Dopaminergic pharmacophore of ergoline and its analogues. A molecular electrostatic potential study.

Spatial correspondence between apomorphine, a prototype dopaminergic (DA) drug, and ergoline and some of its (partial) analogues were derived by matching their molecular electrostatic potential (MEP) patterns surrounding the aromatic moieties with respect to the coincident aliphatic N atoms. The MEP patterns were calculated from ab initio wave functions of model molecules. The congruent superimpositions of the molecular frameworks obtained between apomorphine and DA active ergoline analogues might corroborate the hypothesis that they bind with the same receptor sites when activating certain subtypes of the DA receptor.

Correlation between affinity toward adrenergic receptors and approximate electrostatic potentials of phenylethylamine derivatives. 1. Effects of the side chain.

The molecular electrostatic potential (VN) in the region of the nitrogen lone pair of a series of substituted propylamines is used in a correlation with the dissociation constants of parent phenylethylamine-type ligands obtained on beta-adrenoceptors by Bilezikian et al. It is shown that VN is a more effective index for quantitative structure-activity relationship studies than an optimal set of substituent constants used in additive, linear models. No significant correlation between the total electronic charge on the nitrogen and the binding potencies was obtained in the examined series. Protonation energies of the propylamines have been computed, but no meaningful correlation with the dissociation constants was obtained.

Conformationally restricted dopamine congeners--a molecular mechanics-based study.

Potential energies of several systems containing the phenylethylamine fragment were computed by the QCFF/PI method and some of them also by the PCILO method. The systems considered are: octahydrobenzo [f]- and [g]-quinolines, aporphine, 1-phenylbenzazepine, 4-phenyltetrahydroisoquinoline, 3-phenylpiperidine and 9-aminodihydrophenanthrene. No common set of torsion angles defining the stereostructure around the amine head is apparent if only the lowest energy conformations are considered. Leaving out the orientation of the N-CH3 group, and considering also some higher energy conformations, two groups of systems may be formed, A and B, the members of which are congruent amongst themselves in parameters defining the spatial relations of the amine site and the catechol ring, and in the orientation of the N+-H bond. The stereostructure of the rigid representatives of group A is postulated to be the one required by the brain and cardioaccelerator nerve receptor. A corresponding postulate for the vascular bed DA receptors cannot be made since systems forming group B, the derivatives of which are active both on brain and vascular bed receptors, have more conformation space and, moreover, they carry additional potential anchoring groups.

FT infrared and Raman investigation of saccharide-phosphatidylcholine interactions using novel structure probes.

Conformational consequences of adduct formation between saccharides (trehalose, glucose, raffinose) and sorbitol with dipalmitoylphosphatidylcholine (DPPC) in multibilayers are revealed by relative intensity changes of the band components corresponding to the nu asN(CH3)3 and nu sC-N(CH3)3 stretching modes of the choline chain terminal and those of the nu C = O band. The conformational sensitivity of those modes was demonstrated previously (J. Grdadolnik et al., Chem. Phys. Lipids 65 (1993) 121) and used to demonstrate the effects of stepwise hydration of phosphatidylcholines. The latter are compared with the effects of saccharide binding and found to be qualitatively similar, but not identical. The same is true of the low frequency shifts of the nu asPO2- vibration: the shifts due to saccharide binding correspond to the binding of six to seven water molecules per phosphate which is about 20 cm-1 less than the shift caused by full hydration. A particularly interesting finding concerns the appearance of two bands in the nu asPO2- region of the DPPC-saccharide adducts. The relative intensities of the two bands (1243 and 1223 cm-1) change on additional hydration; it is the one at 1223 cm-1 that prevails at high hydration levels. Major changes in saccharide conformation are not detectable but minor differences between the DPPC bound and crystal spectra are observed.

[Appendiceal mucocele]. / Mukokéla apendixu.

