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M Q Zhang

Publications and source records attributed to M Q Zhang.

At least 19 recordsLinked to original sources
PubMed1997

Synthesis and structure-activity relationships of carboxylated chalcones: a novel series of CysLT1 (LTD4) receptor antagonists.

The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.

Animals↗
PubMed1997

Identification of protein coding regions in the human genome by quadratic discriminant analysis.

A new method for predicting internal coding exons in genomic DNA sequences has been developed. This method is based on a prediction algorithm that uses the quadratic discriminant function for multivariate statistical pattern recognition. Substantial improvements have been made (with only 9 discriminant variables) when compared with existing methods: HEXON [Solovyev, V. V., Salamov, A. A. & Lawrence, C. B. (1994) Nucleic Acids Res. 22, 5156-5163] (based on linear discriminant analysis) and GRAIL2 [Uberbacher, E. C. & Mural, R. J. (1991) Proc. Natl. Acad. Sci. USA 88, 11261-11265] (based on neural networks). A computer program called MZEF is freely available to the genome community and allows users to adjust prior probability and to output alternative overlapping exons.

Base Sequence↗
PubMed1995

(Piperidinylalkoxy)chromones: novel antihistamines with additional antagonistic activity against leukotriene D4.

A series of novel chromone derivatives, in which the chromone moiety is connected to a (diphenylmethylene)-, (diphenylmethyl)-, or (diphenylmethoxy)piperidine via an alkyloxy spacer, were synthesized as antiallergic and antiasthmatic agents. In addition to their potent antihistaminic activity, the compounds also inhibit contraction in guinea pig ileum induced by leukotriene D4. When analyzed by radioligand binding assays in guinea pig lung membranes, one of the compounds, 7-[[3-[4-(diphenylmethylene)piperidin-1- yl]propyl]oxy]-2-(5-tetrazolyl)-4-oxo-4H-1-benzopyran, showed dissociation constants (KD) of 5.62 nM and 2.34 microM for H1- and LTD4-receptors, respectively. In vivo at the dose of 10 mg/kg, the compound inhibited the histamine- and LTD4-induced increase of vascular permeability in guinea pigs by 95 and 30%, respectively. The inhibition of LTD4-induced increase in vascular permeability by the compound was increased to 56% when a dose of 50 mg/kg was employed. Similar to terfenadine, the compound does not readily occupy the brain H1-receptors when given intraperitoneally to mice, implying no sedating side effects.

Animals↗
PubMed1995

Alignment of molecular sequences seen as random path analysis.

We propose a generating functional method--random path analysis (RPA)--that generalizes the classical dynamic programming (DP) method widely used in sequence alignments. For a given cost function, DP is a deterministic method that finds an optimal alignment by minimizing the total cost function for all possible alignments. By allowing uncertainty, RPA is a statistical method that weights fluctuating alignments by probabilities. Therefore, DP maybe thought of as the deterministic limit of RPA when the fluctuations approach zero. DP is the method of choice if one is only interested in optimal alignment. But we argue that, when information beyond the optimal alignment is desired, RPA gives a natural extension of DP for biological applications. As an algebraic approach, RPA is computationally intensive for long sequences, but it can provide better parametric control for developing analytical or perturbational results and it is more informative and biologically relevant. The idea of RPA opens up new opportunities for simulational approaches and more importantly it suggests a novel hardware implementation that has the potential of improving the way a sequence alignment is done. Here we focus on deriving a mathematically rigorous solution to RPA both in its combinatorial form and in its graphical representation; this puts DP in logical perspective under a more general conceptual framework.

Animals↗
PubMed1994

A sequence compilation and comparison of exons that are alternatively spliced in neurons.

Alternative splicing is an important regulatory mechanism to create protein diversity. In order to elucidate possible regulatory elements common to neuron specific exons, we created and statistically analysed a database of exons that are alternatively spliced in neurons. The splice site comparison of alternatively and constitutively spliced exons reveals that some, but not all alternatively spliced exons have splice sites deviating from the consensus sequence, implying diverse patterns of regulation. The deviation from the consensus is most evident at the -3 position of the 3' splice site and the +4 and -3 position of the 5' splice site. The nucleotide composition of alternatively and constitutively spliced exons is different, with alternatively spliced exons being more AU rich. We performed overlapping k-tuple analysis to identify common motifs. We found that alternatively and constitutively spliced exons differ in the frequency of several trinucleotides that cannot be explained by the amino acid composition and may be important for splicing regulation.

