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Biomedical subjects

U Norinder

Publications and source records attributed to U Norinder.

13 recordsLinked to original sources
PubMed1992

Determinants for DNA-binding site recognition by the glucocorticoid receptor.

The glucocorticoid receptor binds with high specificity to glucocorticoid response elements, discriminating them from other closely related binding sites. Three amino acids in the recognition alpha-helix of the DNA-binding domain of the receptor are primarily responsible for this specific DNA binding activity. In this study we analyze in detail how these residues determine the specific DNA binding by studying a series of mutant glucocorticoid receptor DNA-binding domains containing all combinations of glucocorticoid and estrogen receptor-specific residues at these positions. Statistical analysis of the results enables us to create models describing the association between amino acids and base pairs. Several strategies appear to be used in accomplishing discrimination between the glucocorticoid and estrogen response elements. Single residues (i.e., Val-443 in the glucocorticoid receptor and Glu-439 in the estrogen receptor) appear to form both positive contacts with specific base pairs in the cognate binding site and negative contacts in the non-cognate site. In the glucocorticoid receptor Ser-440 is pleiotropically negative for all sites tested but the negative effect is stronger for the estrogen response element thus contributing to binding site discrimination. Furthermore, combinations of amino acids appear to act synergistically, most often causing a reduction in binding to non-cognate sites.

Amino Acid Sequence↗
PubMed1992

Inhibition of [3H]paroxetine binding by various serotonin uptake inhibitors: structure-activity relationships.

Fifty-four compounds structurally related to zimeldine or alaproclate and eight reference substances were examined as inhibitors of the high affinity binding of [3H]paroxetine to rat cerebral cortical membranes as a measure of the affinity of the 5-hydroxytryptamine (5-HT) transporter. None of the compounds had an affinity as high as paroxetine (KD = 0.026 nM). The most potent compound, 3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine (2) had a 5 times lower affinity than paroxetine. Some other diphenyl-1-methyl-propylamines displayed high affinity, e.g. the 4-bromo (4) and 2-bromo (7) derivatives. The primary amine analogue of zimeldine substituted with an alpha-methyl group (19) had an affinity only slightly less than that of norzimeldine (11) but an almost 100 times higher affinity than that of the unsubstituted primary zimeldine analogue (57). These observations indicate that a methyl group on the alpha-carbon and on the nitrogen both increase the affinity for the [3H]paroxetine binding site. The structure activity relationship for the compounds to inhibit [3H]paroxetine binding was highly significantly correlated to the inhibition of 5-HT uptake in mouse brain slices (P less than 0.01) and to the inhibition of noradrenaline uptake in the same slices (P less than 0.05). QSAR analysis of the zimeldine series of compounds indicates that substitution of halogens of the 2-position of the phenyl ring is unfavourable. The cis configuration promotes higher activity than the trans configuration.

Animals↗
PubMed1992

Experimental design-based quantitative structure-toxicity relationship of some local anaesthetics using the PLS method.

A quantitative structure-toxicology (LD50) relationship for some N-alkylsuccinimides is presented. The relationship is based on a small and carefully selected training set using experimental design methodology. The good predictability, an overall r2 value of 0.75, with such an approach is demonstrated. Factors such as large N-alkyl groups, substitution in the aromatic ring and a long side chain between the two nitrogens are favourable for low toxicity.

Least-Squares Analysis↗
PubMed1992

PLS-based quantitative structure-activity relationship for substituted benzamides of clebopride type. Application of experimental design in drug design.

The advantageous approach of using an experimentally designed training set as the basis for establishing a quantitative structure-activity relationship with good predictive capability is described. The training set was selected from a fractional factorial design scheme based on a principal component description of physico-chemical parameters of aromatic substituents. The derived model successfully predicts the activities of additional substituted benzamides of 6-methoxy-N-(4-piperidyl)salicylamide type. The major influence on activity of the 3-substituent is demonstrated.

Benzamides↗
PubMed1992

A quantitative structure-activity relationship for some dopamine D2 antagonists of benzamide type.

A quantitative structure-activity relationship (QSAR) for some 6-methoxybenzamides having 1-ethyl-2-pyrrolidinylmethyl side chains with respect to the inhibition of [3H]spiperone binding is established using the PLS method. An experimental design approach to select the training set compounds is demonstrated. The established relationship between structure and in vitro activity indicates the dominating influence of the substituents in the 3-position as well as the importance of (S)-configuration in the side chain. A methoxy substituent in the 5-position is also beneficiary for high activity. Both salicylamides and non-salicylamides could be accommodated in the analysis, which supports the notion of a common binding site in the receptor.

Benzamides↗
PubMed1988

Structural factors of importance for 5-hydroxytryptaminergic activity. Conformational preferences and electrostatic potentials of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some related agents.

The conformational characteristics of two series of 5-hydroxytryptamine (5-HT) receptor agonists, monophenolic N,N-dialkylated 2-aminotetralins and trans-2-phenylcyclopropylamines, have been studied by a combination of experimental (NMR spectroscopy) and theoretical (molecular mechanics and MNDO calculations) methods. In addition, molecular electrostatic potentials have been calculated for selected conformations and the absolute configuration of the potent 5-HT-receptor agonist (+)-cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin has been determined, by X-ray crystallography of the synthetic precursor, to be 1S,2R. Results obtained are discussed in terms of conformational, steric, and electronic requirements for 5-HT-receptor activation. It is suggested that different conformations of the 5-HT-receptor agonists (1R,2S)-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine [(1R,2S)-4] and its 3-hydroxy isomer (1R,2S)-5 are able to activate 5-HT receptors. The strongly increased stereoselectivity of 2, 4, and 5 as compared to that of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 1) is rationalized on the basis of steric factors. Conformational factors appear to be responsible for the inability of the trans-C1-methyl-substituted derivative of 1 to activate 5-HT receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1987

Crystallographic, theoretical and molecular modelling studies on the conformations of the salicylamide, raclopride, a selective dopamine-D2 antagonist.

The structure of the potent dopamine-D2 antagonist, raclopride, (S)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-methoxysalicylamid e (+)-tartrate, has been determined by X-ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side-chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side-chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (less than 4.0 kcal mol-1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N-ethyl-2-pyrrolidinylmethyl side-chains interact with the dopamine-D2 receptor in a folded or a half-folded conformation.

Crystallization↗