Search PubMed⌕ Search

Biomedical subjects

J M Cook

Publications and source records attributed to J M Cook.

At least 55 records · Page 3Linked to original sources
PubMed1997

Grandmother involvement in child caregiving in an urban community.

In a community-defined, epidemiologic sample in East Baltimore, we examined grandmothers' rates of co-residence and their involvement in four parenting activities. Co-residence rates exceeded the national average. Six types of family households with grandmothers were identified, and their frequency varied by race. Neither grandmother age nor employment was associated with grandmothers' parenting involvement, although family structure was. Grandmothers who were the sole parent (21%) or co-parent with a grandfather (6.5%) were most involved in child care and had the fewest number of helpers. Grandmothers living with single mothers (41%) were the next most involved, while grandmothers in mother/father households (9%) were least involved.

Adult↗
PubMed1997

[3H]RY 80: A high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits.

The radiochemical synthesis and pharmacological properties are described of [3H]RY 80 (ethyl-8-acetylene-5, 6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a][1, 4]benzodiazepine-3-carboxylate, [ethyl-3H]). This compound is one of a series of 8-substituted imidazobenzodiazepines that exhibits both high affinity and selectivity for gamma-aminobutyric acid (GABA)A receptors containing alpha-5 subunits. Saturable, high-affinity (Kd approximately 0.7 nM) binding of [3H]RY 80 was observed in hippocampal membranes. The maximum number (Bmax) of [3H]RY 80 binding sites was approximately 18% of that obtained with [3H]flunitrazepam, a radioligand that labels all "diazepam-sensitive" GABAA receptors. This value is consistent with previous estimates (10-20%) of the proportion of rat hippocampal GABAA receptors containing alpha-5 subunits determined by immunoprecipitation with selective antibodies and competition experiments using an alpha-5-selective ligand. In recombinant GABAA receptors composed of alpha-5 beta-3 gamma-2 subunits, the Kd of [3H]RY 80 (approximately 0.5 nM) was consistent with the value obtained in hippocampus, whereas the Bmax value was not significantly different from that obtained with [3H]flunitrazepam. The potencies of several benzodiazepine site ligands to inhibit [3H]RY 80 binding to hippocampal membranes were in agreement with the values obtained in recombinant (alpha-5 beta-3 gamma-2) GABAA receptors. [3H]RY 80 was used both in a "GABA shift" assay to correctly predict the in vivo actions of a novel, alpha-5-selective ligand and to characterize a population of GABAA receptors containing alpha-5 subunits in neonatal rat cortex. These findings demonstrate that [3H]RY 80 can be used as a radioligand to examine the properties of GABAA receptors containing alpha-5 subunits.

Alkynes↗
PubMed1996

Induction of apoptosis by diethylstilbestrol in hormone-insensitive prostate cancer cells.

BACKGROUND: Diethylstillbestrol (DES) and diethylstilbestrol diphosphate (DESdP) are effective agents for the treatment of advanced prostate cancers. Tumor-inhibiting effects of DES and DESdP are presumed secondary to suppression of androgen production in vivo. Little is known, however, about the direct cellular mechanisms of the tumor inhibition. Estrogens have been reported not only to stimulate growth but also to disrupt microtubule formation in prostate cancer cells. PURPOSE: The study was designed to examine and compare mechanisms of in vitro growth inhibition of DES and DESdP in human androgen-insensitive prostate cancer cells (DU145, 1-LN, and PC-3) and human androgen-sensitive prostate cancer cells (LNCaP) and to examine estrogen receptor modulation of such effects. METHODS: The cytotoxic effects of DES and DESdP were examined in vitro by use of a standard microculture tetrazolium assay to quantitate numbers of viable cells. Immunofluorescence microscopy, DNA fragmentation analysis, and fluorescence flow cytometry were used to investigate microtubules, the induction of apoptosis, and changes in cell cycle distribution. The degree of estrogen receptor positivity of untreated and treated cells was determined by immunohistochemistry and quantitative image analysis. RESULTS: LD50 levels (the dose at which 50% of cells are no longer viable) in the concentration range of 19-25 microM were observed for both DES and DESdP in all cell lines examined. DESdP-induced growth inhibition was found to be dependent on heat-labile phosphatases present in fetal calf serum. DES-induced cytotoxicity was not affected by the presence of 17 beta-estradiol, and it was not dependent on the presence of estrogen receptor. Estrogen receptor-positive cells and estrogen receptor-negative cells were equally responsive to DES. PC-3 cells stained with fluorescent anti-tubulin, phalloidin (actin stain), and 4',6-diamidino-2-phenylindole (DNA stain) showed no inhibition of microtubules or actin filaments but revealed the presence of apoptotic bodies in the nuclei. Fluorescence flow cytometry of nuclear DNA content of propidium iodide-stained nuclei from androgen-insensitive prostate cancer cells treated with 15 or 30 microM DES or DESdP revealed an increase in relative numbers of hypodiploid (apoptotic) nuclei, a depletion of G1- and S-phase cells, and an accumulation of cells in G2/M phase. Conversely, androgen-sensitive cells contained a lower percentage of hypodiploid nuclei but no accumulation of cells in G2/M phase. CONCLUSIONS: Direct cytotoxic effects of DES in prostate cancer cells are estrogen receptor independent and do not involve disruption of microtubule architecture but do involve the promotion of cell cycle arrest and apoptosis. These are the first data confirming direct cytotoxic effects of DES and DESdP in prostate cancer cells via an apoptotic mechanism. IMPLICATIONS. These results suggest that DES and DESdP have potential value as agents against androgen-insensitive prostate neoplasms through induction of an apoptotic cascade.