Appendiceal mucocele is a rare condition encountered it only 0.07-0.4% of all appendectomies. The male to female ratio is 1:4 and an average age at the time of diagnosis is over 50 years. Mucocele of the appendix is defined as appendiceal obstruction leading to lumen distension with accumulation of mucoid material. The disease ranges from benign forms to malignant cystadenocarcinoma. The cause of the obstruction may be classified based on histology into four groups. These groups include simple mucocele, mucosal hyperplasia, cystadenoma, and cystadenocarcinoma. Abdominal ultrasound and CT scan may suggest the diagnosis. The authors discuss two cases of simple appendiceal mucocele. A 48-year-old man presented with acute right lower quadrant pain. Ultrasound examination was performed and the structure in the right iliac fossa was reported as an periappendiceal abscess. The patient underwent acute exploratory laparotomy, which revealed an appendiceal mucocele filled with gelatinous material. It was performed ileocoecal resection. A 65-year-old man presented with abdominal distension and discomfort of several week duration. At laparotomy, a smooth cystic tumor of the appendix was found. This patient underwent appendectomy alone. Pathology revealed an simple appendiceal mucocele.

Potential energy functions and the role of the conformational entropy of clonidine-like imidazolidines in determining their affinity for alpha-adrenergic receptors.

Energy as a function of the ring interplanar torsional angle was calculated for 12 2-(phenylimino)imidazolidines by the method of perturbation configuration interaction using localized orbitals. The potential energy functions indicate that the molecules may assume any conformation within rather broad limits. The functions were used in calculating the gas phase and solution conformational entropies. The latter were used as the independent variable in regression analysis to derive equations connecting the conformational entropy with pKi (pKi = -log Ki) for [3H]clonidine displacement (literature data). As a comparison, correlations between pKi and several other parameters (modified neglect of diatomic overlap-computed highest occupied and lowest unoccupied molecular orbital energies and dipole moments; pKa; log P; substituent steric parameters) were sought. Correlation coefficients C greater than 0.6 were obtained with the conformational entropy (-0.77), and the ortho steric parameters (-0.71). The correlation with the conformational entropy was not markedly improved by adding other parameters in multiple regression analysis. This result is discussed in terms of the contribution to the ligand-receptor complexation free energy arising from the conformational restriction of the ligands upon binding to the receptor.

Bioactive conformations of small peptides: a method for selection of candidates based on conformations of active and inactive analogues and its application to muramyl dipeptide.

A method has been developed that selects a subset of candidates for the bioactive conformation based on the comparison of conformation clusters of the active and inactive ligands. Those conformations of the active ligand that cannot be reached by inactive ligands in spatially presenting preselected "target" atoms (conformations "unique" to the active ligand) are extracted. The method is applied to muramyl dipeptide (MDP); the selection of candidates was performed using two of its diastereomers that have no immunostimulative properties. A third diastereomer and a rigidified analogue, both inactive, and the protein-bound conformation of a related peptidoglycan containing the MurNAc-L-Ala-D-Glu sequence are used as test cases; the latter was found to be most similar to one member of the set of unique conformations of MDP.

The biologically active conformation of ergot alkaloids.

Molecular mechanics and NMR studies of the D ring conformation of ergot alkaloids demonstrate that both D1 and D2 forms may exist in solution. The comparison of the geometric parameters defining the spatial relations between the aromatic moieties and the basic nitrogen of conformationally restricted dopamine analogs, and that of ergolene, shows the D1 conformation to be the bioactive one.

On achieving better than 1-A accuracy in a simulation of a large protein: Streptomyces griseus protease A.

Computational methods are frequently used to simulate the properties of proteins. In these studies accuracy is clearly important, and the improvement of accuracy of protein simulation methodology is one of the major challenges in the application of theoretical methods, such as molecular dynamics, to structural studies of biological molecules. Much effort is being devoted to such improvements. Here, we present an analysis of a 187-ps molecular dynamics simulation of the serine protease Streptomyces griseus protease A in its crystal environment. The reproduction of the experimental structure is considerably better than has been achieved in earlier simulations--the root mean square deviation of the simulated structure from the x-ray structure being less than 1 A, a significant step toward the goal of simulating proteins to within experimental error. The use of a longer cutoff with truncation rather than a switching function, inclusion of all crystalline water and the counterions in the crystallization medium, and use of the consistent valence force field characterize the differences in this calculation.