A novel N-methyl, N-phenyl-[6-chloro-2-(4-chlorophenyl)-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide (compound Ⅴ) was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies sh...A novel N-methyl, N-phenyl-[6-chloro-2-(4-chlorophenyl)-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide (compound Ⅴ) was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies showed that MDA-MB-231 cells yield four-fold higher specific uptake of [^131I]-compound Ⅵ than MCF-7 cells, corresponding to the increased expression of PBR in MDA-MB-231 cells. Blocking studies significantly reduced the MDA-MB-231 cells uptake of [^131I]-compound Ⅵ. It indicated that [^131I]-compound Ⅵ might be a potential SPECT radioligand for imaging of PBR.展开更多
3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazo...3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.展开更多
PK11195, a ligand of peripheral-type benzodiazepine receptor can stimulate thealdosterone secretion of isolated adrenal glomerulosa cell: this effect could be abolished by nifedipinewhich mainly blocks the calcium cha...PK11195, a ligand of peripheral-type benzodiazepine receptor can stimulate thealdosterone secretion of isolated adrenal glomerulosa cell: this effect could be abolished by nifedipinewhich mainly blocks the calcium channel in plasma membrane, but could not be abolished bydantrolene, a selective blocker of mitochondria calcium channel. Even under the condition of themaximum stimulative effects on aldosterone secretion, PK11195 could not change the cyclic AMP(cAMP) content in isolated glomerulosa cells. These results indicated that in the modulatory mecha-nism of benzodiazepine receptor on aldosterone secretion, the intracellular messenger might be theCa<sup>2+</sup> from extracellular Ca<sup>2+</sup> pool, but not the Ca<sup>2+</sup> from mitochondria Ca<sup>2+</sup> pool or cAMP.展开更多
Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribe...Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.展开更多
Rearing is an exploratory behavior induced by novelty, such as exposure to an open field. Stimulation of certain brain regions, including the hippocampus, induces both rearing and clonic convulsions. Brain excitabilit...Rearing is an exploratory behavior induced by novelty, such as exposure to an open field. Stimulation of certain brain regions, including the hippocampus, induces both rearing and clonic convulsions. Brain excitability is controlled by gamma-aminobutyric acid (GABA) inhibitory neurotransmission through its ionotropic GABAA/allosteric benzodiazepine site. Drugs that decrease GABAA receptor fast inhibitory neurotransmission induce clonic convulsions and rearing when injected into the hippocampus. Therefore, individual differences in rearing behavior may be related to the susceptibility to clonic convulsions, which could involve differences in brain excitability controlled by GABAA/allosteric benzodiazepine site receptors. Adult, male Wistar rats were divided into high- (HR) and low-rearing (LR) groups based on the number of rearings in the open field test. Groups of HR and LR rats were challenged with convulsant drugs that antagonize GABA neurotransmission via different mechanisms of action (3-mercaptopropionic acid, a glutamate decarboxilase inhibitor;bicuculline, a GABAA receptor antagonist;pentylenetetrazol and picrotoxin, both GABAA receptor chloride channel blockers and DMCM, a benzodiazepine inverse agonist). The convulsant doses that induced 50% of clonic convulsions were determined for each drug. The LR rats had a higher susceptibility (a lower convulsant dose 50%) to clonic convulsions induced by DMCM than the HR rats, but there were no differences between the groups in the susceptibility to tonic convulsions induced by the same drug. There were no significant differences in the convulsant dose 50% for clonic convulsions between the groups for all other drugs injected. In another experiment, additional HR and LR rats were injected with a sedative-hypnotic dose of diazepam, which caused a significantly higher hypnotic effect (sleeping-time) in the LR rats than in the HR rats. The LR group was also shown to have a significantly lower density of [3H]-Flunitrazepam bound to the GABAA receptor in hippocampal membranes. Our data suggest that inter-individual differences in rearing are related, at least in part, to the GABA inhibitory neurotransmission controlled by the benzodiazepine allosteric site in the GABAA receptor.展开更多