Antineoplastic Agents, Hormonal↗
PubMed1996

Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for alpha 5-containing GABAA receptors.

The synthesis and pharmacological properties of imidazobenzodiazepines with both high affinity and selectivity for alpha 5-containing GABAA receptors are described. Four of these compounds (5, 6, 8, and 9) inhibited [3H]flunitrazepam binding to recombinant alpha 5 beta 2 gamma 2 GABAA receptors with IC50 values between approximately 0.4 and 5 nM. These compounds were > or = 24-75-fold more selective for recombinant receptors containing alpha 5 subunits compared to other, "diazepam-sensitive" GABAA receptors containing either alpha 1, alpha 2, or alpha 3 subunits. Imidazobenzodiazepine 9 (used as the prototypical alpha 5 selective ligand) inhibited [3H]flunitrazepam binding to hippocampal membranes with high- and low-affinity components (IC50 0.6 +/- 0.2 and 85.6 +/- 13.1 nM, respectively), representing approximately 16% and approximately 84% of the receptor pool. Inhibition of [3H]flunitrazepam binding to cerebellar membranes with imidazobenzodiazepine 9 was best fitted to a single population of sites with an IC50 of 79.8 +/- 18.3 nM. These imidazobenzodiazepines behaved as GABA negative ligands in recombinant GABAA receptors expressed in Xenopus oocytes and were convulsant in mice after parenteral administration. The relative potencies of flumazenil and zolpidem in blocking convulsions induced by 9 and DMCM, respectively, indicated that occupation of alpha 5-containing GABAA receptors substantially contributed to the convulsant properties of acetylene analog 9. These 8-substituted imidazobenzodiazepines (5, 6, 8 and 9) should prove useful in examining the physiological roles of GABAA receptors bearing an alpha 5 subunit and may also lead to the development of novel, subtype selective therapeutic agents.

Animals↗
PubMed1996

Platinum metal concentrations in urban road dust and soil in the United Kingdom.

Concentrations of Pt, Pd, Rh and Au in soils and road dusts taken from areas of high and low traffic flows in the London Borough of Richmond and from a section of the Kingston bypass (A3) at New Malden, Surrey, have been measured. High concentrations of platinum are associated with high traffic densities. Samples taken from streets of lower traffic flows were found to contain the lower concentrations of the ranges. These values correlated well with the levels of lead which were also high at roundabouts. If the preliminary results obtained in this study apply more generally throughout the UK, then the potential for exposure to enhanced levels of Pt would appear to be higher for road users and for those living in urban environments or along major highways.

Journal Article↗
PubMed1995

Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors.

