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Biomedical subjects

D G Rhodes

Publications and source records attributed to D G Rhodes.

30 records · Page 2Linked to original sources
PubMed1991

New approaches to drug design and delivery based on drug-membrane interactions.

In this review, the complex physical and chemical interactions of drugs with model and biological membranes under normal and pathological conditions are examined at the molecular level. The results of our own published and unpublished structural studies are discussed and correlated with kinetic binding studies to assess the potential role of nonspecific drug interaction with the membrane bilayer in the overall receptor binding mechanism for membrane-bound receptors in heart and brain.

Algorithms↗
PubMed1990

Structure of polymerizable lipid bilayers: water profile of a diacetylenic lipid bilayer using elastic neutron scattering.

Elastic neutron scattering experiments have been used to study the hydration of multibilayers of 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC). Previously published FTIR spectroscopic data had suggested, based on shifts in the carbonyl (C = O) stretch frequencies, that the phosphocholine headgroup in these polymerizable lipid bilayers was much less hydrated than that of saturated phosphatidylcholines. Our results demonstrate that the DC8,9PC headgroup is at least as well hydrated as that of dipalmitoylphosphatidylcholine (DPPC), a saturated lipid, under the same conditions.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1989

Structure of the calcium channel antagonist, nimodipine.

Isopropyl 2-methoxyethyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5- pyridinedicarboxylate, C21H26N2O7, Mr = 418.45, orthorhombic, P2(1)2(1)2(1), a = 12.5897 (6), b = 14.6410 (9), c = 11.636 (1) A, V = 2144.8 (2) A3, Z = 4, Dm = 1.29, Dx = 1.30 g cm-3, lambda(Cu K alpha) = 1.54178 A, mu = 7.77 cm-1, F(000) = 888, T = 298 K, R = 0.047 for 1629 observed reflections. The structure of the title compound is similar to that of related analogs, the nitrophenyl ring being roughly normal to the dihydropyridine ring, which is in a boat conformation (N1 is 10.75 degrees out of the C2-C3-C5-C6 plane; C4 is 19.55 degrees out of plane). The 3,5 substituents are in an extended conformation, away from the 2,6 methyl groups. The nitro group is distal to N1. Structure/activity relationships of 1,4-dihydropyridines are discussed in light of this structure.

Chemical Phenomena↗
PubMed1989

Interaction of 1,4 dihydropyridine calcium channel antagonists with biological membranes: lipid bilayer partitioning could occur before drug binding to receptors.

The binding of dihydropyridine calcium channel agonists and antagonists to receptors in cardiac sarcolemmal membranes is a complex reaction that may involve an interaction with the lipid bilayer matrix of the sarcolemma. Membrane/buffer partition coefficients (lambda) for three dihydropyridine calcium channel antagonists were measured directly in the sarcolemma and sarcoplasmic reticulum membranes and found to be in the range of 5,000 to 150,000. These drugs interact primarily with the membrane bilayer component of these membranes but may also bind to non-receptor proteins. The intrinsic forward rate constants for dihydropyridine binding to sarcolemmal calcium channel receptors were apparently not strongly dependent on their membrane partition coefficients. For example, nimodipine (lambda = 6300) had a forward rate constant of 6.8 +/- 0.6 x 10(6)/M/S, whereas the forward rate constant for Bay P 8857 (lambda = 149,000) was 1.4 +/- 0.8 x 10(7)/M/S. Model calculations for this binding reaction demonstrated that since these drugs are highly lipid soluble, the dependence of these rates on lipid solubility would probably not be reflected in the experimental forward rate constants. In addition, the intrinsic forward rate constant for nimodipine binding to sarcolemmal calcium channel receptors was found not to be linearly dependent on the viscosity of the buffer medium over a five-fold range. The rate of nonspecific (non-receptor protein) drug binding to highly purified sarcoplasmic reticulum membranes essentially devoid of specific receptors for these drugs appears to be extremely fast, at least 10(3) times faster than specific drug binding to the receptor in the sarcolemma. Thus, it appears that partitioning into the lipid bilayer matrix of the sarcolemma could be a general property of dihydropyridine calcium channel antagonists and may be a prerequisite for their binding to sarcolemmal membrane receptors.

Animals↗
PubMed1988

Structure of polymerizable lipid bilayers. I--1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine, a tubule-forming phosphatidylcholine.

