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Biomedical subjects

Q Jiang

Publications and source records attributed to Q Jiang.

At least 163 records · Page 9Linked to original sources
PubMed1994

14 alpha,14' beta-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis (7,8-dihydromorphinone) and 14 alpha,14' beta-[dithiobis[(2-oxo-2,1- ethanediyl)imino]]bis[7,8-dihydro-N-(cyclopropylmethyl)normorphinone]: chemistry and opioid binding properties.

14 alpha,14' beta-[Dithiobis[(2-oxo-2,1-ethanediyl)imino]] bis(7,8-dihydromorphinone) (TAMO) (13) was synthesized by condensing 14 beta-amino-7,8-dihydromorphine (4) with acetylthioglycolyl chloride and hydrolyzing the resulting ester with mild base to give a mixture of the thiol 9 and the disulfide 13. Chromatography of the mixture resulted in conversion of the bulk of the thiol 9 to the disulfide 13 by air oxidation. The disulfide 13 was also prepared by condensing the tert-butyldimethylsilyl ether of 4 with the dithiodiglycolyl chloride and treating the resulting product with F- to give the desired product. The pure thiol 9 free of contamination with the disulfide was prepared by treating 13 with excess N-acetyl-L-cysteine and processing the reaction mixture without resorting to chromatography for purification. The corresponding N-(cyclopropylmethyl) nor compound 15 was prepared from the silyl ether 6 and acetylthioglycolyl chloride followed by hydrolysis, treatment with F-, and air oxidation. Incubation of bovine striatal membranes with 13 and 15 resulted in wash-resistant inhibition of the binding of the mu-selective peptide [3H][D-Ala2,(Me)Phe4,Gly(ol)5]-enkephalin (DAMGO). Incubation of membranes with mu but not kappa or delta ligands protected the mu binding sites from alkylation by 13 and 15. The wash-resistant inhibition of mu opioid binding was partially reversed by the addition of the reducing reagent dithiothreitol (DTT). A Scatchard plot of the effect of 13 and 15 on [3H]DAMGO binding showed that these affinity ligands caused a marked decrease in the Bmax value without affecting the Kd value. The wash-resistant inhibition of binding, the reduction in the number of binding sites, the partial reversal of wash-resistant inhibition of binding by DTT, and previously observed long-term antagonism of mu opioid receptors in vivo support the conclusion that 13 and 15 bind covalently to the mu opioid receptor.

Alkylation↗
PubMed1994

An electrophilic affinity ligand based on (+)-MK801 distinguishes PCP site 1 from PCP site 2.

The electrophilic affinity ligand, (+)-3-isothiocyanato-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycl ohepten-5,10 - imine hydrochloride [(+)-MK801-NCS] was characterized for its ability to acrylate phencyclidine (PCP) and sigma binding sites in vivo. Initial studies, conducted with mouse brain membranes, characterized the binding sites labeled by [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP). The Kd values of [3H]TCP for PCP site 1 (MK801-sensitive) and PCP site 2 (MK801-insensitive) were 12 nM and 68 nM, with Bmax values of 1442 and 734 fmol/mg protein, respectively. Mice were sacrificed 18-24 hours following intracerebroventricular administration of the acylator. The administration of (+)-MK801-NCS increased [3H]TCP binding to site 2, but not to site 1. Although (+)-MK801-NCS decreased [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d; ccyclohepten-5,10-imine maleate ([3H](+)-MK801) binding to site 1, it had no effect on [3H]TCP binding to site 1. Viewed collectively with other published data, these data support the hypothesis that PCP sites 1 and 2 are distinct binding sites, and that [3H]TCP and [3H](+)-MK801 label different domains of the PCP binding site associated with the NMDA receptor.

Affinity Labels↗
PubMed1994

The effect of hypothermia on transient focal ischemia in rat brain evaluated by diffusion- and perfusion-weighted NMR imaging.

The effect of moderate whole-body hypothermia (30 degrees C) on transient middle cerebral artery (MCA) occlusion in the rat was evaluated using diffusion- and perfusion-weighted magnetic resonance imaging. Two hours of transient MCA occlusion was induced by intracarotid insertion of a nylon filament under normothermic (n = 14) and hypothermic (n = 7) conditions. Diffusion- and perfusion-weighted imaging were performed before, during, and after focal ischemia from 30 min up to 7 days. In hypothermic animals, scattered neuronal necrosis was localized to select areas of the caudate putamen and the parietal and insular cortex. In contrast, the normothermic ischemic animals exhibited pan-necrosis and infarct encompassing the damaged area. The diffusion and perfusion data measured from caudate putamen indicate that hypothermia causes a significant reduction in the apparent diffusion coefficient of water (ADCw) and CBF values from normothermic control values (p < 0.01). In both normothermic and hypothermic animals after onset of MCA occlusion, ADCw and CBF values in the core of the ischemic region (striatum) significantly declined from the preischemic and homologous contralateral control ADCw and CBF values (p < 0.05). However, ADCw and CBF in the hypothermic group returned toward control more rapidly than in the normothermic group. These results suggest that the protective effect of hypothermia on ischemic cell damage is reflected in the early return of ADCw during reperfusion and the reduction of ischemic cell damage by hypothermia may be mediated by the improved CBF during acute reperfusion.

