Pharmacological characterization of H3 receptor antagonists with imidazole, thioimidazole and thioimidazoline polar groups in the side chain.
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Animals↗
Biomedical subjects
M Mor
Publications and source records attributed to M Mor.
Design and synthesis of melatonin receptors agonists and antagonists.
We review our work towards the design and synthesis of high-affinity melatonin (N-acetyl-5-methoxytryptamine) agonist and antagonist compounds. High affinity melatonergic agonists were obtained by shifting the melatonin side chain from C3 to N1 of the indole ring system. Conversely, by moving the side chain from C3 to C2 it was possible to obtain melatonin antagonist compounds, albeit of moderate affinity.
Animals↗
Statistical analysis on a series of glycine antagonists.
Quantitative structure-activity relationships of two series of glycine antagonists, pyrido[2,3-b]pyrazines and pyrido[2,3-b]pyrazine N-oxides, was performed using PLS (Projection on Latent Variables) and traditional physico-chemical and topological descriptors. The effect of substitution on the heteroaromatic ring was investigated with the aim of further improving the affinity (expressed as pKi) of these derivatives towards the strychnine-insensitive glycine binding site associated with the NMDA receptor. A significant model was obtained for both series of compounds. Structure-activity implications are discussed.
Chemical Phenomena↗
Structure-property relationships on histamine H3-antagonists: binding of phenyl-substituted alkylthioimidazole derivatives to rat plasma proteins.
The binding of a series of H3-antagonists to rat plasma proteins was investigated by dialysis experiments, with RP-HPLC measurement of the free ligand. The series was composed of 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazoles having, on the phenyl ring, meta- and para-substituents, with different physico-chemical characteristics. As high protein binding had been proposed as being one of the features limiting brain access for the reference H3-antagonist thioperamide, the title series was employed to test the possibility of achieving lower protein binding by modulation of lipophilicity, while maintaining good receptor affinity. The compounds tested showed quotas of bound drug ranging from 60 to 97.5%, while for thioperamide a 78% bound drug quota was observed at high total concentrations, with a steep increase in bound percentage at lower concentrations. Two of the tested compounds, having a carboxamide substituent, showed lower protein binding compared to thioperamide over a wide range of total concentration, without a significant loss in affinity with respect to the parent compound. A strict dependence of protein binding on lipophilicity was observed, and a QSPR model was derived which could also account for the protein binding observed for thioperamide, while receptor affinity had been reported to be quite insensitive to phenyl ring substitution. It is therefore possible to modulate protein binding of these H3-antagonists, through lipophilicity adjustment, without losing receptor affinity; this finding could help in the design of new compounds with improved brain access.
Animals↗
Synthesis and biological assays of new H3-antagonists with imidazole and imidazoline polar groups.
New histamine H3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives (2a-f) with tetramethylene chain (pKi 8.03-8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles (1a-i) and that of 2-alkylthioimidazolines (3a-h). In contrast, a general lowering of affinity (pKi 5.90-7.63) was observed for compounds of the last series (3a-h), with a complex dependence on the terminal lipophilic group and chain length.
Animals↗
October 17, 2000 8:30-8:45. The New Technology of Combined Transmission and Emission F-18 FDG Tomography (FDG-TET) in the Diagnosis and Management of Cancer Patients.
The purpose of the study was to evaluate a new technology of simultaneous transmission and F-18 FDG emission tomography (FDG-TET) in tumor imaging and its impact on patient management.Emission and transmission devices were installed on the same gantry. 167 patients with histologically proven malignancy were evaluated at diagnosis or during follow up. Eight mCi of FDG were injected for PET and a low dose X-ray tube was used for CT. The FDG and CT were first interpreted independently, without knowledge of findings in other imaging modality. Subsequently fusion images were analyzed.FDG-TET changed the interpretation of PET or CT in 75 patients (45%). In 60 patients TET allowed for correct localization of lesions on the PET studies. In 15 patients, FDG uptake was found in sites of physiologic activity. In 12 patients lesions previously missed on CT were retrospectively identified. In 21 patients, TET detected 34 previously unknown sites of disease.FDG-TET changed the clinical management of 29 patients (17%). The stage of disease was changed in 9 patients. Early diagnosis of recurrence was made in 8 patients. Seven patients were referred for previously unplanned surgery. In 6 patients surgery was cancelled. Fifteen patients received additional chemo- or radiotherapy.Diagnosis of cancer on CT is based on a change in size or attenuation of a mass. PET shows the metabolic status of a lesion but lacks anatomical landmarks. FDG-TET improves the diagnostic accuracy in cancer and may have a significant impact on patient management.
