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S Dove

Publications and source records attributed to S Dove.

17 recordsLinked to original sources
PubMed2001

Distinct interaction of human and guinea pig histamine H2-receptor with guanidine-type agonists.

It is unknown why the potencies and efficacies of long-chained guanidine-type histamine H2-receptor (H2R) agonists are lower at the H2R of human neutrophils than at the H2R of the guinea pig atrium. To elucidate these differences, we analyzed fusion proteins of the human H2R (hH2R) and guinea pig H2R (gpH2R), respectively, and the short splice variant of Gsalpha (GsalphaS) expressed in Sf9 cells. The potencies and efficacies of small H2R agonists in the GTPase assay and the potencies of antagonists at inhibiting histamine-stimulated GTP hydrolysis by hH2R-GsalphaS and gpH2R-GsalphaS were similar. In contrast, the potencies and efficacies of guanidines were lower at hH2R-GsalphaS than at gpH2R-G(salphaS). Guanidines bound to hH2R-GsalphaS with lower affinity than to gpH2R-GsalphaS, and high-affinity binding of guanidines at gpH2R-GsalphaS was more resistant to disruption by GTPgammaS than binding at hH2R-GsalphaS. Molecular modeling suggested that the nonconserved Asp-271 in transmembrane domain 7 of gpH2R (Ala-271 in hH2R) confers high potency to guanidines. This hypothesis was confirmed by Ala-271-->Asp-271 mutation in hH2R-GsalphaS. Intriguingly, the efficacies of guanidines at the Ala-271-->Asp-271 mutant and at hH2R/gpH2R chimeras were lower than at gpH2R. Our model suggests that a Tyr-17/Asp-271 H-bond, present only in gpH2R-GsalphaS but not the other constructs studied, stabilizes the active guanidine-H2R state. Collectively, our data show 1) distinct interaction of H2R species isoforms with guanidines, 2) that a single amino acid in transmembrane domain 7 critically determines guanidine potency, and 3) that an interaction between transmembrane domains 1 and 7 is important for guanidine efficacy.

Alternative Splicing↗
PubMed2000

Structure-activity relationships of neuropeptide Y Y1 receptor antagonists related to BIBP 3226.

Analogues of BIBP 3226, (R)-N(alpha)-diphenylacetyl-N-(4-hydroxybenzyl)argininamide, were synthesized and investigated for Y1 antagonism (Ca2+-assay, HEL cells) and binding on Y1, Y2 and Y5 receptors. Replacing the benzylamino by a tetrahydrobenzazepinyl group preserves most of the Y1 activity. Combination with a N(G)-phenylpropyl arginine and a N(alpha)-p-biphenylylacetyl moiety shifted the NPY receptor selectivity towards Y5.

Animals↗
PubMed2000

Phosphatidylinositol 4,5-bisphosphate regulates two steps of homotypic vacuole fusion.

Yeast vacuoles undergo cycles of fragmentation and fusion as part of their transmission to the daughter cell and in response to changes of nutrients and the environment. Vacuole fusion can be reconstituted in a cell free system. We now show that the vacuoles synthesize phosphoinositides during in vitro fusion. Of these phosphoinositides, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) are important for fusion. Monoclonal antibodies to PI(4,5)P(2), neomycin (a phosphoinositide ligand), and phosphatidylinositol-specific phospholipase C interfere with the reaction. Readdition of PI(4, 5)P(2) restores fusion in each case. Phosphatidylinositol 3-phosphate and PI(3,5)P(2) synthesis are not required. PI(4,5)P(2) is necessary for priming, i.e., for the Sec18p (NSF)-driven release of Sec17p (alpha-SNAP), which activates the vacuoles for subsequent tethering and docking. Therefore, it represents the kinetically earliest requirement identified for vacuole fusion so far. Furthermore, PI(4,5)P(2) is required at a step that can only occur after docking but before the BAPTA sensitive step in the latest stage of the reaction. We hence propose that PI(4,5)P(2) controls two steps of vacuole fusion.

