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G Wong

Publications and source records attributed to G Wong.

At least 109 records · Page 6Linked to original sources
PubMed1994

Factors affecting the mobilization of primitive and committed hematopoietic progenitors into the peripheral blood of cancer patients.

Rapid hematopoietic reconstitution following peripheral blood progenitor cell (PBPC) autotransplantation is thought to result from reinfusion of committed progenitor cells. This has raised concern that PBPC autografts might be rich in committed hematopoietic progentors responsible for early engraftment, but deficient in more primitive progenitors required for long-term hematopoietic reconstitution. The granulomonocytic colony-forming unit (CFU-GM) assay measures committed progenitors responsive to a single species of colony-stimulating activity such as granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas the pre-CFU assay identifies more primitive progenitors by measuring interleukin-3 (IL-3) and kit ligand (KL) induced generation of secondary CFU-GM from CD34+, 4-hydroperoxycyclophosphamide resistant progenitors that require multiple cytokine stimuli. Paired bone marrow (BM) and PBPC samples from 17 breast and ovarian cancer patients participating in four separate clinical trials were compared in these assay systems. In seven of nine patients, PBPC autografts mobilized with cyclophosphamide rebound and G-CSF compared favorably with paired BM autografts in both committed and primitive progenitor capacity. Failure to mobilize substantial primitive progenitor cell numbers occurred in two of nine patients undergoing this mobilization regimen and could not have been predicted by either circulating CFU-GM or CD34+ cell number. Prior myelosuppressive treatment experiences reduced peripheral progenitor yields somewhat, but still allowed for the collection of PBPC autografts which compared favorably with BM autografts in total CFU-GM and Pre-CFU. Mobilization of PBPC with G-CSF or GM-CSF alone in patients who had received prior myelosuppressive therapies produced autografts which were relatively deficient in committed progenitors, but absolutely deficient in primitive progenitors. We conclude that optimization of patient characteristics and mobilization parameters can achieve PBPC autografts rich in both the primitive and committed hematopoietic progenitor cells.

Adult↗
PubMed1994

Chronic exposure to benzodiazepine receptor ligands uncouples the gamma-aminobutyric acid type A receptor in WSS-1 cells.

Chronic exposure to benzodiazepines can result in an "uncoupling" of gamma-aminobutyric acid (GABA) receptors and benzodiazepine receptors (BzR) both in primary neuronal cell cultures and in vivo. The effect of chronic exposure to BzR ligands was examined in an engineered cell line (WSS-1) stably expressing "type I" GABAA receptors. Chronic exposure to flurazepam produced a concentration- (EC50, approximately 1.1 microM after a 48-hr exposure) and time-dependent (t1/2, approximately 3 hr at 100 microM) reduction in the efficacy (Emax) of GABA to enhance [3H]flunitrazepam binding to BzR, a characteristic of uncoupling in native GABAA receptor isoforms. Uncoupling of GABAA receptors and BzR without concomitant changes in BzR density was also produced by chronic exposure to other, structurally diverse, BzR ligands, including Ro 15-1788 and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, but was not manifested after exposure to the 5-hydroxytryptamine reuptake blocker fluoxetine. Chronic (12-48-hr) exposure to flurazepam did not remarkably alter levels of alpha 1 and gamma 2 mRNAs, which constitute GABAA receptors in this cell line. Based on these findings, it is hypothesized that uncoupling of GABAA receptors and BzR in this engineered cell line can proceed without the elaboration of additional novel subunits and could involve either post-translational modification of GABAA receptor proteins or changes in subunit stoichiometry.

Cell Line↗
PubMed1994

Surrogate endpoint biomarker assays in phase II chemoprevention clinical trials.

Surrogate endpoint biomarker (SEB) assays carried out in rodent models have benefitted from large amounts of available colonic tissue, abundant well-aligned colonic crypts, and population groups with fairly uniform biological characteristics. In contrast, SEB assays in human colon studies have often been carried out on small groups of subjects, without the advantages inherent in rodent studies. Some factors that contribute to variations in human colon SEB assays include differences in genetic background, the extent and duration of previous colonic diseases, degree of previous chronic irritation to the colonic mucosa, the initial levels of nutrients ingested prior to the study, administration of large volumes of fluid prior to SEB measurement which induce hypermetabolic and then quiescent changes in the mucosa, failure to use strict morphologic criteria in counting colonic crypts, and availability of only a small number of crypts for analysis. Measurements of adenoma recurrence over short durations are limited by factors that include a large potential miss-rate of small adenomas, a window of observation with short duration which limits the stage of adenoma observed, and the consequent inability to measure mechanisms that a chemopreventive intervention is affecting in a different stage of adenoma development.