Journal Article↗
Point-of-care testing: a critical review.
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Child↗
Percutaneous endoscopic gastrostomy: high mortality rates in hospitalized patients.
OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is a widely used method for insertion of a gastrostomy tube in patients who are unable to eat but have a normally functioning gut. Complications have been described, especially in fragile, debilitated patients, and 30-day mortality rates of 4.1-26% have been reported. We assessed the outcome of PEG tube placement for inpatients and outpatients, based on morbidity, mortality, and long-term survival. METHODS: We reviewed the medical records of all patients who underwent PEG at our institution between January 1, 1995 and December 31, 1996. Four groups of patients were compared: Group 1, patients from nursing homes; Group 2, hospitalized patients; Group 3, hospitalized patients matched to Group 2 for diseases, except mental disorder, and not treated with PEG; and Group 4, the general hospital population matched for age. RESULTS: A total of 114 PEG tubes were inserted in 114 patients, 47 from Group 1, 67 from Group 2. Eighty-seven percent of patients in Group 1 underwent PEG because of dementia, versus 46% of Group 2 (p<0.001). The mortality rate was five times higher in Group 2 than in Group 3 (p<0.001). The 30-day mortality was seven times higher in Group 2 than in Group 1, twice that in Group 3, and five times higher than in Group 4 (p = 0.002 and p<0.001, respectively). When intention-to-treat analyses were applied to the data, 19/48 patients died (39.5%) in Group 1, and 60/83 (72.0%) died in Group 2, (p<0.001). CONCLUSIONS: Patients hospitalized with acute illness are at high risk for serious adverse events after PEG insertion and this procedure should be avoided.
Aged↗
Aggressive non-Hodgkin lymphoma: early prediction of outcome with 67Ga scintigraphy.
PURPOSE: To evaluate use of gallium 67 scintigraphy early during chemotherapy to predict the outcome in patients with aggressive non-Hodgkin lymphoma. MATERIALS AND METHODS: Among 118 patients, 67Ga scintigraphy was performed after one cycle of chemotherapy in 51 patients, after a median of 3.5 cycles in 97 patients, and both in 30 patients. Computed tomography (CT) was performed after a median of 3.5 cycles of treatment in 87 patients. The failure-free survival was compared between patients with positive or negative 67Ga or CT scans by using the log-rank test. Multivariate analysis helped determine the relation between 67Ga scintigraphic and CT findings and the outcome. RESULTS: The differences in failure-free survival between patients with positive versus negative 67Ga scans after one cycle of treatment (P < .001) and at midtreatment (P < .001) were significant. There was no statistically significant difference in failure-free survival between patients with positive versus negative CT findings during treatment. In multivariate analysis, 67Ga scintigraphy after one cycle (P < .045) and at midtreatment (P < .006) was an independent factor associated with outcome. CONCLUSION: Gallium 67 scintigraphic findings after one cycle of chemotherapy and at midtreatment are predictive of outcome in patients with aggressive non-Hodgkin lymphoma. CT findings are not predictive. Early 67Ga scintigraphy during chemotherapy is a good indicator of patients who may benefit from a change to a more aggressive treatment. A future study is necessary to investigate the potential effect of early change of treatment.
Adolescent↗
Experimental and theoretical analysis of the interaction of (+/-)-cis-ketoconazole with beta-cyclodextrin in the presence of (+)-L-tartaric acid.
1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using beta-cyclodextrin in the presence of (+)-L-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.
Antifungal Agents↗
Hodgkin disease: prediction of outcome with 67Ga scintigraphy after one cycle of chemotherapy.
