Search

Crystal structures of three class I antiarrhythmic agents: (1) iso-butyl 3-(1-pyrrolidinylmethyl)-4-(hydroxy)-methylphenylacetate hydrochloride, (2) 1,4-benzodioxan-2-methyl-3-(1-pyrrolidinylmethyl)-4-(hydroxy)-methylphenylacetate hydrochloride and (3) 1,4-benzodioxan-2-methyl-3-(1-pyrrolidinylmethyl)methylphenylacetate oxalate were determined. All three compounds are protonated at the N atom of the pyrrolidine ring. The protonated amine forms strong N-H...Cl or N-H...O intermolecular hydrogen bonds with the anions (either the chloride ion or the O atom of the hydrogen oxalate). The pyrrolidine rings are found in a similar orientation relative to the phenyl ring in all these compounds. The separations between the N atom of the pyrrolidine ring and the carbonyl O atom are observed in a range close to the N...O distance for class Ic antiarrhythmic agents found by Glowka, Dargie & Codding [J. Med. Chem. (1991), 34, 2678-2684]. Molecular mechanics calculations are used to identify the structural similarity of these antiarrhythmic agents, and to establish possible binding features required for class I agents.

The tripeptide crystallizes as a zwitterion with a protonated histidyl ring and the C-terminus ionized and with five water molecules of hydration (C21H27N5O5(.5)H2O). The tripeptide adopts an all trans extended conformation with the histidine and phenyl rings parallel to one another. The C-terminus coils into a helical conformation. An intramolecular hydrogen bond between the C-terminus and the N delta atom of the histidine ring stabilizes the helical conformation. The principal torsion angles are phi 1 = -67.7 (8), psi 1 = 140.8 (5), omega 1 = 171.0 (6), phi 2 = -156.5 (5), psi 2 = 162.7 (5), omega 2 = 175.0 (5), phi 3 = -96.4 (6), psi T1 = 14.5 (8) and psi T2 = -164.6 (6) degrees [IUPAC-IUB Commission on Biochemical Nomenclature (1970). J. Mol. Biol. 52, 1-17]. The tripeptides are linked in infinite chains through a short intermolecular hydrogen bond between the C-terminal carboxylate group and the protonated histidy1 N epsilone atom.

The structure of 5,7-dichlorokynurenic acid hydrate (IU-PAC name: 5,7-dichloro-4-oxo-1,4-dihydro-2-quinoline-carboxylic acid hydrate), C 10 H 5 Cl 2 NO 3 .H 2 O, has been determined by X-ray analysis. The molecule exists as a keto tautomer. All hydrogen-bond donors and acceptors take part in the hydrogen-bonding network which connects molecules into a three-dimensional array. Graphset analysis shows that there are both rings and chains in the network; however, there are no carboxylic acid dimers. The O-H portion of the carboxylic acid group is in a trans orientation with respect to the N-H group of the bicyclic ring system; the plane of the carboxylic group makes an angle of 7.6 (2)° with the plane of the heterocyclic ring.

17 beta-Hydroxy-5 beta-androstan-3-one, C19H30O2, Mr = 290.45, orthorhombic, P2(1)2(1)2(1), a = 11.7821 (6), b = 21.2184 (8), c = 6.5322 (2) A, V = 1633.0 (2) A3, Z = 4, D chi = 1.181 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.58 mm-1, F(000) = 640, T = 293 K, R = 0.033 for 1849 unique observed reflections. The molecular conformation of 5 beta-dihydrotestosterone shows the strong bending typical of 5 beta-steroids: the bowing angle of the A ring, relative to the remainder of the steroid, is 65.1 degrees. Bowing shortens the distance between the terminal O atoms, O(3) and O(17), to 9.824 (2) A which is ca 1 A shorter than was observed in 5 alpha-dihydrotestosterone and testosterone. The effects of both the bowing and the shorter separation between O(3) and O(17) may explain a difference in the affinity of 5 beta-dihydrotestosterone for the dexamethasone binding site on membranes compared to that of the other two compounds. A unique conformational feature of 5 beta-dihydrotestosterone is the flattening of the A ring on the side containing the C(3)--C(4) bond; this may be due to the combination of the 3-oxo substitution and the 5 beta-configuration.