Membrane Fusion↗
PubMed2000

Pharmacology and quantitative structure-activity relationships of imidazolylpropylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y1 receptor antagonists.

The design of non-peptide, Y1-selective antagonists of neuropeptide Y (NPY) as pharmacological tools is in progress and is increasingly important as therapeutic applications are expected. Starting from the potent histamine H2 agonist and weak NPY Y1 antagonist arpromidine, 16 imidazolylpropylguanidine derivatives were synthesized and tested for Y1 antagonistic activity (inhibition of NPY-stimulated Ca2+ increase in human erythroleukemic cells), where the pheniramine-like moiety of arpromidine was replaced with 2-pyridylaminoalkyl, benzyl-(2-pyridyl)aminoalkyl, and phenyl-(2-pyridyl)alkylaminoalkyl partial structures derived from mepyramine. The pA2 values of the most active compounds are in the range of 6.2-6.5. Quantitative structure-activity relationships (QSAR) were investigated by fragment regression analysis. Results indicate that a tetramethylene spacer between the guanidino group and the amino nitrogen is optimal. For an at least moderate degree of Y1 antagonistic activity, a second benzyl or phenyl group must be present in addition to the 2-pyridyl ring. At this second group, hydrophobic substituents such as 3,4-di-CI and 4-Br further enhance Y1 antagonism. The most active derivative additionally bears a 5-Br substituent at the 2-pyridyl moiety. Structure-activity relationships suggest that the compounds might be able to partially imitate the role of NPY when interacting with Y1 receptors and thus behave as moderate non-peptide NPY Y1 antagonists.

Guanidines↗
PubMed1998

NPY Y1 antagonists: structure-activity relationships of arginine derivatives and hybrid compounds with arpromidine-like partial structures.

Previously, omega-guanidino- and omega-aminoalkanamides, structurally derived from arpromidine-like histamine H2 receptor agonists, were reported as novel neuropeptide Y Y1 antagonists. Regardless of the backbone, they resemble BIBP 3226, an argininamide with high NPY Y1 receptor affinity and selectivity, with respect to nature and arrangement of the 'terminal' diaryl, guanidine, and hydroxyphenyl groups. Hybrid compounds were synthesized combining the argininamide backbone of BIBP 3226 or partial structures derived from the C-terminal dipeptide of NPY with characteristic substructures of arpromidine- or amide-type NPY antagonists. Additionally, some analogs of BIBP 3226 with reduced flexibility were prepared. Structure-activity relationships indicate that, in contrast to alkanamides, homologs and/or isomers of BIBP 3226 with vicinal arrangement of the phenyl rings have decreased Y1 antagonistic activity (Ca2+-assay in HEL cells). Replacement of the hydroxybenzyl group by an imidazole ring further decreases activity. It is concluded that the binding sites of NPY antagonists with one and with two basic groups are not identical. Analogs with a rigid tetrahydro-2-benzazepine or an indan group in place of the benzyl moiety in BIBP 3226 are active, indicating the role of the OH group and supporting the model proposed for the interaction of BIBP 3226 with the Y1 receptor.

Arginine↗
PubMed1998

Imidazolylpropylguanidines as histamine H2 receptor agonists:3D-QSAR of a large series.

Imidazolylpropylguanidines are potent histamine H2 receptor agonists and act as inotropic vasodilators. A large series of 141 derivatives was tested in the isolated guinea pig atrium and submitted to CoMFA. Since all compounds are full compounds are full agonists, pD2 values reflect H2 receptor binding. Hydrophobicity was considered as sigma f of the variable structural moiety, calculated by the Leo-Hansch method. Preliminary Hansch analysis with sigma f, (sigma f)2 and indicator variables showed that pD(2) additively depends on contributions of certain substructures and has a hydrophobic optimum. For CoMFA, all 3D structures were optimized and aligned. Partial Least Squares analysis of pD2 as function of steric and electrostatic field variables and of sigma f and (sigma f)2 led to models with r(2) of 0.78 with and 0.93 without hydrophobicity. Results indicate a parabolic dependence of pD(2) on hydrophobic effects. The 3D distribution of field influences on pD(2) suggests a model (shape and electrostatic potential) of the binding site. The role of branching and different substituent effects of a first and a second ring indicate that adequately branched structures induce a conformational change of the binding site enabling a favourable accommodation of the second ring with various substituents.