PURPOSE: To investigate gallium 67 scintigraphy performed early during treatment as a means to predict outcome and thus to optimize treatment of Hodgkin disease (HD) in the future. MATERIALS AND METHODS: Ninety-eight patients with HD were examined. Thirty-one patients underwent 67Ga scintigraphy after one chemotherapy cycle and 83 patients after a mean 3.5 cycles (range, 2-5 cycles). Sixteen patients underwent 67Ga scintigraphy both after one cycle and at midtreatment. Patients underwent whole-body scintigraphy and single photon emission computed tomography of the torso. Torso computed tomography (CT) was performed after a mean 3.5 cycles (range, 2-6 cycles). Failure-free survival was compared between patients with positive and patients with negative test findings (Kaplan-Meier method), and the significance of the difference was calculated. The association of failure-free survival with various prognostic clinical factors before treatment was compared (log-rank test univariate analysis). RESULTS: Failure-free survival differed significantly (P < .002) between patients with positive and patients with negative 67Ga scintigrams after one chemotherapy cycle but not at midtreatment. Failure-free survival was not significantly different between patients with positive and patients with negative CT scans at midtreatment. Twenty-two (92%) of 24 patients with negative 67Ga scintigrams after one cycle and 64 (82%) of 78 patients with negative scintigrams at midtreatment remained in complete response. In four (57%) of seven patients with positive 67Ga scintigrams after one cycle, treatment failed. CONCLUSION: 67Ga scintigraphy after one cycle of chemotherapy is a good early predictor of outcome of HD.
Adult↗
Melatonin.
Melatonin is the principal hormone secreted by the pineal gland, produced in humans with a circadian rhythm characterized by elevated blood levels during the night. It is involved in the regulation of several rhythmic functions in various vertebrates, and participates in the processing of photoperiodic information. Although its role in human physiologic and pathologic processes is not yet completely understood, MLT exerts a number of actions, in physiological or pharmacological concentrations, which could be of interest for future therapeutic uses. The mechanisms involved in MLT actions include interaction with membrane receptors, recently classified as mt1/MT2/MT3, and with nuclear sites corresponding to orphan members of the nuclear receptor superfamily, RZR/ROR; MLT also acts as a radical scavenger, exerting a protective action against various oxidative injuries. The present review is mainly addressed to the medicinal chemistry of ligands at the MLT membrane receptors, focusing on the models of binding interaction published in the literature. Several different pharmacophore and 3D-QSAR models have been reported so far, and a re-consideration of known active compounds, in the light of the recently developed biological tests on cloned receptors, could help to resolve the incongruities among these models; to this end, additional information is becoming available from new, conformationally constrained ligands, and from antagonist compounds with a selective affinity for receptor subtypes.
Animals↗
Melatonin receptor ligands: synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study.
The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.
Animals↗
2-[N-Acylamino(C1-C3)alkyl]indoles as MT1 melatonin receptor partial agonists, antagonists, and putative inverse agonists.
The synthesis of several novel indole melatonin analogues substituted at the 2-position with acylaminomethyl (8-11), acylaminoethyl (5a-k), or acylaminopropyl (13) side chains is reported. On the basis of a novel in vitro functional assay (specific binding of [35S]GTPgammaS), which can discriminate agonist from partial agonist, antagonist, and inverse agonist ligands, 5a,g, h,j and 13 were shown to be partial agonists, 5d,e and 8-11 competitive antagonists, and 5b,c,k putative inverse agonists. Binding and functional assays were performed on cloned human MT1 receptor. Structure-activity relationship considerations indicate that N-[1-aryl-2-(4-methoxy-1H-indol-2-yl)(C1-C2)alkyl]alkanamides represent a lead structure for this type of ligands.
3T3 Cells↗
Isolation, replication and polyhedrin gene sequence of an Israeli Helicoverpa armigera single nucleopolyhedrovirus.
A local strain of Helicoverpa armigera baculovirus was isolated from infected H. armigera larvae. Infectivity to Helicoverpa cells, restriction enzyme analysis and electron microscopy allowed its identification as a single embedded nucleopolyhedrovirus, designated HaSNPV-IS. Analysis of DNA replication, protein synthesis and polyhedrin expression in HaSNPV-infected cells located the late and very late phases of the viral cycle at 24 and 48 h after infection, respectively. The viral polyhedrin gene was isolated and characterized. It encoded for a polypeptide of 246 amino acid residues. A 32 kDa polypeptide was identified by immunoblot analysis using antipolyhedrin antiserum. The HaSNPV-IS polyhedrin DNA sequence revealed 99.4% of homology to the HzSNPV polyhedrin. The availability of this efficient replication system and the above knowledge paves the way to future genetic engineering of the HaSNPV.
