionate ([35 S]TBPS) binding to the GABA-activated chloride channel. This site is found on GABAA receptor complexes containing sites for GABA agonist-like benzodiazepines and neuroactive steroids. The importance of the α subunit was further demonstrated as substitution of either α1 or α3 for the α2 subunit did not reconstitute a 4'-chlorodiazepam recognition site that was capable of modulating [35 S]TBPS binding under the same experimental conditions. The 4'-chlorodiazepam modulatory site was shown to be distinct from the benzodiazepine site, but the phenylquinolines PK 8165 and PK 9084 produced effects similar to 4'-chlorodiazepam, consistent with the previous analysis of the 4'-chlorodiazepam site in brain homogenates. Further analysis of the subunit requirements revealed that coexpression of α2 and β1 alone reconstituted a 4'-chlorodiazepam recognition site. It is interesting, however, that the 4'-chlorodiazepam site was found to inhibit [35 S]TBPS binding to the GABA-activated chloride channel. Thus, the 4'-chlorodiazepam site may be reconstituted with only the α and β polypeptides. 相似文献
8.
Avermectin B1a, an antihelminthic macrocyclic lactone, has been previously shown to reduce muscle membrane resistance by stimulating γ-aminobutyric acid-mediated chloride conductance. Since the benzodiazepine receptor is coupled to a receptor for γ-aminobutyric acid and related chloride ionophore, the effects of Avermectin B1a on [3H]diazepam binding to the benzodiazepine receptor were studied. In well-washed membrane fragments from rat cerebral cortex, Avermectin B1a markedly increased the binding of [3H]diazepam to benzodiazepine receptors. This effect was qualitatively similar to that observed with either γ-aminobutyric acid or chloride ion and was partially reversed by the γ-aminobutyric acid receptor antagonist, bicuculline. In contrast to the effects of γ-aminobutyric acid and chloride, the enhanced binding of [3H]benzodiazepine elicited by Avermectin B1a was reversed by extensive washing of the membrane preparation. Avermectin B1a appears to irreversibly modify benzodiazepine receptors at a γ-aminobutyric acid-chloride recognition site and may be valuable in biochemical studies of the regulation of benzodiazepine receptor function. 相似文献
9.
《Life sciences》1987,40(15):1537-1543
The pineal gland and particularly its major hormone, melatonin, may participate in several physiological functions, including sleep promotion, anticonvulsant activity and the modulation of biological rhythms and affective disorders. These effects may be related to an interaction with benzodiazepine receptors, which have been demonstrated to be present in the pineal gland of several species including man. The present study examined the characteristics of benzodiazepine binding site subtypes in the human pineal gland, using [3H] flunitrazepam and [3H] PK 11195 as specific ligands for central and peripheral type benzodiazepine binding sites respectively. Scatchard analysis of [3H] flunitrazepam binding to pineal membrane preparations was linear, indicating the presence of a single population of sites. Clonazepam and RO 15-1788, which have a high affinity for central benzodiazepine binding sites, were potent competitors for [3H] flunitrazepam binding in the human pineal, whereas RO 5-4864 had a low affinity for these sites. Analyses of [3H] PK 11195 binding to pineal membranes also revealed the presence of a single population of sites. RO 5-4864, a specific ligand for peripheral benzodiazepine binding sites was the most potent of the drugs tested in displacing [3H] PK 11195, whereas clonazepam and RO 15-1788 were weak inhibitors of [3H] PK 11195 binding to pineal membranes. Overall, these results demonstrate, for the first time, the coexistence of peripheral and central benzodiazepine binding sites in the human pineal gland. 相似文献
10.