OBJECTIVE To identify the involvement of flumazenil-insensitive benzodiazepine(BZD) binding site in mediating BZD-induced immobility.The distribution of this nonclassical binding site and its key amino acid residues i...OBJECTIVE To identify the involvement of flumazenil-insensitive benzodiazepine(BZD) binding site in mediating BZD-induced immobility.The distribution of this nonclassical binding site and its key amino acid residues in GABAAreceptors(GABAARs) were also investigated.METHODS Using a zebrafish larvae locomotion model,we investigated the detailed dose-dependent effects of diazepam and other BZDs on zebrafish larvae behaviors,with a focus on their high-dose effects.We then evaluated the influence of the classical BZD antagonist flumazenil,GABAARs antagonist bicuculline,and the antagonist of a proposed BZD binding site in α4/6β3δ subtype receptor Ro15-4513 on BZDs induced immobility.Using wholecell patch clamp electrophysiological recordings on recombinant GABAARs,we investigated the modulation of diazepam alone or combined with flumazenil on GABA-elicited current in wildtype and mutated receptors.RESULTS Diazepam dose-dependently decreased the locomotor activities of zebrafish larvae at doses of 0.4,2,10,20,30,50 and 75 mg·L^(-1).The hypolocomotion(sedation-like state) induced by diazepam at10 and 20 mg·L^(-1) were effectively antagonized by flumazenil with EC150 of 0.086 mg·L-and1.295 mg·L^(-1),while the immobility(anesthesialike state) induced by diazepam at 30 mg·L^(-1) was abolished by bicuculline(3 mg·L^(-1)),but not affected by flumazenil(even at concentration up to150 mg·L^(-1)) or Ro15-4513(100 mg·L^(-1)).The immobility induced by clonazepam and lorazepam(100 mg·L^(-1)) was also resistant to flumazenil(100 mg·L^(-1)).In the α1β2γ2 subtype receptor expressed in HEK293 T cells,diazepam dose-dependently potentiated GABA-elicited current,and this potentiation was effectively antagonized by flumazenil(100 μmol·L^(-1)).However,in α1β2 subtype receptor,diazepam(150 μmol·L^(-1)) induced potentiation was insensitive to flumazenil(100 μmol·L^(-1)),but was abolished by the mutation of β2 N265 I.CONCLUSION These results provide direct in vivo evidence for the nonclassical binding sites,which may be located at the second transmembrane domain of GABAAR,mediate BZD-induced anesthesia.展开更多
OBJECTIVE To identify benzodi⁃azepine(BZD)effects that are insensitive to the classical BZD binding site antagonist,flumazenil.Whether the flumazenil-insensitive BZD effects have selectivity on different GABAA recepto...OBJECTIVE To identify benzodi⁃azepine(BZD)effects that are insensitive to the classical BZD binding site antagonist,flumazenil.Whether the flumazenil-insensitive BZD effects have selectivity on different GABAA receptor sub⁃types was also investigated.METHODS The high-concentration effects of BZDs and their sensitivity to flumazenil were determined on recombi⁃nant synaptic(α1β2γ2,α2β2γ2,α5β2γ2)and extra-synaptic(α4β2δ)GABAA receptors using the voltage-clamp electrophysiology technique.The in vivo evaluation of flumazenil-insensitive BZD effects was conducted in mice loss of right reflex(LORR)test.RESULTS Diazepam induced a biphasic potentiation for theα1β2γ2,α2β2γ2 andα5β2γ2 receptor channels,but did not affect theα4β2δreceptor.In contrast to the nanomolar com⁃ponent of potentiation,the second potentiation elicited by micromolar diazepam was insensitive to flumazenil.Midazolam,clonazepam,and loraz⁃epam at 200μmol·L-1 exhibited similar flumaze⁃nil-insensitive effects onα1β2γ2,α2β2γ2 andα5β2γ2 receptors,whereas the potentiation induced by 200μmol·L-1 zolpidem or triazolam was abol⁃ished by flumazenil.Consistent with the in vitro results,flumazenil antagonized the zolpidem(50 mg·kg-1)-induced LORR,but not those induced by 50 mg·kg-1 diazepam or 100 mg·kg-1 midazolam.CONCLUSION The existence of non-classical BZD binding sites on certain GABAA receptor subtypes and the flumazenil-insensitive effects depend on the chemical structures of the allosteric modulators.展开更多
As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negativel...As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.展开更多
In our experiments the isolated rat adrenal glomerulosa cells displayed perlpheral-type benzodiazepine receptors, which could bind to [<sup>3</sup>H] PKl1195 with an apparent equilibrium dissociation const...In our experiments the isolated rat adrenal glomerulosa cells displayed perlpheral-type benzodiazepine receptors, which could bind to [<sup>3</sup>H] PKl1195 with an apparent equilibrium dissociation constant (KD) of 9.4±2.8 nmol/L and a maximal binding capacity (B<sub>max</sub>) of 5.6q-1.8 pmol/10<sup>6</sup> cells. The effects of five ligands: PKl1195, Ro5--4846, flunitrazepam, diazepam and clonazepam on aldosterone secretion responses of isolated glomerulosa cells to anglotensin Ⅱ or extracellular potassium ions were observed. The logarithm of EO<sub>50</sub> for these ligands as stimulators was well correlated with the logarithm of their Ki value for [<sup>3</sup>H] PK11195 binding, suggesting that the stimulative effects might be mediated by the benzodiazepine receptor in isolated glomerulosa cells.展开更多