The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABAA receptors. Although imidazobenzodiazepines such as Ro 15-4513, 20, are the most potent DI GABAA receptor ligands described to date, their selectivity for DI versus DS GABAA receptors is only marginal. Previous structure-activity relationship (SAR) studies of imidazobenzodiazepines have indicated that the 3- and 8-positions are critical for high-affinity binding to DI GABAA receptors (J. Med. Chem. 1993, 36, 479-490. J. Med. Chem. 1993, 36, 1001-1006. J. Med. Chem. 1993, 36, 1820-1830). In order to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted imidazobenzodiazepines. The SAR analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABAA receptors. Furthermore, the imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABAA receptors. Thus, a pharmacophore is proposed for DI GABAA receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABAA receptors are consistent with those predicted by the DI GABAA receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABAA receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABAA receptor selective ligands in the future.(ABSTRACT TRUNCATED AT 400 WORDS)

Affinity Labels↗
PubMed1995

Reliability and concurrent validity of two instruments for measuring cervical range of motion: effects of age and gender.

This study set out to determine the reliability and concurrent validity of two instruments for measuring cervical range of motion and, using these instruments, to establish age and gender effects on cervical mobility. 84 asymptomatic subjects were investigated for age and gender effects on cervical range of motion using the CROM and single inclinometer. Thirty of these subjects also took part in the reliability study. Intraclass correlation coefficients (ICC) for inter- and intra-examiner reliability of the CROM were 0.88 and 0.96 (flexion/extension), 0.84 and 0.96 (lateral flexion) and 0.92 and 0.92 (rotation) respectively. Corresponding values for the inclinometer were 0.84 and 0.94; 0.82 and 0.92; and 0.81 and 0.89. Reliability of the CROM and single inclinometer was thus supported. Concurrent validity of the two instruments was supported for flexion/extension (0.80) and lateral flexion (0.79) but not for rotation (-0.18). Using both measuring devices, cervical mobility decreased with age in all planes of motion (p < 0.0001) but was not significantly affected by gender. Based on our findings, reassessment of normative values of cervical range of motion is indicated taking age, but not gender, into account.

Journal Article↗
PubMed1995

Low temperature reversibly inhibits transport from tubular endosomes to a perinuclear, acidic compartment in African trypanosomes.

We have used electron microscopy and flow cytofluorimetry to study endocytosis and intracellular transport of fluid phase bovine serum albumen gold complexes and membrane bound concanavalin A through endosomal compartments of bloodstream forms of Trypanosoma brucei rhodesiense. Both markers were rapidly endocytosed from the flagellar pocket. Within 20 minutes at 37 degrees C the markers reached a large, vesicular, perinuclear compartment that stained heavily with the CB1 monoclonal antibody. Neither marker left the flagellar pocket and entered cells at 4 degrees C. When cells were incubated at 12 degrees C, both markers entered the cell and were transported to collecting tubules, a tubular endosomal compartment that receives endocytosed material from coated endocytic vesicles. However, no material was transported from collecting tubules to the late, perinuclear compartment at 12 degrees C. The morphology of collecting tubule membranes was specifically altered at 12 degrees C; tubules became shorter and were arrayed near the flagellar pocket. The morphological alteration and the block in transport of endocytic markers to the perinuclear compartment seen at 12 degrees C were reversed 10 minutes after cells were returned to 37 degrees C. We also used flow cytofluorimetric measurements of pH dependent fluorescence quenching to measure the pH of the terminal endocytic compartment. Fluoresceinated lectins accumulated in a terminal compartment with a pH of 6.0-6.1, a value considerably higher than that of mammalian lysosomes. Fluorescence from fluoresceinated lectins in this terminal endocytic compartment was dequenched when bloodstream forms were incubated in the presence of chloroquine.

Acids↗
PubMed1995

Development of a comprehensive pharmacophore model for the benzodiazepine receptor.

A unified pharmacophore model of the benzodiazepine receptor (BzR) has been developed using the techniques of chemical synthesis, radioligand binding, and receptor mapping. This model is based on 136 different ligands spanning ten structurally diverse classes of compounds and qualitatively accounts for the relative affinities, efficacies, and functional effects (agonism vs. antagonism vs. inverse agonism) displayed by various ligands at the BzR. In addition, the model is expanded to account for the pharmacology of a recently discovered BzR receptor subtype termed the 'Diazepam-Insensitive' (DI) BzR. Moreover, the unified model described here is compared and contrasted with other published pharmacophore models. As previously reported, the synthesis of both partial agonists and partial inverse agonists has been achieved by using parts of this model. Partial agonists are of interest as potentially improved agents for treatment of anxiety disorders, while the partial inverse agonists may furnish important clues for the treatment of age-associated memory impairment.