G. Le Fur M.L. Perrier N. Vaucher F. Imbault A. Flamier J. Benavides A. Uzan C. Renault M.C. Dubroeucq C. Guérémy 《Life sciences》1983,32(16):1839-1847
[3H] R05-4864 binding sites have been characterized in kidney, heart, brain, adrenals and platelets in the rat. In all these organs the following order of potency in the R05-4864 displacement was found : R05-4864 > diazepam > clonazepam indicating that they correspond to the “peripheral type” of benzodiazepine binding sites. PK 11195, an isoquinoline carboxamide derivative, displaces [3H] R05-4864 from its binding sites in all the organs. PK 11195 was as potent as R05-4864 in the platelets, heart, adrenals, kidney and several brain regions (midbrain, hypothalamus, medulla + pons and hippocampus. However it was 5 to 10 times more effective in cortex and striatum. In conclusion PK 11195 might represent a new tool to elucidate the physiological relevance of “peripheral type” benzodiazepine binding sites and might help to discriminate the hypothetical subclasses of these binding sites. 相似文献
11.
J Bénavidès F Begassat T Phan C Tur A Uzan C Renault M C Dubroeucq C Guérémy G Le Fur 《Life sciences》1984,35(12):1249-1256
[3H]PK 11195 binding to peripheral type benzodiazepine binding sites in kidney membranes is inhibited by the histidine blocking agent diethylpyrocarbonate. This reagent irreversibly decreases the Bmax for [3H]PK 11195 without affecting the affinity. By contrast binding of [3H]RO5-4864 is not affected by diethylpyrocarbonate treatment. However RO5-4864 can protect in a concentration dependent manner the [3H]PK 11195 binding site from diethylpyrocarbonate whereas clonazepam and RO15-1788 are not active. These results suggest that PK 11195 and RO5-4864 interact with different conformational states of the receptors that RO5-4864. This is in agreement with our previous hypothesis that PK 11195 is an antagonist and RO5-4864 an agonist at the "peripheral type" benzodiazepine receptors. 相似文献
12.
Charlap JH Donahue RJ Knudsen TB 《Birth defects research. Part A, Clinical and molecular teratology》2003,67(2):108-115
BACKGROUND
Treatment of pregnant mice with 2‐chloro‐2′‐deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp).METHODS
Pregnant CD‐1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT‐PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure.RESULTS
The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co‐treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA.CONCLUSIONS
The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53‐dependent mode of action of 2CdA on ocular development. Birth Defects Research (Part A) 67:108–115, 2003. © 2003 Wiley‐Liss, Inc.13.
Electrophysiological investigations have revealed that benzodiazepines, applied either locally or systemically, reduce central nervous system excitability. The studies summarized here indicate that this depression of excitability by benzodiazepines is a result of an increase in gamma-aminobutyric acid (GABA) mediated inhibition. This increase in inhibition may result from benzodiazepines increasing the activity of some GABAergic neurons and also from a modulatory action of benzodiazepines on GABA actions at some postsynaptic receptor sites. The modulatory action is observed with doses of benzodiazepines that do not cause any direct effects on neuronal excitability or membrane polarization. Specificity tests indicate that benzodiazepines do not enhance inhibition mediated by glycine or monoamines such as norepinephrine or serotonin. Results of experiments with a convulsant benzodiazepine compound, which causes a specific reduction in GABA-mediated inhibition, are also presented, The data are discussed in terms of a model in which the benzodiazepine receptor, the GABA receptor, and the chloride ionophore are functionally linked. Furthermore, it is proposed that some postsynaptic actions of GABA may be continually regulated by the occupancy of a benzodiazepine receptor, and that occupancy of the benzodiazepine receptor may be permissive for the GABA-elicited increase in chloride ion permeability. 相似文献
14.
Rosario R. Trifiletti Adele M. Snowman Solomon H. Snyder 《Biochemical and biophysical research communications》1984,120(2):692-699
Binding activity for the cage convulsant [35S]--butylbicyclophosphorothionate, which appears to label a site closely associated with the chloride ionophore of the GABAA/benzodiazepine receptor complex has been solubilized from rat cerebral cortex using the zwitterionic detergent CHAPS. Of several detergents screened, only CHAPS and CHAPSO were capable of solubilizing the binding activity with good recovery. The pharmacologic specificity of soluble [35S]--butylbicyclophosphorothionate binding is very similar to the membrane state. In both the membrane and soluble state, [35S]--butylbicyclophosphorothionate binding is enhanced by anions which support inhibitory post-synaptic potentials (“Eccles anions”), suggesting that [35S]--butylbicyclophosphorothionate may label chloride channels thought to be involved in these potentials. Since this solubilization procedure also preserves GABA and benzodiazepine binding and their regulation by drugs such as barbiturates, purification and isolation of the macromolecular complex including chloride channel and GABA-benzodiazepine sites may be feasible. 相似文献
15.