This report presents the first X-ray diffraction data on diacetylenic phospholipids. The tubule-forming polymerizable lipid, 1,2-bis(10,12-tricosadiynoyl)-sn-glycero-3-phosphocholine (DC8,9PC), was studied by low angle X-ray diffraction from partially dehydrated oriented multibilayers in both polymerized and unpolymerized form. Bilayers of this material were found to be highly ordered, yielding as many as 16 orders of lamellar diffraction, in both the polymerized and unpolymerized states. The unit cell dimension was very small for a lipid of this size. In addition to the features usually observed in the electron density profile structure of phospholipid bilayers, the electron-dense diacetylenic portions of the fatty acyl chain produced electron density maxima at two well-defined levels on each side of the bilayer approximately 15 A and 9 A from the bilayer midplane. A model molecular conformation deduced from the one-dimensional electron density map features all-trans acyl chains tilted at approximately 28 degrees from the bilayer normal that are interdigitated with chains of the opposing monolayer by approximately two carbons at the bilayer center. The linear diacetylene moieties on beta- and gamma-chains appear at different positions along the bilayer normal axis and are roughly parallel to the bilayer surface. This model is discussed in terms of a polymerization mechanism.

Diynes↗
PubMed1985

Kinetics of binding of membrane-active drugs to receptor sites. Diffusion-limited rates for a membrane bilayer approach of 1,4-dihydropyridine calcium channel antagonists to their active site.

Using the model of 1,4-dihydropyridine calcium channel-blocking drug binding to receptors in the cardiac sarcolemmal membrane, diffusion-limited rates of association were calculated for two distinct approaches. In the "aqueous approach," the drug reaches the receptor by diffusion through the bulk solvent, whereas in the "membrane approach," the drug partitions into the membrane bilayer and then diffuses laterally to a specific receptor site. Calculated rates for the membrane approach were approximately 3 orders of magnitude greater than those for the aqueous approach. The membrane approach diffusion-limited rate depends weakly on the sizes of the binding site, the drug molecule, and the vesicle, but depends strongly on ligand asymmetry. Although the measured binding rates for several 1,4-dihydropyridines were all slower than the calculated diffusion-limited rates for either model, other experimental data (such as very high partition coefficients and specific positions of these drugs in the membrane bilayer) suggest that the membrane approach is the most likely. These results have important implications for specifying critical characteristics of active 1,4-dihydropyridines.

Animals↗
PubMed1984

Rapid precision interferometry for the analytical ultracentrifuge. III. Determination of period of rotation, frequency of rotation, and elapsed time.

The approaches presented in this series of papers make possible rapid gathering, reduction, and analysis of data from the Rayleigh interference optical system of an analytical ultracentrifuge. Instrumentation described in this paper provides some of the timing and measurement circuits necessary for a microprocessor or minicomputer to determine the rotor frequency, rotor period, and elapsed time of an experiment. It includes simple but effective circuits to generate precise rotor timing pulses that are useful for synchronization of pulsed light sources. Circuits to control photographic operations in the ultracentrifuge are described briefly. All of these circuits are interfaced to a simple microcomputer address/data bus. An adapter between this bus and a Q-bus (for a DEC LSI-11/2 or LSI 11/23 microcomputer) is also described. The circuits presented have been used in this laboratory over a 3-year period. They have proven reliable and form an integral part of the real-time data acquisition systems that have been constructed.

Interferometry↗
PubMed1980

Purification and structural characterization of rat liver threonyl transfer ribonucleic acid synthetase.

Threonyl-tRNA synthetase was purified approximately 500-fold from a high-speed supernatant fraction of rat liver. The purified enzyme was estimated to be > 95% pure from acrylamide gel electrophoresis under denaturing and nondenaturing conditions. Based on a native molecular weight from sedimentation equilibrium of 154000 and a subunit molecular weight of 85000 obtained bo sodium dodecyl sulfate gel electrophoresis, the protein appears to be an alpha 2 dimer. The alpha 2 structure was also supported by cross-linking studies of the native enzyme. The purified protein has an S20,w of 7.2 and an isoelectric point of 6.4. Amino acid analyses revealed no unusual features, but attempts at automated sequence analyses suggested that both amino termini are blocked. Preliminary carbohydrate analyses suggested that the enzyme is a glycoprotein. Antibodies were raised against the purified protein which could inactivate and precipitate threonyl-tRNA synthetase.

Adsorption↗