Animals↗
PubMed1994

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone: mu-selective irreversible opioid antagonists.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) and its corresponding N-cyclopropylmethyl analog, N-cyclopropylmethylnor-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)- 7,8-dihydromorphinone (N-CPM-MET-CAMO) were tested in opioid receptor binding assays and in the mouse tail-flick test in order to characterize the affinity, selectivity and antinociceptive properties of these two compounds. Incubating bovine striatal membranes with either MET-CAMO or N-CPM-MET-CAMO produced a wash-resistant, concentration- and time-dependent inhibition of the binding of the mu-selective ligand, [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin, but with no change in delta or kappa binding. Preincubating membranes with N-CPM-MET-CAMO decreased the maximum binding value for [3H]-[D-Ala2,MePhe4,Gly(ol)5]enkephalin binding without changing the Kd value. In the mouse tail-flick assay, MET-CAMO and N-CPM-MET-CAMO did not produce any antinociception up to a dose of 100 nmol after i.c.v. administration. However, pretreatment of mice with either compound produced a time- and dose-dependent antagonism of morphine-induced antinociception. Analgesia mediated by delta or kappa opioids was not altered by either MET-CAMO or N-CPM-MET-CAMO at a dose of up to 100 nmol. The mu antagonistic effect of 1 nmol of MET-CAMO and N-CPM-MET-CAMO appeared at 8 hr and lasted up to 72 hr, with a maximal effect at 16 to 24 hr after i.c.v. administration. Pretreatment of mice with 1 nmol of MET-CAMO or N-CPM-MET-CAMO, given by i.c.v. administration at -24 hr, produced a rightward and downward shift of dose-response line of i.c.v. morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Temporal evolution and spatial distribution of the diffusion constant of water in rat brain after transient middle cerebral artery occlusion.

The regional distribution and temporal evolution of the diffusion coefficient (Dw) of water in rat brain was measured during and after transient middle cerebral artery (MCA) occlusion. Male Wistar rats (n = 14) were subjected to 2 h of middle cerebral artery occlusion, induced by intracarotid insertion of a filament. Diffusion (n = 14) and perfusion (n = 7) weighted magnetic resonance imaging were performed before, and at various time points after MCA occlusion, ranging from 30 min up to 7 days. Our data demonstrate that the temporal profiles of Dw differ between the severely and the least damaged regions of tissue. In the core of the lesion, where the tissue evolved to necrosis, Dw declined significantly (P < 0.001) within 0.5 h after onset of ischemia, and remained depressed until 24 h after withdrawal of the suture. However, no statistically significant decline in Dw was found in the perifocal regions containing morphologically intact cells. Perfusion MRI qualitatively exhibited a hypoperfusion and reperfusion during, and after 2 h MCA occlusion, respectively. A significant (r > or = 0.71, P < 0.01) correlation was found between delta Dw (the difference in Dw between the ipsilateral ischemic and homologous contralateral control regions) obtained immediately before withdrawal of the suture (2 h of ischemia) and at specific early time points after withdrawal of the suture, and the degree of ischemic cell damage. No significant (P > 0.01) correlation was detected at an early time points of ischemia or at other time points after withdrawal of the suture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

14 beta-[(p-nitrocinnamoyl)amino]morphinones, 14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinones, and their codeinone analogues: synthesis and receptor activity.

A series of 14 beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5 beta-methyl group, were prepared from 14 beta-aminocodeinones and 14 beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5 beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5 beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5 beta-methyl-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET- CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [3H]DAMGO ([3H]D-Ala2, (Me)-Phe4, Gly(ol)5] enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the Bmax value and a marginal effect on the Kd value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

Animals↗
PubMed1993

Antinociceptive evaluation of 14 beta-(bromoacetamido)-7,8-dihydro- N(cyclopropylmethyl)-normorphinone in mice.

This study evaluated the supraspinal opioid effects of 14 beta-(bromoacetamido)-7,8-dihydro-N(cyclopropylmethyl)-normorphinone+ ++ (N-CPM-H2BAMO) in the mouse acetic acid-induced writhing and tail-flick assays. In the writhing test, N-CPM-H2BAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a 50% antinociceptive response being obtained with 0.28 (0.19-0.39) nmol when given 10 min before testing. The antinociceptive effect of N-CPM-H2BAMO was antagonized in a dose-dependent manner by the kappa-selective opioid receptor antagonist, nor-binaltorphimine. In the mouse tail-flick assay, N-CPM-H2BAMO failed to produce any antinociception after i.c.v. administration. N-CPM-H2BAMO produced a dose-dependent antagonism of morphine-induced antinociception but not antinociception induced by the delta-opioid receptor agonist [D-Pen2,D-Pen5]enkephalin. Nor-binaltorphimine (0.3 nmol) at dose that completely antagonized N-CPM-H2BAMO-induced antinociception in the writhing assay did not prevent the antagonistic effect of N-CPM-H2BAMO on morphine-induced antinociception. Therefore, these data indicate that N-CPM-H2BAMO produces antinociception by acting at supraspinal kappa-opioid receptors in the writhing assay, and also acts as a mu-opioid receptor antagonist.