Tamara Hirsch Didier Decaudin Santos A. Susin Philippe Marchetti Nathanael Larochette Michèle Resche-Rigon Guido Kroemer 《Experimental cell research》1998,241(2):426
One critical step of the apoptotic process is the opening of the mitochondrial permeability transition (PT) pore leading to the disruption of mitochondrial membrane integrity and to the dissipation of the inner transmembrane proton gradient (ΔΨm). The mitochondrial PT pore is a polyprotein structure which is inhibited by the apoptosis-inhibitory oncoprotein Bcl-2 and which is closely associated with the mitochondrial benzodiazepine receptor (mBzR). Here we show that PK11195, a prototypic ligand of the 18-kDa mBzR, facilitates the induction of ΔΨmdisruption and subsequent apoptosis by a number of different agents,including agonists of the glucocorticoid receptor,chemotherapeutic agents (etoposide, doxorubicin),gamma irradiation, and the proapoptotic second messenger ceramide. Whereas PK11195 itself has no cytotoxic effect, it enhances apoptosis induction by these agents. This effect is not observed for benzodiazepine diazepam, whose binding site in the mBzR differs from PK11195. PK11195 partially reverses Bcl-2 mediated inhibition of apoptosis in two different cell lines. Thus, transfection-enforced Bcl-2 overexpression confers protection against glucocorticoids and chemotherapeutic agents, and this protection is largely reversed by the addition of PK11195. This effect is observed at the level of ΔΨmdissipation as well as at the level of nuclear apoptosis. To gain insights into the site of action of PK11195, we performed experiments on isolated organelles. PK11195 reverses the Bcl-2-mediated mitochondrial retention of apoptogenic factors which cause isolated nuclei to undergo apoptosis in a cell-free system. Mitochondria from control cells, but not mitochondria from Bcl-2-overexpressing cells, readily release such apoptogenic factors in response to atractyloside, a ligand of the adenine nucleotide translocator. However, control and Bcl-2-overexpressing mitochondria respond equally well to a combination of atractyloside and PK11195. Altogether, these findings indicate that PK11195 abolishes apoptosis inhibition by Bcl-2 via a direct effect on mitochondria. Moreover, they suggest a novel strategy for enhancing the susceptibility of cells to apoptosis induction and, concomitantly, for reversing Bcl-2-mediated cytoprotection. 相似文献
16.
Comparison of the distribution of convulsant/barbiturate and benzodiazepine receptors using light microscopic autoradiography 总被引:4,自引:0,他引:4
Some convulsant drugs elicit CNS excitation by blocking neuronal activity at GABAergic synapses whereas depressant compounds may result in the enhancement of GABAergic transmission. These effects are thought to involve drug actions at a multireceptor complex involving a benzodiazepine receptor, GABA receptor, picrotoxin receptor and a chloride ionophore. A radiolabeled convulsant, [35S]t-butylbicyclophosphorothionate [( 35S]-TBT) has been developed and used to characterize the binding to the "picrotoxin" or convulsant/barbiturate site. The microscopic distribution of the convulsant/barbiturate sites are reported in this communication, as demonstrated by receptor autoradiography after labeling tissue sections with [35S]-TBT. Comparison of the distribution of these sites with those of the benzodiazepine receptors show a close regional correlation in many areas. The convulsant/barbiturate sites and the benzodiazepine receptors, however, are unevenly distributed in the rat cerebellum and exist in separate lamina. 相似文献
17.