Animals↗
PubMed1994

Poor perinatal outcome associated with retained cerclage in patients with premature rupture of membranes.

OBJECTIVE: To evaluate the role of immediate cerclage removal versus retention in patients experiencing premature rupture of the membranes remote from term (PROM). METHODS: Thirty patients with prophylactic cerclage experiencing PROM at 24-32 weeks were managed expectantly after either immediate removal in 20 (67%) or retention of the cerclage in ten (33%). Thirty-three patients without cerclage and with PROM at the same gestational age were used as controls. RESULTS: More patients with retained cerclage (nine of ten, 90%) had delivery delayed for at least 48 hours after PROM compared to patients with immediate cerclage removal (ten of 20, 50%) (P < .05). Perinatal mortality was significantly higher for those with retained cerclage (seven of ten, 70%) than with immediate removal (two of 20, 10%) or in the control group (six of 33, 18%) (P < .001). Sepsis was responsible for most of the poor outcomes in the retained-cerclage group (71%). CONCLUSIONS: Although retaining the cerclage prolonged the latency period between PROM and delivery, that benefit was more than offset by a greatly increased perinatal mortality rate. Our study supports immediate cerclage removal regardless of gestational age in cases of PROM.

Adult↗
PubMed1994

Clinical and laboratory comparison study of refrigerated and cryopreserved bone marrow for transplantation.

Refrigerated storage for short-term preservation of bone marrow is an alternative to cryopreservation where chemotherapeutic regimens include drugs with short in vivo half-lives. We performed a clinical and laboratory comparison of bone marrow stored at 4 degrees C for up to 9 days to bone marrow cryopreserved at -90 degrees C for autotransplantation. After adjusting for the confounding effects of disease type or sex, no clinically meaningful variation in post-transplant course between refrigerated storage and cryopreserved was found. Therefore, the data presented in this study suggest that the clinical recovery indices following transplantation between the two storage groups are essentially equivalent. One potential advantage to refrigerated storage, however, is that it may provide an opportunity for extended exposure to growth factors and/or purging agents in vitro prior to transplantation. To prepare for an in vitro analysis of this hypothesis, we concentrated the stem cell population and compared the nucleated cell recovery, viability and colony forming potential following refrigerated storage of whole bone marrow and buffy coat to cryopreserved bone marrow stored for the same interval. While the nucleated cell recovery for cryopreserved marrow was significantly greater than for refrigerated storage, the viability and colony forming potential of the refrigerated storage was superior or equivalent, independent of prior processing.

Adolescent↗
PubMed1993

Labelling of diazepam-sensitive and -insensitive benzodiazepine receptors with [3H]tert-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine 3-carboxylate (ZG-63).

A diazepam-insensitive subtype of benzodiazepine receptor has been identified in the cerebella of several species, including man. t-Butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzodiazepine 3-carboxylate (ZG-63) was recently described as a selective, high affinity ligand at diazepam-insensitive benzodiazepine receptors. This compound was tritiated, and its properties as a radioligand evaluated in rat brain membranes. Consistent with the high affinity and selectivity described for the non-radioactive form of this compound, saturation analyses of [3H]ZG-63 binding to cerebellar diazepam-insensitive and other, diazepam-sensitive benzodiazepine receptors revealed Kd values of 2.6 +/- 0.2 nM and 10.6 +/- 1.4 nM, respectively. The density (Bmax) of cerebellar diazepam-insensitive receptors labelled with [3H]ZG-63 was not significantly different from values obtained with the prototypical diazepam-insensitive receptor ligand [3H]Ro 15-4513, representing approximately 30% of total cerebellar benzodiazepine receptors. [3H]ZG-63 also labelled cortical diazepam-sensitive benzodiazepine receptors, with Bmax values that were not significantly different from those obtained with [3H]flunitrazepam. Diazepam-insensitive benzodiazepine receptors in rat cerebral cortex could be detected with [3H]ZG-63, but the densities of these sites are a very minor component (< or = 5%) of total benzodiazepine receptors. In the presence of GABA, [3H]ZG-63 behaved as a 'gamma-aminobutyric acid (GABA) -positive', 'GABA-negative', and 'GABA-neutral' ligand at cortical diazepam-sensitive receptors, cerebellar diazepam-sensitive receptors, and cerebellar diazepam-insensitive benzodiazepine receptors, respectively. This profile differs from the prototype diazepam-insensitive receptor ligand, [3H]Ro 15-4513. Competition studies demonstrated a very high correlation (r2 = 0.98; P < 0.002) between the potencies of a series of benzodiazepine receptor ligands to inhibit [3H]ZG-63 and [3H]Ro 15-4513 binding to cerebellar diazepam-insensitive receptors. The high affinity and selectivity of [3H]ZG-63 for diazepam-insensitive receptors (diazepam-insensitive/diazepam-sensitive ratio of approximately 0.25) together with a GABA-shift profile which differs from Ro 15-4513 suggests that this compound may be useful in elucidating the function(s) of this benzodiazepine receptor subtype.