C 24 H 32 N 4 O 3 cristallise dans P2 1 /c avec a=15,740, b=17,279, c=8,757 A, β=101,67°, Z=4; affinement jusqu'a R=0,057. La molecule est chimiquement semblable a plusieurs antiarythmiques actifs de type I mais elle est inactive. Les resultats structuraux indiquent que le manque d'activite peut etre du a des modifications du groupement lipophilique pharmacophore plutot qu'a des differences conformationnelles

The tripeptide crystallizes as a zwitterion with a protonated histidyl ring and the C-terminus ionized and with five water molecules of hydration (C21H27N5O5(.5)H2O). The tripeptide adopts an all trans extended conformation with the histidine and phenyl rings parallel to one another. The C-terminus coils into a helical conformation. An intramolecular hydrogen bond between the C-terminus and the N delta atom of the histidine ring stabilizes the helical conformation. The principal torsion angles are phi 1 = -67.7 (8), psi 1 = 140.8 (5), omega 1 = 171.0 (6), phi 2 = -156.5 (5), psi 2 = 162.7 (5), omega 2 = 175.0 (5), phi 3 = -96.4 (6), psi T1 = 14.5 (8) and psi T2 = -164.6 (6) degrees [IUPAC-IUB Commission on Biochemical Nomenclature (1970). J. Mol. Biol. 52, 1-17]. The tripeptides are linked in infinite chains through a short intermolecular hydrogen bond between the C-terminal carboxylate group and the protonated histidy1 N epsilone atom.

Studies of derivatives of the anticonvulsant methaqualone led to the discovery that unsaturation in the 2-substituent produced active, but less toxic compounds; accordingly, 2-arylethanone derivatives have been developed. The crystal structures of five 2arylethanone derivatives of methaqualone were determined to probe structure-activity relationships. Although these compounds display different activities, the solid-state and calculated structures are similar: each compound is observed as the enamine tautomer containing an intramolecular hydrogen bond between the ethanone and the amine N atom and the molecular conformations are the same. These studies conclude that recognition of the anticonvulsants arises from specific binding of an ortho substituent on the N(3) phenyl substituent, rather than from binding of a particular conformation or tautomeric form adopted by the compound containing an ortho substituent, and that such recognition is characteristic of a broad range of anticonvulsant drugs. Crystal data: (1), 2-[2-oxo-2-(4-pyridyl)ethyl]3-phenyl-4(3H)-quinazolinone, C21H15N302, Mr = 341.37, monoclinic, P2~, a= 12.1646 (5), b = 5.5988(2), c--12.389(2) A, fl=90.47(1) °, V= 843.8 (1)A 3, Z=2, Dx = 1.35 gcm -3, A(Cu Ka) = 1.5418A, #=7.31cm ~, T--293K, R--0.039, 1764 unique reflections; (2), 3-(2-chlorophenyl)-2-[2oxo-2-(4-pyridyl)ethyl]-4(3H)-quinazolinone, C2~HI4CIN302, Mr=375.82, monoclinic, P21/a, a =

17 beta-Hydroxy-5 beta-androstan-3-one, C19H30O2, Mr = 290.45, orthorhombic, P2(1)2(1)2(1), a = 11.7821 (6), b = 21.2184 (8), c = 6.5322 (2) A, V = 1633.0 (2) A3, Z = 4, D chi = 1.181 Mg m-3, lambda(Cu K alpha) = 1.54178 A, mu = 0.58 mm-1, F(000) = 640, T = 293 K, R = 0.033 for 1849 unique observed reflections. The molecular conformation of 5 beta-dihydrotestosterone shows the strong bending typical of 5 beta-steroids: the bowing angle of the A ring, relative to the remainder of the steroid, is 65.1 degrees. Bowing shortens the distance between the terminal O atoms, O(3) and O(17), to 9.824 (2) A which is ca 1 A shorter than was observed in 5 alpha-dihydrotestosterone and testosterone. The effects of both the bowing and the shorter separation between O(3) and O(17) may explain a difference in the affinity of 5 beta-dihydrotestosterone for the dexamethasone binding site on membranes compared to that of the other two compounds. A unique conformational feature of 5 beta-dihydrotestosterone is the flattening of the A ring on the side containing the C(3)--C(4) bond; this may be due to the combination of the 3-oxo substitution and the 5 beta-configuration.

There are relatively few women in the Canadian scientific community and most of the available research explains this fact in terms of girls' low enrolment in high school science programmes. The research presented here suggests that the substantial seepage of women from science at a later decision-point also contributes to the lack of women in the science professions. The career goals of a matched sample of male and female senior science undergraduates at nine Canadian universities (N = 204) are examined. The data show (1) that there are substantial gender discrepancies in the defection rates and career aspirations of male and female science undergraduates; (2) that fathers occupation emerges as a relevant background variable distinguishing female science students from their male counterparts; and (3) academic performance affects the defection rate of women from science-the top performers are more likely than average performers to defect from science. These findings are related to cross-national data and strategies for further research are suggested.