Benzodiazepines↗
PubMed1994

Synthesis of benzo-fused benzodiazepines employed as probes of the agonist pharmacophore of benzodiazepine receptors.

The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These "molecular yardsticks" were employed to probe the spatial dimensions of the lipophilic pocket L2 in the benzodiazepine receptor (BzR) cleft and to determine the effect of occupation of L2 with respect to agonist activity. Of the new analogs synthesized, the 7,8-benzo-fused benzodiazepine 6 displayed moderately high affinity for the BzR (IC50 = 55 nM) and exhibited both anticonvulsant (ED50 approximately 15 mg/kg) and muscle relaxant (ED50 approximately 15 mg/kg) activity. As expected, 2 and 4 interacted with the repulsive regions of interaction, S1 and S2, and exhibited low affinities for BzR. The rigid nature of these molecular yardsticks (especially 6, Figure 7) has been employed to probe the depth of L2. Moreover, in the case of 6 full occupation of L2 has resulted in an increase in the muscle relaxant effect at the expense of the anticonvulsant/anxiolytic effect.

Animals↗
PubMed1994

Epoxide metabolite of quinine and inhibition of the multidrug resistance pump in human leukemic lymphoblasts.

Multidrug resistance (MDR) in neoplastic cells is usually due to decreased cellular retention of drugs such as vincristine or doxorubicin. An ATP-dependent drug efflux pump has been detected in MDR-1-phenotypic cells; inhibition of the MDR pump is probably the primary mechanism for reversal of MDR. Although quinine (SQ1) and quinidine are reversal agents and inhibitors of the MDR pump, the results from in vivo experiments and in vitro experiments with these diastereomers are contradictory. These observations suggest that an oxidized metabolite of SQ1 is a more potent inhibitor of the MDR pump than is the parent compound. The chemical synthesis of the epoxides of SQ1 and quinidine is reported. The epoxy compounds have been tested as inhibitors of the ATP-dependent MDR pump in human CEM/VLB100 cells. The procedure is based on preloading the cells with an inhibitor and a low concentration of a substrate, rhodamine 123 (R123). After several cold rinses, the cell suspension is passed through a filtration-flow apparatus and the R123 in the filtrate (determined by fluorescence measurements) reveals the initial efflux of R123 through the MDR pump. When tested as an inhibitor of the MDR pump, quinine-10,11-epoxide is approximately 8-fold more potent than SQ1.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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

Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication.

Pseudomonas aeruginosa is an opportunistic human pathogen that causes a variety of infections in immunocompromised hosts and individuals with cystic fibrosis. Expression of elastase, one of the virulence factors produced by this organism, requires the transcriptional activator LasR. Experiments with gene fusions show that gene lasl is essential for high expression of elastase. The lasl gene is involved in the synthesis of a diffusible molecule termed Pseudomonas autoinducer (PAI). PAI provides P. aeruginosa with a means of cell-to-cell communication that is required for the expression of virulence genes and may provide a target for therapeutic approaches.

Amino Acid Sequence↗
PubMed1993

A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model.

This laboratory has previously used a window chamber model to measure red blood cell velocity in mammary tumors and normal granulation tissues of the F-344 rat. Because red cell flux and hematocrit more accurately reflect the oxygen carrying potential of blood, we used this model to measure these parameters. Red blood cells were labelled with fluorescein isothiocyanate, and 0.2 ml. packed cells were injected intravenously into rats bearing an 8 to 10 day old R-3230 mammary carcinoma. beta-phycoerythrin (0.15 mg.) was also injected and served as a plasma dye to outline the blood vessels. A sample of peripheral blood was then taken and analyzed by flow cytometry to determine the labeled fraction of red blood cells. Flowing tumor and normal tissue vessels were recorded onto a VCR, and these video images were used to determine vascular length and diameter, RBC flux and velocity, and hematocrit. Median vessel diameter and loge (red blood cell flux) were significantly greater in tumors than in normal tissues (p = 0.007 and p < 0.025, respectively). After controlling for these variables, the median tumor hematocrit of 19% was not significantly greater than the median normal tissue hematocrit of 15%. This technique provides a nontoxic and reproducible method that is now being used to assist in the in vivo definition of tumor oxygenation.