Animals↗
PubMed1993

Synthetic and computer-assisted analysis of the structural requirements for selective, high-affinity ligand binding to diazepam-insensitive benzodiazepine receptors.

Several 1,4-diazepines were recently reported to bind with high affinities to the "diazepam-insensitive" (DI) isoform of the benzodiazepine receptor (BzR) (Korpi, E.R.; Uusi-Oukari, M.; Wegelius, K. Eur. J. Pharm. 1992, 213, 323-329. Wong, G.; Skolnick, P. Eur. J. Pharmacol. Mol. Pharm. Sec. 1992, 225, 63-68). However, only the putative ethanol antagonist 1 (Ro 15-4513) displayed modest selectivity for the DI site compared to other "diazepam-sensitive" (DS) BzR isoforms. In order to probe the requirements for selective, high-affinity binding to the DI site, the affinities of 47 benzodiazepines have been determined at both DI and DS BzR sites. In addition, single X-ray crystallographic analyses for three of these derivatives, 5 (Ro 17-1812), 6 (Ro 16-6028), and 42 (Ro 14-5974), are reported. The radioligand binding studies reveal that modifications to the 3-, 7-, and 8-positions of 6-oxoimidazo[1,5-alpha] [1,4]benzodiazepines have a marked influence on the Ki(DI)/Ki(DS) ratios. In order to more precisely determine the structural requirements for both high affinity and selectivity at DI BzR relative to DS, 3D-QSAR analyses were carried out on ligand affinities at both of these BzR isoforms. This analysis was based, in part, on the new X-ray crystallographic data. Satisfactory cross-validated regression equations were obtained individually for the logarithms of ligand affinities at DI and DS as well as for the differences of the logarithms of their affinities at these two isoforms (cross-validated R2 > 0.70 for all three regression equations). The steric and electrostatic 3D-QSAR DI and DS maps are in qualitative accord with the structure-activity relationship (SAR) data. Furthermore, the DI and DI/DS maps may be useful in the design of ligands with enhanced DI affinity and DI/DS selectivity, respectively.

Animals↗
PubMed1993

Synthesis and evaluation of imidazo[1,5-a][1,4]benzodiazepine esters with high affinities and selectivities at "diazepam-insensitive" benzodiazepine receptors.

A series of imidazo[1,5-a][1,4]benzodiazepine esters have been synthesized with varying ester side chains and 8-position substituents. The affinities of these compounds were evaluated at both "diazepam-insensitive" (DI) and diazepam-sensitive (DS) subtypes of the benzodiazepine receptor (BZR). A profound steric effect of the 3-position ester side chain moiety was observed on ligand affinity at DI. In contrast, ester size had a less robust effect on ligand affinity at DS. The tert-butyl ester compound 8 displayed the highest affinity (Ki = 1.7 nM) for DI within a series of 8-chloro esters. Furthermore, halogens at the 8-position resulted in an enhancement of both ligand affinity and selectivity at DI among the series of tert-butyl esters examined. The 8-nitro derivative 23 and 8-isothiocyanato congener 25 had high affinities for both DI and DS but exhibited little subtype selectivity (10.8 and 2.7 nM at DI versus 14 and 3.7 nM at DS, respectively). The 8-azido tert-butyl ester 29 exhibited a significantly higher affinity (Ki = 0.43 nM) and selectivity (DI/DS ratio of 0.2) than the corresponding ethyl ester, the prototypic DI ligand 1 (Ro 15-4513). Among the compounds synthesized, 29 is the highest affinity ligand for DI described to date while its 8-bromo analog 18 is the most selective ligand (DI/DS ratio of 0.17) for this novel BZR subtype.