We have investigated the action of procainamide on batrachotoxin (BTX)-activated sodium channels from bovine heart and rat skeletal muscle. When applied to the intracellular side, procainamide induced rapid, open-channel block. We estimated rate constants using amplitude distribution analysis (Yellen, G. 1984. J. Gen. Physiol. 84:157). Membrane depolarization increased the blocking rate and slowed unblock. The rate constants were similar in both magnitude and voltage dependence for cardiac and skeletal muscle channels. Qualitatively, this block resembled the fast open-channel block by lidocaine (Zamponi, G. W., D. D. Doyle, and R. J. French. 1993. Biophys. J. 65:80), but procainamide was about sevenfold less potent. Molecular modeling suggests that the difference in potency between procainamide and lidocaine might arise from the relative orientation of their aromatic rings, or from differences in the structure of the aryl-amine link. For the cardiac channels, procainamide reduced the frequency of transitions to a long-lived closed state which shows features characteristic of inactivation (Zamponi, G. W., D. D. Doyle, and R. J. French. 1993. Biophys J. 65:91). Mean durations of kinetically identified closed states were not affected. The degree of fast block and of inhibition of the slow closures were correlated. Internally applied QX-314, a lidocaine derivative and also a fast blocker, produced a similar effect. Thus, drug binding to the fast blocking site appears to inhibit inactivation in BTX-activated cardiac channels.

6-(7-Chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-4-methyl-7- oxo-5H-1,4-dithiino[2,3-c]-pyrrol-5-yl-1-piperazinecarboxylic++ + acid, C20H20C1N5-O3S2, Mr = 477.9, triclinic, P1, a = 8.7066 (3), b = 9.7665 (8), c = 14.2515 (16) A, alpha = 80.986 (9), beta = 75.168 (6), gamma = 65.884 (5) degrees, V = 1067.4 (2) A3, Z = 2, F(000) = 496, room temperature, Dm = 1.482, D chi = 1.487 g cm-3, lambda(Cu K alpha) = 1.54178 A, Ni filter, mu = 36.3 cm-1, R = 0.053, omega R = 0.070 for the 3538 reflections included in the refinement. Comparisons of the structures of the two enantiomers of suriclone and the active conformer of the 1,4-benzodiazepine anxiolytics allow the identification of the active form of suriclone as the R isomer.

Three crystalline modifications of the bacterial serine peptidase Streptomyces griseus Protease B have been grown. A 4.5 Å resolution electron density map of one form has been computed from the multiple isomorphous replacement (MIR) phases deduced from two heavy metal derivatives plus the anomalous dispersion effects of one of the derivatives. The crystalline modification used was grown from 0.7–1.0 M KH2PO4 at pH 4.2. These crystals have space group P21212 and unit cell dimensions of a = 44.15 (5) Å, b = 108.72 (10) Å, and c = 37.28 (5) Å. The crystal asymmetric unit contains a protein mass of approximately 19 000 daltons. The electron density map, mean figure of merit 0.80, clearly shows the molecular boundary; relatively long stretches of extended chain are discernable. The active site has been identified from a difference electron density map computed using the MIR protein phases and the amplitude differences between a crystal of the enzyme inhibited at the active serine in solution by p-iodobenzenesulfonyl fluoride (PIPSYL) and those from a crystal of the native enzyme. In addition to showing the site of the PIPSYL binding, there is an apparent conformational change in which the histidine side chain moves away from the serine residue by approximately 4.3 Å.

Ligands that bind to the benzodiazepine receptor have three possible effects. The ligand can be an agonist and reduce anxiety, an antagonist and have no biological effect, or an inverse agonist and promote convulsions. This receptor complex is unique in its spectrum of response to ligands, and conformational changes in the receptor are implicated. The x-ray crystal structure of an imidazobenzodiazepine antagonist ligand, Ro15-1788, was determined and compared to the structures of the 1,4-benzodiazepine agonists and to two other types of antagonists, beta-carbolines and a pyrazoloquinolinone, CGS-8216. The antagonists were found to have similar arrangements of binding features including an aromatic ring, a carbonyl oxygen atom, and a hydrophobic side chain. The structures of these antagonists could be superimposed in a model binding site with three common features for all of the antagonists and a fourth hydrogen-bonding site for the pure antagonists (or inverse agonists), the beta-carbolines, and CGS-8216. A comparison of the shapes of the antagonist benzodiazepine, Ro15-1788, and several agonists showed that RO15-1788 has a unique azepine ring conformation that distorts the usual arrangement of the aromatic A ring, carbonyl oxygen atom, and imine N atom of the agonists. A conformational adjustment in the receptor would be required to accommodate both of these types of ligands. A summary of the superpositions of typical agonists and the antagonists leads to a model with 7 conformationally mobile binding points. Inverse agonists are distinguished from antagonists by the length of the hydrophobic side chain. Antagonists are distinguished from agonists in part by the lack of a binding feature similar to the imine N atom of the diazepine ring. This model accounts for the key features found in ligands for the benzodiazepine receptor and provides an explanation for the spectrum of responses elicited by receptor binding.

Structures cristallines de la biperidene et du derive mandelate. Relation entre la structure et l'activite biologique