Acetates↗
PubMed1993

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone: a long-lasting mu-opioid receptor antagonist devoid of agonist properties.

5 beta-Methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromorphinone (MET-CAMO) suppressed morphine-induced antinociception but had no effect on antinociception mediated by delta- or kappa-opioid receptors after a single i.c.v. 1-nmol injection from 8 to 72 h before testing. MET-CAMO had no agonist effects in the mouse tail-flick assay in doses up to 100 nmol. MET-CAMO is the first N-methylated morphine derivative which shows such long-lasting mu-selective opioid receptor antagonism with no agonistic properties.

Analgesics↗
PubMed1993

An efficient method for computer-aided dosage form design.

It is desirable to have slow-release dosage form to be taken once daily, or at most twice daily, as compared to three or four times in a single day. However, the existing computer-aided dosage form design method requires a large amount of computer time when applied to nonlinear disposition drugs. This large commitment of computer time makes it inconvenient to study the feasibility for prolonged-release products containing such drugs. Instead of evaluating all possible combinations of the amount of dose and release rates that produce acceptable steady-state plasma concentrations, only the contour of the dose-release rate domain needs to be determined. An image boundary tracking method has been used to determine such contours. When combined with several modifications of the numerical solution process, the acceptable dose and release rate constants can be determined efficiently. When this modified boundary tracking method was applied to phenytoin, which exhibits nonlinear disposition, the required computer time was reduced to about 5% of the previous method, making the dosage form feasibility assessment practical.

Computer Simulation↗
PubMed1993

Pharmacological study of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)-normor phinone (N-CPM-TAMO).

Opioid effects of 14 beta-(thioglycolamido)-7,8-dihydro-N(cyclopropylmethyl)- normorphinone (N-CPM-TAMO) were studied in the mouse tail-flick and acetic acid writhing assays. In the tail-flick test, N-CPM-TAMO failed to produce any antinociception after i.c.v. administration of up to 300 nmol. However, pretreatment of mice with N-CPM-TAMO produced a time- and dose-dependent antagonism of morphine-induced antinociception. The antagonism by N-CPM-TAMO lasted up to 48 hr, with a maximal effect at 24 hr after i.c.v. administration. Similarly, pretreatment of mice with N-CPM-TAMO at 24 hr also produced a dose-dependent antagonism of kappa-mediated antinociception, induced by U50,488 However, the antagonistic potency of N-CPM-TAMO against U50,488 was 100-fold less than against morphine. Pretreatment with N-CPM-TAMO had no effect on delta opioid receptor-mediated antinociception, as measured with [D-Pen2,D-Pen5]enkephalin. In the writhing assay, N-CPM-TAMO produced a time- and dose-dependent antinociception after i.c.v. administration, with a value of the dose producing 50% analgesia of 18.4 (10.6-31.9) nmol. The antinociceptive effect lasted up to 3 hr after administration. N-CPM-TAMO-induced antinociception was antagonized by coadministration of the kappa-selective antagonist, norbinaltorphimine. Pretreatment of mice with N-CPM-TAMO also produced a time- and dose-dependent antagonism of U50,488-induced antinociception, which lasted up to 72 hr, with a maximal effect at 24 hr after administration. These data indicate that N-CPM-TAMO is a mu-selective, long-term antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1993

DNA double-strand break rejoining deficiency in TK6 and other human B-lymphoblast cell lines.

TK6, WI-L2, SB and three other B-lymphoblast lines were deficient in the rejoining of DNA double-strand breaks (DSBs) induced by ionizing radiation. Cells of these cell lines rejoin less than 50% of the breaks in 60 min after exposure, as assayed by filter elution at pH 9.6. The deficiency in TK6 cells was confirmed using the comet assay. IN TK6 cells the percentage of DSB rejoining did not vary markedly with dose and was similar for G1, S, and G2 + M-phase cells. Two B-lymphocyte lines (Raji and GM0606), three T-lymphoblast lines (MOLT-4, Jurkat, and CCRF-HSB-2), HL-60 promyelocytes, and GM3440 human skin fibroblasts rejoined more than 50% of the DSBs in this period after exposure. Radiation sensitivity in terms of cell survival was measured in those cells forming colonies. Of the cell lines tested, those that were deficient in DSB rejoining were radiation-sensitive (TK6 and WI-L2: D0 = 0.64 Gy). However, not all lines that were proficient in DSB rejoining were radiation-resistant, since Jurkat and GM0606 cells were relatively radiation-sensitive (D0 = 0.63-0.73 Gy). TK6 and WI-L2 cells were more sensitive to bleomycin (D0 = 8-9 micrograms/ml) than were HL-60 and Raji cells (D0 = 40-54 micrograms/ml). No relationship of DSB rejoining to V(D)J recombinase activity was observed, since no mRNA hybridizing to the cDNA probes for RAG-1 or RAG-2 was detected in any of the cell lines tested.

B-Lymphocytes↗