Animals↗
PubMed1993

Desensitization of the NMDA receptor complex by glycinergic ligands in cerebellar granule cell cultures.

Glutamate neurotoxicity was examined in cultured cerebellar granule neurons following both prolonged (20-24 h) and brief (45 min) exposure to compounds acting at strychnine-insensitive glycine receptors. Glutamate neurotoxicity was reduced in a concentration-dependent fashion by brief exposure to the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+-)-3-amino-1-hydroxy-2-pyrrolidone (HA-966) and the competitive antagonist, 7-chlorokynurenic acid (7-CK) with a rank order efficacy: 7-CK > HA-966 > ACPC. Neither D-cycloserine (D-CS) nor glycine affected neurotoxicity produced by maximum glutamate concentrations, while glycine but not D-CS augmented the effects of submaximum glutamate concentrations. Prolonged exposure of cultures to either full (glycine) or partial agonists (ACPC, D-CS, HA-966) abolished the neuroprotective effects of ACPC and significantly diminished the neuroprotective effects of HA-966. In contrast, the neuroprotective effects of 7-CK were only marginally reduced by prolonged exposure to glycinergic ligands, while the neuroprotection afforded by compounds acting at other loci on the NMDA receptor complex (e.g. 2-amino-5-phosphonopentanoate (APV) and dizocilpine (MK-801)) were unaltered. These effects may represent homologous desensitization of the NMDA receptor complex at its strychnine-insensitive glycine receptor induced by prolonged exposure to glycinergic agonists and partial agonists. Nonetheless, levels of the NMDA receptor subunit zeta 1 mRNA were unaffected by prolonged exposure to ACPC, indicating the apparent desensitization could involve a post-translational modification of the NMDA receptor complex.

2-Amino-5-phosphonovalerate↗
PubMed1993

Synthesis and structure-activity relationships of 3,5-disubstituted 4,5-dihydro-6H-imidazo[1,5-a][1,4]benzodiazepin-6-ones at diazepam-sensitive and diazepam-insensitive benzodiazepine receptors.

A series of imidazobenzodiazepin-6-ones possessing varying substituents at the 3- and 5-positions were synthesized and evaluated for their affinities at diazepam-sensitive (DS) and diazepam-insensitive (DI) benzodiazepine receptors (BzR) in rat cortical and cerebellar membranes. Replacement of an ester substituent at the 3-position with a carbamate, acetylamino, formylamino, isothiocyanato, 2-oxazolinyl, 2-benzoxazolyl, or p-tolylsulfonyl groups lead to > 100-fold reductions in affinity at both DS and DI BzR. Replacement of a methyl group on the nitrogen at the 5-position with propyl, allyl, or phenethyl groups also led to significant reductions in affinity at both BzR isoforms. However, incorporation of a benzyl group yields ligands (11f,h,i and 14a-c) with moderate to high affinities at DS BzR, suggesting the presence of a hydrophobic pocket at the receptor site. Introduction of chlorine at the 7-position enhances ligand affinity at DS BzR while chlorine at the 8-position decreases affinity (IC50: 11f, 9.3 nM; 11h, 2.4 nM; 11i, 37.8 nM). In contrast, chlorine substitution at the 7- as well as the 8-position increases affinity at DI BzR (Ki: 11f, 112 nM; 11h, 20.2 nM; 11i, 10.9 nM). Compound 11 is among the few described high affinity DI-site ligands with a selectivity comparable to that of Ro 15-4513. Despite their in vitro affinities, compounds 11f, 11h, and 11i exhibit low in vivo activities that may be attributable to unfavorable metabolic or pharmacokinetic properties.

Animals↗
PubMed1993

Basic fibroblast growth factor counteracts the suppressive effect of transforming growth factor-beta 1 on human myeloid progenitor cells.

We have previously shown that basic fibroblast growth factor (bFGF) is mitogenic for human bone marrow stromal cells and enhances myelopoiesis in human long-term bone marrow culture. In the present study, we examined the mechanism by which bFGF enhances granulopoiesis. We observed that bFGF significantly abrogated the inhibitory effect of transforming growth factor-beta 1 (TGF-beta 1) on granulocyte-macrophage colony-stimulating factor (GM-CSF)-supported progenitor cell growth (P = .009). The partial reversal of TGF-beta 1-mediated suppression was dependent on the dose of bFGF used. In addition, we noted that the inclusion of neutralizing antibody to TGF-beta 1 significantly augmented the clonogenic response to GM-CSF. We have also shown that 10 ng/mL or 100 ng/mL of bFGF resulted in a 30% to 100% increase in GM-CSF-mediated progenitor cell growth (P = .0001). These data suggest that bFGF may enhance myelopoiesis by modulating the inhibitory response to TGF-beta 1.