2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors ...2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy,stroke and amyotrophic lateral sclerosis(ALS).How to make better inhibitors,such as 2,3-BDZs,has been an enduring quest in drug discovery.Among a few available tools to address this specific question for making better 2,3-BDZs,perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists.Here I review recent work in this area,and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.展开更多
Benzodiazepines (BZs) are anxiolytic drugs which are commonly used in clinics; however, their mechanism of actions is still unclear. Since the late 1970s, receptors for benzodiazepine (BZ-R) were discovered in rat bra...Benzodiazepines (BZs) are anxiolytic drugs which are commonly used in clinics; however, their mechanism of actions is still unclear. Since the late 1970s, receptors for benzodiazepine (BZ-R) were discovered in rat brain and it was found that the action strength of BZs in the central nervous system (CNS) is related to the affinity of BZ-R. There was much evidence which indicated that BZ-R,γ-aminobutyric acid type A (GABA_A) receptor, and supermolecular complex of the chloride ion (Cl^-) channel interact with展开更多
文摘A novel N-methyl, N-phenyl-[6-chloro-2-(4-chlorophenyl)-8-iodoimidazo[1, 2-a]- pyridine-3-yl]acetamide (compound Ⅴ) was synthesized, radiolabelled with 131I and evaluated in vitro. In vitro cell uptake studies showed that MDA-MB-231 cells yield four-fold higher specific uptake of [^131I]-compound Ⅵ than MCF-7 cells, corresponding to the increased expression of PBR in MDA-MB-231 cells. Blocking studies significantly reduced the MDA-MB-231 cells uptake of [^131I]-compound Ⅵ. It indicated that [^131I]-compound Ⅵ might be a potential SPECT radioligand for imaging of PBR.
基金Financial support from the Swedish Board for Scientific Research(VR),the Knut and Alice Wallenberg Foundation,the Research School for Pharmaceutical Sciences at Lund University,Carlsberg Foundation,Denmark,and the NeuroScience PharmaBiotec Research Center,Den-mark,is gratefully acknowledged.
文摘3-Arylisothiazolo[5,4-b]quinolin-4(9H)-ones and 3-arylisoxazolo[5,4-b]quinolin-4(9H)-ones were synthesized and assayed for affinity for the benzodiazepine binding site of the GABAA receptors. While the 3-arylisothiazoloquinolin-4-ones were found to be potent ligands, with affinities (expressed as the affinity Ki value) down to 1 nM, the 3-arylisoxazoloquinolin-4-ones are less potent. This is suggested to depend on sterical repulsive interaction of the 3-arylisoxazoloquinolin-4-ones with the receptor essential volume of the binding site, and a higher electron density at the nitrogen in the azole ring (N-2) as well as the carbonyl oxygen in the isothiazoloquinolin-4-ones enabling them to interact stronger with hydrogen bond donor sites at the binding site.
文摘PK11195, a ligand of peripheral-type benzodiazepine receptor can stimulate thealdosterone secretion of isolated adrenal glomerulosa cell: this effect could be abolished by nifedipinewhich mainly blocks the calcium channel in plasma membrane, but could not be abolished bydantrolene, a selective blocker of mitochondria calcium channel. Even under the condition of themaximum stimulative effects on aldosterone secretion, PK11195 could not change the cyclic AMP(cAMP) content in isolated glomerulosa cells. These results indicated that in the modulatory mecha-nism of benzodiazepine receptor on aldosterone secretion, the intracellular messenger might be theCa<sup>2+</sup> from extracellular Ca<sup>2+</sup> pool, but not the Ca<sup>2+</sup> from mitochondria Ca<sup>2+</sup> pool or cAMP.
文摘Benzodiazepines and related benzodiazepine-receptor agonists such as the pyrazolopyrimidinezalepl -on;?the imidazopyridine zolpidem;and the cyclopyrroloneszopiclone and eszopiclone, are among the most widely prescribed drugs, and for a variety of conditions. Surprisingly: 1) there are only a few conditions for which there is a good evidence basis, 2) efficacy has only been well demonstrated for short-term use (i.e., less than 4 weeks), and 3) much less is known about the basic science of these drugs than is widely believed. We suggest that the use of these drugs beyond four or less weeks exceeds the available knowledge base, so best-practice use suggests that the prescribing of these drugs for most patients should be limited to only short-term use until more is known about the basic pharmacology of their actions in the brain and in the periphery.