Guanidines↗
PubMed1997

Synthesis and neuropeptide Y Y1 receptor antagonistic activity of N,N-disubstituted omega-guanidino- and omega-aminoalkanoic acid amides.

Potent arpromidine-type histamine H2 receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y1 receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted omega-guanidino and omega-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr36 in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y1 antagonists in human erythroleukemia (HEL) cells (Ca2+ assay) achieving pKB values in the range of 6.3-6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H2 receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y1 antagonists than the ethylene homologs. Concerning the spacer in the omega-amino or omega-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the correspondence strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.

Amides↗
PubMed1993

A biochemical characterization of the photophore lenses of the midshipman fish, Porichthys notatus Girard.

The present study is a biochemical characterization of the photophore lenses of the midshipman fish, Porichthys notatus, a species that bears 800 photophores distributed over the body surface. The biochemical properties of the photophore lenses were compared with those of the eye lens with which they share a similar developmental origin and analogous function. To achieve a high refractive index, the vertebrate eye lens has a relatively high concentration of structural proteins (20-50%, depending on species) and a simple protein composition, that is, relatively few proteins are synthesized in comparison to other tissues. Similarly, the photophore lenses of P. notatus had a relatively high protein concentration (average = 29%, n = 5) and approximately 60% of the total soluble protein was represented by two subunit species of 33 kD and 35 kD on denaturing polyacrylamide gels. The structural proteins of the eye lens are of two principle types: 1) beta and gamma polypeptides which belong to vertebrate lens-specific crystallin families, and, 2) enzymes recruited into the lens which take on the function of structural proteins. Here, we report that the two major photophore lens subunits of 33 kD and 35 kD are biochemically similar to each other, but are clearly distinct from any of the previously characterized crystallins. Therefore, we propose that photophore lenses appear to recruit a novel protein.

Amino Acid Sequence↗
PubMed1993

Computer modelling of estrogenic transcriptional activation can account for different types of dose-response curves of estrogens.

Estrogenic activity of diphenylethanes and -ethenes was determined by uterine growth in immature mice and analyzed by weighed regression of logit-transformed effect on log dose values. This resulted in a range of Hill coefficients nH from 0.3 to 2 corresponding to the molecular mechanism of estrogenic transcriptional activation. Binding of agonists (hormones, H) to estrogen receptors (ER) leads to receptor dimerization depending on the structure of the ligand. Three hormone-receptor complexes, H-ER, H-ER-ER, and H-ER-ER-H, which bind with different affinity to short palindromic DNA sequences (estrogen responsive elements), can be proposed. Transcriptional activating functions of the DNA-bound ER are subsequently induced. We have derived an equilibrium model including these steps. Computer simulations of Hill plots based on the model have completely reproduced the range of observed nH values. Hill coefficients are > 1.5 if the homodimer H-ER-ER-H and < 0.7 if the heterodimer H-ER-ER strongly predominates. If ER dimerization is disturbed (H-ER monomer predominant), nH is closer to 1. Hill coefficients and pD2 values (negative decadic logarithms of molar estrogen doses causing 50% of the maximal effects) are related to parameters of ER dimerization and the two steps of hormone-receptor dissociation. When a series of 1,2-bis(3'-or 4'-hydroxyphenyl)ethanes and -ethenes is studied, a rather simple dependence of nH and pD2 on the nature of alkyl groups symmetrically substituted at C-atoms 1 and 2 can be observed. In terms of the model this implies that ethyl and alpha-branched higher alkyl substituents (nH >> 1) appear to stabilize the homodimer, while methyl and CF3 groups (nH << 1) could lead to a rapid dissociation of the homodimer to the heterodimer. With longer n-alkyl and beta-branched alkyl substitution (nH from 0.66 to 1.3), dimerization itself can be limited or the ligand-homodimer dissociation is only moderately increased. Thus, a strong sterical constraint could exist with respect to the stabilization of the second ligand-receptor bond in the homodimer.