Antibodies↗
PubMed1993

Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer.

BACKGROUND: Smoking is a risk factor for several cancers and may also limit the efficacy of treatment. In this study, we evaluated the influence of cigarette smoking during radiation therapy on the efficacy of treatment in patients with head and neck cancer. METHODS: Using a questionnaire, we obtained information on smoking behavior at base line and weekly during therapy in 115 patients with head and neck cancer who were treated with radiation therapy with or without fluorouracil. The side effects of therapy were evaluated weekly, and response was assessed 13 weeks after treatment was completed. The main outcomes measured were treatment response and survival. RESULTS: The prognostic variables were similar among the patients who smoked and those who did not smoke during treatment. The 53 patients who continued to smoke during radiation therapy had a lower rate of complete response (45 percent vs. 74 percent, P = 0.008) and poorer two-year survival (39 percent vs. 66 percent, P = 0.005) than the 62 patients who did not smoke or who had quit before treatment. Among the nonsmoking patients, mortality was influenced by the length of time between quitting and treatment, with a risk reduction (relative to that for patients who continued to smoke) of 40 percent for patients who had quit less than 12 weeks before diagnosis and of 70 percent for patients who had quit more than 1 year before diagnosis. After adjustment for other variables with proportional-hazards regression analysis, smoking remained an independent prognostic factor (P = 0.002), with a relative risk of 2.5 (95 percent confidence interval, 1.4 to 4.4) favoring the patients who abstained from smoking. The results could not be explained by the type of chemotherapy received, the presence of coexisting morbid conditions, differences in the side effects of radiation, or the number of interruptions of treatment. CONCLUSIONS: Patients with head and neck cancer who continue to smoke during radiation therapy have lower rates of response and survival than patients who do not smoke during radiation therapy.

Aged↗
PubMed1993

HIV-related emergencies: frequency, diagnoses, and outcome.

OBJECTIVE: To study the clinical epidemiology and outcome of HIV-related emergencies, and to identify clinical predictors of HIV-related emergency hospitalizations. DESIGN: Case series. SETTING: Emergency facility of a tertiary care teaching hospital. PATIENTS: 350 HIV/AIDS patients followed at the authors' center. MEASUREMENTS AND MAIN RESULTS: 69 of 356 patients made 92 emergency visits with a frequency of 8% per month and 20% per quarter in a three-month study period. Forty-three visits (47%) resulted in hospitalization and contributed to 70% of total AIDS hospitalizations in the period. The five most common acute diagnoses were pneumonia (n = 22; 24%), fever (n = 15; 16%), upper respiratory infection (n = 9; 10%), cellulitis (n = 6; 7%), and gastroenteritis (n = 6; 7%). Three diagnoses accounted for 70% of acute HIV hospitalizations: pneumonia (n = 19), fever (n = 4), and sepsis (n = 4). Analysis of patient disposition as it relates to the patient's clinical presentation and HIV history using multivariate analysis yielded 1) the presence of dyspnea or cough (p = 0.015) and 2) fever with an abnormal chest x-ray (p = 0.008) as independently predictive of hospitalization. CONCLUSION: The findings indicate that HIV/AIDS patients have a frequent need for emergency care and most HIV/AIDS hospitalizations are emergency-related. The acute problems of these patients are related to a limited number of diagnostic categories, and the presence of respiratory or constitutional symptoms with an abnormal chest radiograph are the only reliable factors predictive of hospitalization.

Adult↗
PubMed1993

Neurochemical actions of inhalational anesthetics at the GABAA receptor complex.