Alternative Splicing↗
PubMed1994

Fission yeast gene structure and recognition.

A database of 210 Schizosaccharomyces pombe DNA sequences (524,794 bp) was extracted from GenBank (release number 81.0) and examined by a number of methods in order to characterize statistical features of these sequences that might serve as signals or constraints for messenger RNA splicing. The statistical information compiled includes splicing signal (donor, acceptor and branch site) profiles, translational initiation start profile, exon/intron length distributions, ORF distribution, CDS size distribution, codon usage table, and 6-tuple distribution. The information content of the various signals are also presented. A rule-based interactive computer program for finding introns called INTRON.PLOT has been developed and was used to successfully analyze 7 newly sequenced genes.

Base Sequence↗
PubMed1994

Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity.

A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.

Animals↗
PubMed1994

Chiral manipulation of drug selectivity: studies on a series of terfenadine-derived dual antagonists on H1-receptors and calcium channels.

A series of terfenadine derivatives were evaluated for enantioselectivity on histamine H1-receptors and calcium channels. Whereas H1-receptors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either the phenylbutyl part or the benzhydryl part provided that an appropriate lipophilicity is preserved at the chiral site. It is speculated that the hydrophilicity of the butanol moiety is responsible for the lack of stereoselectivity of terfenadine enantiomers since it drives the side chain out of the stereoselective site of calcium channels, which are lipophilic. In four different test systems, (guinea-pig ileum, guinea-pig lung membranes, rat aorta and rat cortex membranes), this series of compounds generally showed about 10 times higher activity on H1-receptors than on calcium channels. By introducing a chiral center in the different parts of the molecule we were able to increase the selectivity of an enantiomer VUF4648 to calcium channels.

Animals↗
PubMed1993

Terfenadine: a mixture of equipotent antihistamine enantiomers without a clear 'isomeric ballast'.

Terfenadine was the first non-sedating histamine H1 receptor antagonist and one of the most frequently prescribed H1 antihistamines. Terfenadine has one asymmetric centre in the molecule and is currently used as a racemate. Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed in the present paper. Studies on antihistamine activity of the enantiomers, their side-effects on the central nervous system, calcium channel affinity and metabolism are also reviewed and analysed.

Animals↗
PubMed1993

Genome mapping by nonrandom anchoring: a discrete theoretical analysis.

As part of our effort to construct a physical map of the genome of the fission yeast Schizosaccharomyces pombe, we have made theoretical predictions for the progress expected, as measured by the expected length fraction of island coverage and by the expected properties of the anchored islands such as the number and the size of islands. Our experimental strategy is to construct a random clone library and screen the library for clones having unique sequence at both ends. This scheme is essentially the same as the clone-limited double sequence-tagged-site selection scheme which was used in a computer simulation by Palazzolo et al. [Palazzolo, M. J., Sawyer, S. A., Martin, C. H., Smoller, D. A. & Hartl, D. L. (1991) Proc. Natl. Acad. Sci. USA 88, 8034-8038]. Both simulation and ongoing experiments in our laboratory have shown that the nonrandom anchoring method is far superior to random anchoring. In this paper, we propose a theoretical model to explain the simulated data and the experimental data.

Chromosome Mapping↗
PubMed1993

Hypertrophy of rat sensory ganglion neurons following intestinal obstruction.

BACKGROUND: Neuroplastic changes following ileum hypertrophy have been reported in intrinsic enteric neurons. The hypothesis in the present study was that intestinal hypertrophy induces neuronal changes in dorsal root ganglia (DRG). METHODS: Under sodium pentobarbital anesthesia, partial obstruction was produced in the rat by tying a plastic ring around the terminal loop of ileum. Fast Blue (FB) (Sigma, St. Louis, MO) was injected into the obstructed ileum wall, and the rat was perfused after 8 days. DRG were immunostained and examined to identify and measure sizes of perikarya containing FB and/or calcitonin gene-related peptide (CGRP) or FB and/or substance P (SP). RESULTS: Of the DRG neurons that projected to the ileum in control or obstructed animals, approximately 50% were CGRP-immunoreactive (IR) and 30% were SP-IR (colchicine pretreatment was not used). Neurons that projected to the obstructed ileum were increased in size compared with neurons in nonobstructed controls. Some of these neurons were CGRP-IR or SP-IR; some were large FB-labeled neurons that were not SP-IR or CGRP-IR. CONCLUSIONS: The morphology of sensory autonomic neurons in adult animals is influenced by dynamic interactions with the targets they innervate, whether directly or transneuronally.