基金Associacao Fundo de In- centivo a Psicofarmacologia (AFIP)
文摘Rearing is an exploratory behavior induced by novelty, such as exposure to an open field. Stimulation of certain brain regions, including the hippocampus, induces both rearing and clonic convulsions. Brain excitability is controlled by gamma-aminobutyric acid (GABA) inhibitory neurotransmission through its ionotropic GABAA/allosteric benzodiazepine site. Drugs that decrease GABAA receptor fast inhibitory neurotransmission induce clonic convulsions and rearing when injected into the hippocampus. Therefore, individual differences in rearing behavior may be related to the susceptibility to clonic convulsions, which could involve differences in brain excitability controlled by GABAA/allosteric benzodiazepine site receptors. Adult, male Wistar rats were divided into high- (HR) and low-rearing (LR) groups based on the number of rearings in the open field test. Groups of HR and LR rats were challenged with convulsant drugs that antagonize GABA neurotransmission via different mechanisms of action (3-mercaptopropionic acid, a glutamate decarboxilase inhibitor;bicuculline, a GABAA receptor antagonist;pentylenetetrazol and picrotoxin, both GABAA receptor chloride channel blockers and DMCM, a benzodiazepine inverse agonist). The convulsant doses that induced 50% of clonic convulsions were determined for each drug. The LR rats had a higher susceptibility (a lower convulsant dose 50%) to clonic convulsions induced by DMCM than the HR rats, but there were no differences between the groups in the susceptibility to tonic convulsions induced by the same drug. There were no significant differences in the convulsant dose 50% for clonic convulsions between the groups for all other drugs injected. In another experiment, additional HR and LR rats were injected with a sedative-hypnotic dose of diazepam, which caused a significantly higher hypnotic effect (sleeping-time) in the LR rats than in the HR rats. The LR group was also shown to have a significantly lower density of [3H]-Flunitrazepam bound to the GABAA receptor in hippocampal membranes. Our data suggest that inter-individual differences in rearing are related, at least in part, to the GABA inhibitory neurotransmission controlled by the benzodiazepine allosteric site in the GABAA receptor.
基金Foundation for Young Scientists of Beijing Institute of Pharmacology and Toxicology.
文摘OBJECTIVE To identify the involvement of flumazenil-insensitive benzodiazepine(BZD) binding site in mediating BZD-induced immobility.The distribution of this nonclassical binding site and its key amino acid residues in GABAAreceptors(GABAARs) were also investigated.METHODS Using a zebrafish larvae locomotion model,we investigated the detailed dose-dependent effects of diazepam and other BZDs on zebrafish larvae behaviors,with a focus on their high-dose effects.We then evaluated the influence of the classical BZD antagonist flumazenil,GABAARs antagonist bicuculline,and the antagonist of a proposed BZD binding site in α4/6β3δ subtype receptor Ro15-4513 on BZDs induced immobility.Using wholecell patch clamp electrophysiological recordings on recombinant GABAARs,we investigated the modulation of diazepam alone or combined with flumazenil on GABA-elicited current in wildtype and mutated receptors.RESULTS Diazepam dose-dependently decreased the locomotor activities of zebrafish larvae at doses of 0.4,2,10,20,30,50 and 75 mg·L^(-1).The hypolocomotion(sedation-like state) induced by diazepam at10 and 20 mg·L^(-1) were effectively antagonized by flumazenil with EC150 of 0.086 mg·L-and1.295 mg·L^(-1),while the immobility(anesthesialike state) induced by diazepam at 30 mg·L^(-1) was abolished by bicuculline(3 mg·L^(-1)),but not affected by flumazenil(even at concentration up to150 mg·L^(-1)) or Ro15-4513(100 mg·L^(-1)).The immobility induced by clonazepam and lorazepam(100 mg·L^(-1)) was also resistant to flumazenil(100 mg·L^(-1)).In the α1β2γ2 subtype receptor expressed in HEK293 T cells,diazepam dose-dependently potentiated GABA-elicited current,and this potentiation was effectively antagonized by flumazenil(100 μmol·L^(-1)).However,in α1β2 subtype receptor,diazepam(150 μmol·L^(-1)) induced potentiation was insensitive to flumazenil(100 μmol·L^(-1)),but was abolished by the mutation of β2 N265 I.CONCLUSION These results provide direct in vivo evidence for the nonclassical binding sites,which may be located at the second transmembrane domain of GABAAR,mediate BZD-induced anesthesia.
