Characterization of a new synthetic isoflavonoid with inverse agonist activity at the central benzodiazepine receptor

Lopes, Daniele V.S; Caruso, Rodrigo Rêgo Barros; Castro, Newton G.; Costa, Paulo R.R.; Silva, Alcides J. M. da; Noël, François

doi:10.1016/j.ejphar.2004.05.026

Cited by 15 publications

(13 citation statements)

References 48 publications

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“…[ 3 H]flunitrazepam binding is very rapid (half-life=5 min) reaching a plateau after about 30 min and remaining stable during the 90-min incubation period. Bicuculline (30 mM) and picrotoxin (100 mM), which modulate the binding of benzodiazepine to mammalian brain preparations in the presence of GABA (Lopes et al 2004), were also without effect in our preparation from schistosomes. 2-5 nM of the ligand (see Materials and Methods section for details).…”

Section: R E S U L T S [ 3 H]flunitrazepam Bindingmentioning

confidence: 83%

“…2 nM [ 3 H]flunitrazepam binding to P 3 in our standard conditions (4 xC). Neither GABA (1 mM) nor pentobarbital (100 mM) altered the binding of [ 3 H]flunitrazepam to P 3 , in contrast to observations in mammalian brain preparations washed from endogenous GABA (Lopes et al 2004). After having determined these optimal experimental conditions, we studied the concentration-dependence of flunitrazepam binding to S. mansoni by incubating fraction P 3 at 4 xC during 90 min, in the presence of 0 .…”

Section: R E S U L T S [ 3 H]flunitrazepam Bindingmentioning

confidence: 97%

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Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

et al. 2007

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As we have recently shown that GABA should be considered a putative neurotransmitter in Schistosoma mansoni, the present work aimed to search for GABAA receptors in adult worms using [3H]-flunitrazepam to label the allosteric benzodiazepine binding site which is classically present on GABAA receptor complexes. We detected a large population (Bmax=8.25+/-1.1 pmol x mg protein(-1)) of high affinity (Kd=33.6+/-1.5 nM) binding sites for flunitrazepam. These sites harboured a singular pharmacological modulation that does not fit well with a mammalian central benzodiazepine receptor, mainly due to a very high affinity for Ro5-4864 and a very low affinity for clonazepam. We also detected a second population of benzodiazepine binding sites labelled with high affinity (IC50=85 nM) by [3H]-PK11195, a selective ligand of the mammalian peripheral benzodiazepine receptor. In conclusion, this work describes the pharmacological properties of a large population of central-like benzodiazepine receptors supporting their study as putative new targets for the development of anti-parasitic agents. We also describe, for the first time, the presence of peripheral benzodiazepine receptors in this parasite.

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Section: R E S U L T S [ 3 H]flunitrazepam Bindingmentioning

confidence: 83%

Section: R E S U L T S [ 3 H]flunitrazepam Bindingmentioning

confidence: 97%

Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

et al. 2007

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“…[13] The synthetic coumestan scaffold (6Hbenzofuro[3,2-c]chromen-6-one) showed an inverse agonist effect at the benzodiazepine site of the GABA A receptor. [14] To date, there are few reports describing the direct inhibitory effects of naturally occurring genistein and daidzein using func- tional electrophysiological studies on recombinant GABA A receptors. [15] The lack of information on the effects of isoflavones may be due to limited availability of structurally diverse natural and synthetic analogues.…”

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confidence: 99%

Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABA_A Receptors

et al. 2011

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Isoflavones do it too! Enhancement of chloride ion flux at GABAA receptors by positive modulators is an important therapeutic strategy for the treatment of central nervous system (CNS)‐related disorders. Benzopyran‐4‐one derivatives (isoflavones), identified by systematic structure‐driven design, exhibit potent flumazenil‐insensitive positive modulation at human recombinant α1β2γ2L receptors expressed in Xenopus oocytes.

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“…In this and previous studies in the same preparation (Lopes et al, 2004), we have shown that GABA is spontaneously released in culture. Changes in membrane potential or in the concentration gradients of Na ϩ , Cl Ϫ , or GABA can change the set point of the GAT-1 transport system, which fluctuates dynamically between GABA uptake and release modes (Wu et al, 2001;Richerson and Wu, 2003).…”

Section: Discussionmentioning

confidence: 76%

“…To examine the role of endogenous GABA acting through GABA A receptors, cultures were treated for 24 h with midazolam, a benzodiazepine agonist. In our cultures, a fraction of the GABA A receptors, including those mediating tonic background currents, was sensitive to midazolam (Lopes et al, 2004). Treatment with midazolam (0.1 M) significantly potentiated the nicotinic responses (p ϭ 0.021, M-S test) (Fig.…”

Section: Gaba and Kcl Modulate ␣7 Nachr Currents 381mentioning

confidence: 96%

The Magnitude of α7 Nicotinic Receptor Currents in Rat Hippocampal Neurons Is Dependent upon GABAergic Activity and Depolarization

Santos

Ribeiro²,

Setti-Perdigão³

et al. 2006

J Pharmacol Exp Ther

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Hippocampal ␣7* nicotinic acetylcholine receptors modulate the release of GABA and glutamate. The control of functional receptor pools by cell firing or synaptic activity could therefore allow for a local adjustment of the sensitivity to cholinergic input upon changes in neuronal activity. We first investigated whether tonic depolarization or cell firing affected the function of ␣7*. The amplitude of ␣7*-gated whole-cell currents in cultured rat hippocampal neurons exposed to high-extracellular K ϩ (40 mM KCl) for 24 to 48 h increased 1.3 to 5.5 times. The proportion of ␣7*-responsive neurons (99%), the potency of acetylcholine, and the sensitivity to nicotinic antagonists were all unaffected. In contrast, block of spontaneous cell firing with tetrodotoxin for 24 h led to a 37% reduction in mean current amplitude. Reduced ␣7* responses were seen after a 24-h blockade of N-type calcium channels but not of L-type calcium channels, N-methyl-D-aspartate (NMDA), or non-NMDA receptor channels, protein kinase C, or calcium-calmodulin kinases II and IV. The N-type or L-type calcium channel antagonists -conotoxin GVIA and nifedipine did not prevent the currentpotentiating effect of KCl. The GABA A antagonist picrotoxin led to a 44% reduction of the currents, despite increasing action potential firing, and also reversed the potentiating effect of KCl. Treatment with GABA, midazolam, or a GABA uptake blocker led to increased currents. These data indicate that ␣7*-gated currents in hippocampal neurons are regulated by GABAergic activity and suggest that depolarization-induced GABA release may underlie the effect of increased extracellular KCl.

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Characterization of a new synthetic isoflavonoid with inverse agonist activity at the central benzodiazepine receptor

Cited by 15 publications

References 48 publications

Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABA_A Receptors

The Magnitude of α7 Nicotinic Receptor Currents in Rat Hippocampal Neurons Is Dependent upon GABAergic Activity and Depolarization

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Characterization of a new synthetic isoflavonoid with inverse agonist activity at the central benzodiazepine receptor

Cited by 15 publications

References 48 publications

Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

Characterization of two classes of benzodiazepine binding sites in Schistosoma mansoni

Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABAA Receptors

The Magnitude of α7 Nicotinic Receptor Currents in Rat Hippocampal Neurons Is Dependent upon GABAergic Activity and Depolarization

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Identification of Benzopyran‐4‐one Derivatives (Isoflavones) as Positive Modulators of GABA_A Receptors