Animals↗
PubMed1985

7-substituted-4-hydroxyquinoline-3-carboxylic acids as inhibitors of dehydrogenase enzymes and of the respiration of Ehrlich ascites tumor cells: multivariate analysis and quantitative structure-activity relationship for polar substituents.

The inhibitory activities of a set of nine 7-substituted-4-hydroxyquinoline-3-carboxylic acids against three dehydrogenase enzymes and one whole cell system (Ehrlich ascites tumor cells) have been subjected to principal component analysis. The results clearly indicate that activity against the whole cell test system cannot directly be attributed to inhibition of the enzymes evaluated. The enzyme systems are reflected by the first component that can be identified with polar and steric parameters while hydrophobic effects are absent. The second component is entirely due to the inhibition of ascites cell respiration that depends primarily on hydrophobicity.

Analysis of Variance↗
PubMed1984

Similarities of the substrate cleavage catalyzed by proline specific endopeptidase and dipeptidyl peptidase IV.

16 substrates of the types succinyl-alanyl-alanine-pX-anilide, and succinyl-alanyl-proline-pX anilide having different substituents in para-position of the aryl residue were synthesized and characterized. The influence of electronic as well as hydrophobic substituent constants, sigma and pi, on the hydrolysis of the substrates catalyzed by the enzyme Proline Specific Endopeptidase (PSE) has been investigated. In the Hansch approach, the catalytic constants lg kcat and lg (kcat/KM) of succinyl-alanyl-alanine-pX-anilides hydrolyzed by PSE correlate significantly with electronic substituent constants sigma, whereas no correlation in the case of succinyl-alanyl-proline-pX-anilides. The intercorrelation of the constants of the former substrates with corresponding data from Dipeptidyl Peptidase IV (DP IV) catalyzed hydrolysis of alanyl-alanine-pX-anilides suggest that both enzymes act by similar catalytic mechanism.

Chemical Phenomena↗
PubMed1980

On the rational selection of test series. 1. Principal component method combined with multidimensional mapping.

A method for the rational selection of optimal test series with high data variance and low collinearities is presented (PCMM method). The method combines the technique of multidimensional mapping originally introduced by Wootton and colleagues with the principal component method, and it is superior to other selection methods with respect to its collinearity decreasing power. Two examples of the application of PCMM are given, and the results are compared with corresponding results from other selection techniques.

Chemical Phenomena↗
PubMed1980

On the rational selection of test series. 2. Two-dimensional mapping of intraclass correlation matrices.

A rational design of optimal test series can be performed by two-dimensional mapping of intraclass correlation matrices (TMIC method). The method results in a two-dimensional map from which substituents can be selected by simple inspection. Different test series can be obtained from the same map so that synthetic feasibility can easily be taken into account. The approach closely corresponds to the usual way of thinking of organic chemists, and the test series evaluated for an example show high data variance and low collinearities.

Chemical Phenomena↗
PubMed1979

Discriminant--analytical investigation on the structural dependence of hyperglycemic and hypoglycemic activity in a series of substituted o-toluenesulfonylthioureas and o-toluenesulfonylureas.

The influence of a series of substituted o-toluenesulfonylthioureas and o-toluenesulfonylureas on the level of blood sugar was investigated in rats. According to the observed response the compounds were divided into three classes corresponding to hypoglycemic, hyperglycemic, and no activity. The distribution of the compounds over these classes can be described by discriminant functions using substituent constants, RM values, and indicator variables. Most important for the separation of classes are hydrophobic and/or steric properties as well as the presence or absence of the thiomide group. The results indicate that two different mechanisms of action with opposite effect overlap in the case of the series studied.

Animals↗