基金Institutional funding from Beijing Institute of Pharmacology and Toxicology。
文摘OBJECTIVE To identify benzodi⁃azepine(BZD)effects that are insensitive to the classical BZD binding site antagonist,flumazenil.Whether the flumazenil-insensitive BZD effects have selectivity on different GABAA receptor sub⁃types was also investigated.METHODS The high-concentration effects of BZDs and their sensitivity to flumazenil were determined on recombi⁃nant synaptic(α1β2γ2,α2β2γ2,α5β2γ2)and extra-synaptic(α4β2δ)GABAA receptors using the voltage-clamp electrophysiology technique.The in vivo evaluation of flumazenil-insensitive BZD effects was conducted in mice loss of right reflex(LORR)test.RESULTS Diazepam induced a biphasic potentiation for theα1β2γ2,α2β2γ2 andα5β2γ2 receptor channels,but did not affect theα4β2δreceptor.In contrast to the nanomolar com⁃ponent of potentiation,the second potentiation elicited by micromolar diazepam was insensitive to flumazenil.Midazolam,clonazepam,and loraz⁃epam at 200μmol·L-1 exhibited similar flumaze⁃nil-insensitive effects onα1β2γ2,α2β2γ2 andα5β2γ2 receptors,whereas the potentiation induced by 200μmol·L-1 zolpidem or triazolam was abol⁃ished by flumazenil.Consistent with the in vitro results,flumazenil antagonized the zolpidem(50 mg·kg-1)-induced LORR,but not those induced by 50 mg·kg-1 diazepam or 100 mg·kg-1 midazolam.CONCLUSION The existence of non-classical BZD binding sites on certain GABAA receptor subtypes and the flumazenil-insensitive effects depend on the chemical structures of the allosteric modulators.
文摘As aging comes, an increased prevalence of medical maladies and chronic pain independently or interactively disrupt sleep, which in turn can exacerbate either one. Furthermore, anxiety about pain can further negatively impact sleep. Fortunately, good quality sleep can improve pain management. Because benzodiazepine receptor agonists (including the “Z” drugs) can reduce anxiety and improve sleep, they seem a convenient choice. However, their use in this population, particularly for more than short-term (guidelines range from 2 to 6 weeks max), is not recommended because of increased likelihood of falls, further disruption of sleep, dependence, and problems with discontinuation (withdrawal). Besides, this population is often likely to take concomitant medication for pain or other central nervous system depressants leading to potentially serious and even life-threatening interactions involving synergistic amplification of respiratory depression (opioids being a particularly dangerous interaction). Therefore, insomnia in older adults should ideally be treated with a non-benzodiazepine receptor agonist;if indicated, they may be used, but should be closely monitored and tapered to avoid long-term adverse problems (direct or from withdrawal). Older adult patients with insomnia may be more optimally treated with sleep aids that do not interact with the GABAA receptor.
基金Project supported by the National Natural Science Foundation of China
文摘In our experiments the isolated rat adrenal glomerulosa cells displayed perlpheral-type benzodiazepine receptors, which could bind to [<sup>3</sup>H] PKl1195 with an apparent equilibrium dissociation constant (KD) of 9.4±2.8 nmol/L and a maximal binding capacity (B<sub>max</sub>) of 5.6q-1.8 pmol/10<sup>6</sup> cells. The effects of five ligands: PKl1195, Ro5--4846, flunitrazepam, diazepam and clonazepam on aldosterone secretion responses of isolated glomerulosa cells to anglotensin Ⅱ or extracellular potassium ions were observed. The logarithm of EO<sub>50</sub> for these ligands as stimulators was well correlated with the logarithm of their Ki value for [<sup>3</sup>H] PK11195 binding, suggesting that the stimulative effects might be mediated by the benzodiazepine receptor in isolated glomerulosa cells.
基金supported by NIH/NINDS Grant R01 NS060812a grant from Muscular Dystrophy Association(MDA)
文摘2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy,stroke and amyotrophic lateral sclerosis(ALS).How to make better inhibitors,such as 2,3-BDZs,has been an enduring quest in drug discovery.Among a few available tools to address this specific question for making better 2,3-BDZs,perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists.Here I review recent work in this area,and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.
文摘Benzodiazepines (BZs) are anxiolytic drugs which are commonly used in clinics; however, their mechanism of actions is still unclear. Since the late 1970s, receptors for benzodiazepine (BZ-R) were discovered in rat brain and it was found that the action strength of BZs in the central nervous system (CNS) is related to the affinity of BZ-R. There was much evidence which indicated that BZ-R,γ-aminobutyric acid type A (GABA_A) receptor, and supermolecular complex of the chloride ion (Cl^-) channel interact with