Pharmacologically relevant concentrations of inhalational anesthetics such as halothane, enflurane and isoflurane enhance [3H]flunitrazepam (FLU) binding to benzodiazepine receptors prepared from well-washed membranes of murine cerebral cortex and cerebellum. These effects were concentration dependent and markedly enhanced by addition of chloride to the incubation medium. Using halothane as a prototype inhalational agent, it was observed that like barbiturates, increases in [3H]FLU binding were effected through an increase apparent in the apparent affinity of this radioligand with no accompanying change in the maximum number of binding sites. Although previous reports have demonstrated barbiturates augment gamma-aminobutyric acid-enhanced [3H]benzodiazepine binding, halothane exerts an additive effect in the nominal absence of chloride. Isoflurane produces a significant reduction in the EC50 of pentobarbital-augmented [3H]FLU binding. Halothane modestly reduced the binding of a benzodiazepine receptor inverse agonist, [3H]Ro 15-4513. Significant differences were also observed in the potencies and efficacies of both isoflurane and enflurane to enhance [3H]FLU binding to benzodiazepine receptors in cerebellar and cortical membranes. These findings provide a possible molecular basis for the clinical observation that benzodiazepines and barbiturates augment the anesthetic properties of inhalational agents. Moreover, the regional differences in anesthetic potency and efficacy reported here suggest a differential interaction of these inhalational agents among gamma-aminobutyric acidA receptor isoforms.

Administration, Inhalation↗
PubMed1993

Transduction of a discriminative stimulus through a diazepam-insensitive gamma-aminobutyric acidA receptor.

Although there appear to be a large number of possible isoforms of the gamma-aminobutyric acid (GABA)A receptor, the relationship of a particular isoform to a specific behavior or behavioral process has not been identified. In the present study we describe a functional role for a diazepam-insensitive (DI) isoform of the GABAA receptor in the control of a complex discrimination. Pigeons were trained to discriminate the benzodiazepine antagonist flumazenil (100 micrograms/kg) from vehicle by requiring 30 keypeck responses on one key when flumazenil was given and on a different key when vehicle was given. Only ligands with high affinities for DI sites fully substituted for the discriminative stimulus effects of flumazenil. A significant positive correlation was observed between ligand affinities for DI sites and ED50 values for discriminative stimulus effects. These compounds mimicked the discriminative stimulus effects of flumazenil despite partial agonist, inverse agonist or antagonist actions at other diazepam-sensitive GABAA receptors. A specific role of DI GABAA receptors in the control of this behavior was confirmed further by the inability of either a high-affinity agonist (midazolam) or antagonist (ZK 93,426) at diazepam-sensitive receptors (that possess low affinities for DI sites) to block the discriminative stimulus effects of flumazenil. These findings establish a link between a GABAA receptor isoform and a specific behavior.

Animals↗
PubMed1992

Molecular cloning and nucleic acid binding properties of the GAP-associated tyrosine phosphoprotein p62.

p62 is a tyrosine phosphoprotein that associates with p21ras GTPase-activating protein (GAP). Purification and cDNA cloning of p62 reveal extensive sequence similarity to a putative hnRNP protein, GRP33. Recombinant human p62 purified from insect Sf9 cells binds to DNA and to mRNA and, like many proteins involved in mRNA processing, recombinant p62 is modified by dimethylation on multiple arginine residues. p62 also binds tightly to p21ras GAP in vitro: this binding depends on phosphorylation of p62 on tyrosine residues and occurs through SH2 regions of GAP. These data suggest that p120-GAP and p62 play a role in some aspect of mRNA processing or utilization and that this role may be regulated by tyrosine phosphorylation, and indirectly, by p21ras.

3T3 Cells↗
PubMed1992

High affinity ligands for 'diazepam-insensitive' benzodiazepine receptors.

Structurally diverse compounds have been shown to possess high affinities for benzodiazepine receptors in their 'diazepam-sensitive' (DS) conformations. In contrast, only the imidazobenzodiazepinone Ro 15-4513 has been shown to exhibit a high affinity for the 'diazepam-insensitive' (DI) conformation of benzodiazepine receptors. We examined a series of 1,4-diazepines containing one or more annelated ring systems for their affinities at DI and DS benzodiazepine receptors, several 1,4-diazepinone carboxylates including Ro 19-4603, Ro 16-6028 and Ro 15-3505 were found to possess high affinities (Ki approximately 2.6-20 nM) for DI. Nonetheless, among the ligands examined, Ro 15-4513 was the only substance with a DI/DS potency ratio approximately 1; other substances had ratios ranging from 13 to greater than 1000. Ligands with high to moderate affinities at DI were previously classified as partial agonists, antagonists, or partial inverse agonists at DS benzodiazepine receptors, but behaved as 'GABA neutral' (antagonist) substances at DI. The identification of several additional high affinity ligands at DI benzodiazepine receptors may be helpful in elucidating the pharmacological and physiological importance of these sites.

Animals↗