[35S]TBPS binding to the GABAA receptor ionophore binding site is anion dependent. Using autoradiography on rat brain sections, we show that permeabilities
of anions through the receptor channel correlate with their efficiencies to promote basal [35S]TBPS binding. Phosphate made an exception as it induced more binding than expected from its permeability. Well-permeable
anions (chloride, nitrate, formate) allowed [35S]TBPS binding to be effectively displaced by 1 mM GABA, whereas low-permeable anions (acetate, phosphate, propionate) markedly
prevented this GABA effect, especially in the thalamus, the transition from the high to the low GABA effect being between
formate and acetate. In the presence of phosphate, GABA enhanced [3H]flunitrazepam binding to benzodiazepine site of recombinant α1β2γ2 receptors with the same efficacy but lower potency as
compared to the presence of chloride, whereas [35S]TBPS binding was abnormally modulated by GABA. These results suggest that inorganic phosphate affects coupling between agonist
and ionophore sites in GABAA receptors.
Special issue dedicated to Simo S. Oja 相似文献
18.
Effect of picrotoxin on benzodiazepine receptors and GABA receptors with reference to the effect of C1- ion 总被引:3,自引:0,他引:3
Picrotoxin does not by itself affect [3H] diazepam binding to synaptosomal membranes of rat cerebellum; however, picrotoxin stimulated the binding in the presence of Cl? ion or Cl? ion plus low concentrations of GABA. On the other hand, in the presence of GABA at concentrations higher than 1 × 10?6 M, picrotoxin inhibited [3H]diazepam binding. This inhibition seems to be the result of reduced GABA binding, which occurred in the presence of picrotoxin and Cl? ion. These results may indicate that benzodiazepine receptors, GABA receptors, and the Cl? ionophore are closely associated with each other. 相似文献
19.
"Peripheral-Type"Binding Sites for Benzodiazepines in Brain: Relationship to the Convulsant Actions of Ro 5–4864 总被引:1,自引:0,他引:1
B. A. Weissman J. Cott† J. A. Jackson G. T. Bolger K. H. Weber W. D. Horst† S. M. Paul P. Skolnick 《Journal of neurochemistry》1985,44(5):1494-1499
Previous studies have shown that Ro 5-4864 is a potent convulsant and increases the firing rate of substantia nigra zona reticulata neurons. The pharmacologic profile of compounds that antagonize these actions suggested that the effects of Ro 5-4864 were not mediated by "brain-type" benzodiazepine receptors. We examined a number of compounds that are structurally related to Ro 5-4864 for their capacities to displace [3H]Ro 5-4864 from "peripheral-type" binding sites and their potencies as convulsants (or as antagonists of Ro 5-4864-induced convulsions). It was observed that compounds such as KW 3600 (the N-desmethyl analog of Ro 5-4864), which have very low affinities for "peripheral-type" sites, are convulsants with a potency nearly equal to that of Ro 5-4864. 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. Within a series of compounds that are structurally related to Ro 5-4864 there is a good correlation (r = 0.93; p less than 0.01) between their potencies as convulsants and their capacities to displace [35S]t-butylbicyclophosphorothionate from sites that may be associated with the chloride ionophore. Thus, it appears that occupation of "peripheral-type" binding sites by high-affinity ligands may not be directly involved in the convulsant actions of Ro 5-4864 and related compounds. 相似文献
20.
M. Mestre T. Carriot C. Belin A. Uzan C. Renault M.C. Dubroeucq C. Guérémy G. Le Fur 《Life sciences》1984,35(9):953-962
R05-4864 decreased in a dose-dependent manner, from 3 × 10?9 M to 3 × 10?6 M, the duration of intracellular action potential and the contractility in a guinea pig preparation. Diazepam was less effective and clonazepam inactive. The effects of R05-4864 were GABA-independent and antagonized by PK 11195 but not by the selective antagonist of the brain type benzodiazepine receptors R015-1788. These results show the pharmacological relevance of peripheral type benzodiazepine binding sites at the cardiac level. 相似文献