Animals↗
PubMed1993

A weight array method for splicing signal analysis.

A new method of sequence analysis, using a weight array method (WAM), which generalizes the traditional Staden weight matrix method (WMM), is proposed. With the help of a statistical mechanical model, the discriminant function is identified with the energy function describing macromolecular interactions. The method is applied to the study of 5'-splice signals in Schizosaccharomyces pombe pre-mRNA sequences. The results show that there may exist weak pairwise correlations within the signals and that our method can help to better discriminate these signals. Experiments are proposed to test the predictions of the theory.

Animals↗
PubMed1993

Calcium antagonism and structure-affinity relationships of terfenadine, a histamine H1 antagonist, and some related compounds.

Calcium channel affinity of terfenadine and its optical isomers was determined by the displacement of [3H]nitrendipine on rat cerebral cortex membranes. Terfenadine showed a pKd of 6.36 +/- 0.03 whereas its R(+)-isomer (VUF4567) had a pKd value of 6.39 +/- 0.03 and the S(-)-isomer (VUF4568) had a pKd of 6.40 +/- 0.04. The same affinity between the enantiomers suggests that the binding domain on the membrane is not sterically restricted towards the part of the molecule in which the chiral centre is present. The characteristics of terfenadine in regulating [3H]nitrendipine binding were similar to those of some other diphenyl-alkylamine type calcium antagonists. It allosterically altered the binding affinity for nitrendipine and acted at the same site linked to the calcium channel as gallopamil. A structure-affinity relationship among a group of terfenadine analogues is discussed.

Animals↗
PubMed1992

[In vitro measurement of antibacterial activities of topical antibacterial creams].

A new method of in vitro measurement of antibacterial activity of different antimicrobial creams is introduced in this paper. The tested cream in known quantity is uniformed suspended in a solid medium, and bacteria of known quantity are inoculated. The result is expressed in MIC. In this observation, four creams were tested against 3 bacteria. It is the authors impression that the new method is better than the traditional disc method, as it reflects better the actual antibacterial activity of the drug in a cream base. It is helpful in selecting an effective drug or to evaluate the effectiveness of certain drugs in clinical practice.

Escherichia coli↗
PubMed1991

Quinolone antimicrobial agents: structure-activity relationships.

The rapid growth in the quinolone research changed the whole face of the previous SAR concepts. So far structural modifications at all positions of the quinolone nucleus except the 4-oxo group have successfully lead to the discovery of potent antimicrobial agents. At position 1, ethyl and its bioisosteres such as fluoroethyl, methylamino, methoxy, etc, are optimal substituents while some groups with a tert.-carbon atom directly connected with N-1 position such as tert.-butyl, phenyl, etc. are also promising for the activity of the quinolone compounds. Steric bulk is no longer considered as the only factor which influences the activity of the compounds. However, it could only be answered by further research how big such steric bulk tolerance at position 1 would be and what is the precise role that the N-1 substituents play in the mechanism of action of the quinolones. Fluorination has been extensively employed as a modifying technique to almost all possible positions of the quinolone nucleus. While being maintained at C-6, a fluorine atom was also introduced to C-5 and C-8 to produce potent analogues. Fluorination of N-1 substituents, e.g., fluoroethyl, fluorophenyl, etc., and C-7 substituents, e.g. 2-((fluoromethyl)piperazinyl and fluorohomopiperazinyl, etc., yielded also a handful of potent quinolones. Amino-and chloro groups are found to be beneficial for positions 5 and 8, respectively. The "medium size" concept concerning the 7-substituents is no longer valid. Numerous potent quinolones with a "large" group substituted on position 7 have been discovered. A certain amount of free rotation in the 7-substituents appears to emerge as an important factor which influences the activity of the compounds. Some radical modifications in 7-substituents, e.g. C--C linkage between the nucleus and 7-substituents, afforded new insight into the SAR of quinolones. A planarity between the 4-oxo group and 3-carboxylic group may be important for binding to the DNA gyrase as demonstrated by a group of enolized isothiazoloquinolone derivatives. Further research will surely lead to the better understanding on the mechanism of action of quinolones as well as the discovery of analogues with better activity features, lower adverse effects and more favourable pharmacokinetic properties.

4-Quinolones↗