Amino Acid Sequence↗
H3-receptor antagonists: synthesis and structure-activity relationships of para- and meta-substituted 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazoles.
We report the synthesis, octanol/water partition coefficient (log P), dissociation constants (pKa), H3-receptor affinity (pKi in rat brain membranes, [3H]-N alpha-methylhistamine), and H3-antagonist potency (pA2 in guinea ileum, (R)-alpha-methylhistamine) of novel H3-receptor antagonists obtained by introducing a para or meta substituent on the phenyl ring of the lead compound 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazole (3a). The substituents were chosen to obtain broad and uncorrelated variation in their lipophilic, electronic, and steric properties. The log P values of the neutral species cover almost 3 orders of magnitude (from 1.40 to 4.11). The pKa,2 values (protonation of the 2-thioimidazole fragment) vary from 3.13 to 4.34, indicating that this fragment, which incorporates the so-called polar group common to many H3-receptor antagonists, is neutral at physiological pH. The compounds had pKi values in a range too narrow (from 7.28 to 8.03) to derive QSAR equations. In one case (3g), a biphasic displacement curve was observed (pKi,1 = 8.53; pKi,2 = 6.90). The pA2 values ranged 2 orders of magnitude (from 6.83 to 8.87) and yielded a QSAR model (PLS) indicating that antagonist potency depends parabolically on lipophilicity and is decreased by bulky para substituents. The compounds of this series, therefore, maintain a fair-to-good affinity for rat brain H3-receptor and a fair-to-good H3-antagonist potency on guinea pig ileum, although varying markedly in their lipophilicity. The series thus appears as a good candidate for pharmacokinetic optimization leading to brain-penetrating H3-receptor antagonists.
Animals↗
Conformationally restrained melatonin analogues: synthesis, binding affinity for the melatonin receptor, evaluation of the biological activity, and molecular modeling study.
The design, synthesis, and biological profile of several indole melatonin analogues with a conformationally restricted C3 amidoethane side chain are presented. Examination of the accessible conformations of the melatonin side chain led us to explore some of its fully or partially restricted analogues, 2-12, the binding affinity values of which were utilized to gain further insight on the melatonin binding site. Two pharmacophoric models have been devised for melatonin and the active compounds by conformational analysis and superimposition performed using the DISCO program. In these models, the melatonin side chain can adopt a gauche/anti conformation out of the indole plane. Another contribution of this study regards the observation of a possible binding point interaction around the C2 position of the indole, as suggested by the remarkably increased binding affinity observed in the C2-substituted analogues 6 and 9 and especially in the more rigid analogue 5. The biological activity and the efficacy of the new compounds were tested by measuring the inhibition of the forskolin-stimulated cAMP accumulation and the GTP gamma S index. Both analyses demonstrated that all of the compounds were full agonists with the exception of 4 and 9, which showed a slight reduction in efficacy and would seem to be partial agonists.
Animals↗
Nuclear magnetic resonance investigations of the inclusion complexation of gliclazide with beta-cyclodextrin.
The formation of the gliclazide-beta-cyclodextrin (GL-beta-CD) inclusion compound has been studied in the liquid state by phase solubility techniques and by 1H and 13C NMR spectroscopy. From the initial straight portion of the solubility curve (Bs type), the value of the apparent stability constant (Kc) was calculated as 1094 M(-1). The nuclear magnetic resonance studies confirm that GL yields a complex with beta-CD in aqueous medium, which is mainly due to the penetration of the azabicyclooctyl group of GL into the cavity of beta-CD. The study of the monodimensional nuclear Overhauser effect (NOE) of the H3 proton of CD has shown that the tolyl group also interacts with CD, but to a lesser extent than the azabicyclooctyl moiety. Finally, the application of the continous variation technique confirmed the 1:2 drug:CD stoichiometry of the complex.
Cyclodextrins↗