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At least 739 records · Page 41Linked to original sources
PubMed2005

Venular endothelium-derived NO can affect paired arteriole: a computational model.

Venular endothelial cells can release nitric oxide (NO) in response to intraluminal flow both in isolated venules and in vivo. Experimental studies suggest that venular endothelium-released NO causes dilation of the adjacent paired arteriole. In the vascular wall, NO stimulates its target hemoprotein, soluble guanylate cyclase (sGC), which relaxes smooth muscle cells. In this study, a computational model of NO transport for an arteriole and venule pair was developed to determine the importance of the venular endothelium-released NO and its transport to the adjacent arteriole in the tissue. The model predicts that the tissue NO levels are affected within a wide range of parameters, including NO-red blood cell reaction rate and NO production rate in the arteriole and venule. The results predict that changes in the venular NO production affected not only venular endothelial and smooth muscle NO concentration but also endothelial and smooth muscle NO concentration in the adjacent arteriole. This suggests that the anatomy of microvascular tissue can permit the transport of NO from arteriolar to venular side, and vice versa, and may provide a mechanism for dilation of proximal arterioles by venules. These results will have significant implications for our understanding of tissue NO levels in both physiological and pathophysiological conditions.

Animals↗
PubMedDate not supplied

Differential pencil beam dose computation model for photons.

Differential pencil beam (DPB) is defined as the dose distribution relative to the position of the first collision, per unit collision density, for a monoenergetic pencil beam of photons in an infinite homogeneous medium of unit density. We have generated DPB dose distribution tables for a number of photon energies in water using the Monte Carlo method. The three-dimensional (3D) nature of the transport of photons and electrons is automatically incorporated in DPB dose distributions. Dose is computed by evaluating 3D integrals of DPB dose. The DPB dose computation model has been applied to calculate dose distributions for 60Co and accelerator beams. Calculations for the latter are performed using energy spectra generated with the Monte Carlo program. To predict dose distributions near the beam boundaries defined by the collimation system as well as blocks, we utilize the angular distribution of incident photons. Inhomogeneities are taken into account by attenuating the primary photon fluence exponentially utilizing the average total linear attenuation coefficient of intervening tissue, by multiplying photon fluence by the linear attenuation coefficient to yield the number of collisions in the scattering volume, and by scaling the path between the scattering volume element and the computation point by an effective density.

Bone and Bones↗
PubMed2000

A computational model of lateralization and asymmetries in cortical maps.

While recent experimental work has defined asymmetries and lateralization in left and right cortical maps, the mechanisms underlying these phenomena are currently not established. In order to explore some possible mechanisms in theory, we studied a neural model consisting of paired cerebral hemispheric regions interacting via a simulated corpus callosum. Starting with random synaptic strengths, unsupervised (Hebbian) synaptic modifications led to the emergence of a topographic map in one or both hemispheric regions. Because of uncertainties concerning the nature of hemispheric interactions, both excitatory and inhibitory callosal influences were examined independently. A sharp transition in model behavior was observed depending on callosal strength. For excitatory or weakly inhibitory callosal interactions, complete and symmetric mirror-image maps generally appeared in both hemispheric regions. In contrast, with stronger inhibitory callosal interactions, partial to complete map lateralization tended to occur, and the maps in each hemispheric region often became complementary. Lateralization occurred readily toward the side having a larger cortical region or higher excitability. Asymmetric synaptic plasticity, however, had only a transitory effect on lateralization. These results support the hypotheses that interhemispheric competition occurs, that multiple underlying asymmetries may lead to function lateralization, and that the effects of asymmetric synaptic plasticity may vary depending on whether supervised or unsupervised learning is involved. To our knowledge, this is the first computational model to demonstrate the emergence of topographic map lateralization and asymmetries.

Animals↗
PubMed2006

Computational models of structure-function relationships in the pulmonary circulation and their validation.

The pulmonary airway, arterial, venous and capillary networks are vast complex branching and converging systems that are mechanically coupled to the surrounding lung tissue. Early studies that examined vascular or airway geometry relied on measurements from casts, but medical imaging now enables measurement of the lung in vivo, at controlled lung volumes. The high-quality data that imaging provides have prompted development of increasingly sophisticated models of the geometry of the airway and pulmonary vascular trees. The accurate spatial relationships between airway, vessel and tissue in these imaging-derived models are necessary for computational analysis that aims to elucidate regional airway-vessel-tissue interactions. Predictions of blood flow through multiscale imaging-derived models of the pulmonary arteries and capillary bed reveal geometry-dependent patterns of perfusion in response to gravity and lung orientation that cannot be predicted with simplified, summary representations of the pulmonary transport trees. Validation of such predictions against measures from functional imaging holds significant potential for explaining and differentiating normal and disease-related heterogeneity in regional blood flow calculated using perfusion imaging.