Animals↗
PubMed1993

Thrombomodulin activity and localization.

An overview on the properties, actions and localization of thrombomodulin (TM) in situations of tissue injury and in selected tumors is presented. The localization and activity of TM after injury to vascular endothelium shows that following balloon catheter denudation of the endothelium of the rabbit aorta, the activity and immunohistochemical staining is markedly reduced. The functional and antigenic levels approach the control levels approximately one week after the initial injury. The results suggest that the neointimal smooth muscle cells express TM. This phenotypic plasticity of the neointimal smooth muscle cells may be important in conferring thrombo-resistance to the lumenal lining cells of vessels after injury. Studies are also reviewed on the use of soluble recombinant TM to prevent thrombosis after ligature of vessels in an experimental model. Further characterization on the immunohistochemical distribution of TM in normal tissues and tumors shows that staining with a monoclonal anti TM antibody can be very useful in separating mesotheliomas from pulmonary adenocarcinomas. These studies may lead to insights concerning the role of TM in tissue-injury-repair and tissue differentiation.

Adenocarcinoma↗
PubMed1992

Predictive binding of beta-carboline inverse agonists and antagonists via the CoMFA/GOLPE approach.

The synthesis and affinities of six new 3-substituted beta-carbolines (6-10, 12) for the benzodiazepine receptor (BzR) are described. These analogs were used both to probe the dimensions of the hydrophobic pocket in the benzodiazepine receptor and to test the predictive ability of a previously reported 3D-QSAR regression model. Of the new analogs synthesized, the gamma-branched derivatives (isobutoxy, 7, IC50 = 93 nM; isopentoxy, 9, IC50 = 104 nM) display significantly higher affinity for the BzR than either the beta-branched (sec-butoxy, 6, IC50 = 471 nM; tert-butyl ketone, 12, IC50 = 358 nM) or delta-branched (isopentoxy, 8, IC50 = 535 nM) analogs. An exception to this rule is the gamma-branched 3-benzyloxy derivative 10 (IC50 > 1000 nM) which appears to have a chain length that is too long to be accommodated by the BzR. The standard error of prediction for these six new beta-carbolines using the original regression model is significantly lower than the standard error estimate of the cross validation runs on the training set, hence the predictions made using this model are much better than expected. In order to obtain more credible predictions, a new procedure called GOLPE (generating optimal linear PLS estimates) was used to eliminate irrelevant electrostatic and steric descriptors from the regression equation. A substantial reduction in the standard error estimate resulted. The predictions from this new regression equation were somewhat less accurate than the ones obtained with the original regression equation; however the standard error of prediction and the standard error estimate are in much closer agreement. Finally, to probe the effect that the quality of the steric and electrostatic potentials has on 3D-QSAR analyses, the semiempirical MNDO parallel PRDDOE geometries and Mulliken charges used in the original analyses were replaced with ab initio 3-21G parallel 6-31G* geometries and electrostatic potential fit charges. A modest decrease in the standard error estimate and increase in cross validated R2 resulted.

Animals↗
PubMed1992

Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogues of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones at benzodiazepine receptors.

Based on the topology of pyrazoloquinolinones 10-12, a series of 2-phenyl-2H-pyrazolo[4,3-c]isoquinolines 6a-d, 7a-d, 8, and 9 have been synthesized and evaluated for their ability to inhibit radioligand binding to benzodiazepine receptors (BzR). Modification of the hydrogen bonding donor and acceptor characteristics of the NH and C = O functionalities of the pyrazoloquinolinones 10-12 resulted in ligands with dramatically reduced affinities (IC50 much greater than 2 microM) for BzR. The low affinities of 6a-d, 7a-d, 8, and 9 are consistent with the involvement of the NH function present on diverse classes of inverse agonists (beta-carbolines, diindoles, and pyrazoloquinolinones) with a hydrogen bond acceptor site (A2) on the binding protein. Moreover, it supports the involvement of the carbonyl function of the pyrazoloquinolinones and the pyridine nitrogen atom of beta-carbolines and diindoles with a hydrogen bond donor site (H1). Finally, the results from this work indicate that a simultaneous interaction at both hydrogen bond donor (H1) and acceptor sites (A2) at BzR is required for high affinity binding of inverse agonists.

Animals↗