Computer Simulation↗
PubMed2005

In vivo articular cartilage contact kinematics of the knee: an investigation using dual-orthogonal fluoroscopy and magnetic resonance image-based computer models.

BACKGROUND: Quantifying the in vivo cartilage contact mechanics of the knee may improve our understanding of the mechanisms of joint degeneration and may therefore improve the surgical repair of the joint after injury. OBJECTIVE: To measure tibiofemoral articular cartilage contact kinematics during in vivo knee flexion. STUDY DESIGN: Descriptive laboratory study. METHODS: Orthogonal fluoroscopic images and magnetic resonance image-based computer models were used to measure the motion of the cartilage contact points during a quasi-static lunge in 5 human subjects. RESULTS: On the tibial plateau, the contact point moved in both the anteroposterior and the mediolateral directions during knee flexion. On the medial tibial plateau, flexion angle did not have a statistically significant effect on the location of the contact points. The total translation of the contact point from full extension to 90 degrees of flexion was less than 1.5 mm in the anteroposterior direction, whereas the translation in the mediolateral direction was more than 5.0 mm. In the anteroposterior direction, the contact points were centered on the medial tibial plateau. On the lateral tibial plateau, there was a statistically significant difference between the location of the contact point at full extension and the locations of the contact points at other flexion angles in the anteroposterior direction. No significant difference was detected between the location of the contact points at other flexion angles. The overall range of contact point motion was about 9.0 mm in the anteroposterior direction and about 4.0 mm in the mediolateral direction. The contact points were primarily on the inner half of the medial and lateral tibial plateaus (the half closest to the tibial spine). The contact points on both femoral condyles were also on the inner half of the condyles (near the condylar notch). CONCLUSIONS: The tibiofemoral contact points move in 3 dimensions during weightbearing knee flexion. The medial tibiofemoral contact points remained within the central portion of the tibial plateau in the anteroposterior direction. Both the medial and lateral tibiofemoral contact points were located on the inner portions of the tibial plateau and femoral condyles (close to the tibial spine), indicating that the tibial spine may play an important role in knee stability. CLINICAL RELEVANCE: The results of this study may provide important insight as to the mechanisms contributing to the development of osteoarthritis after ligament injuries.

Adult↗
PubMed2003

Inhibitory control of sensory gating in a computer model of the CA3 region of the hippocampus.

A model of the CA3 region of the hippocampus was used to simulate the P50 auditory-evoked potential response to repeated stimuli in order to study the neuronal circuits involved in a sensory-processing deficit associated with schizophrenia. Normal subjects have a reduced P50 auditory-evoked potential amplitude in response to the second of two paired auditory click stimuli spaced 0.5 s apart. However, schizophrenic patients do not gate or reduce their response to the second click. They have equal auditory-evoked response amplitudes to both clicks. When schizophrenic patients were medicated with traditional neuroleptics, the evoked potential amplitude to both clicks increased, but gating of the second response was not restored or improved. Animal studies suggest a role for septohippocampal cholinergic activity in sensory gating. We used a computational model of this system in order to study the relative contributions of local processing and afferent activity in sensory gating. We first compared the effect of information representation as average firing rate to information representation as cell assemblies in order to evaluate the best method to represent the response of hippocampal neurons to the auditory click. We then studied the effects of nicotinic cholinergic input on the response of the network and the effect of GABA(B) receptor activation on the ability of the local network to suppress the test response. The results of our model showed that nicotinic cholinergic input from the septum to the hippocampus can control the flow of sensory information from the cortex into the hippocampus. In addition, postsynaptic GABA(B) receptor activation was not sufficient to suppress the test response when the interstimulus interval was 500 ms. However, presynaptic GABA(B) receptor activity may be responsible for the suppression of the test response at this interstimulus interval.

Acoustic Stimulation↗
PubMedDate not supplied

Voltage-clamp analysis and computational model of dopaminergic neurons from mouse retina.

Isolated dopaminergic amacrine (DA) cells in mouse retina fire rhythmic, spontaneous action potentials and respond to depolarizing current with trains of low-frequency action potentials. To investigate the roles of voltage-gated ion channels in these processes, the transient A-type K+ current (I(K,A)) and Ca2+ current (I(Ca)) in isolated mouse DA cells were analyzed by voltage clamp. The I(K,A) activated at -60 mV and inactivated rapidly. I(Ca) activated at around -30 mV and reached a peak at 10 mV without apparent inactivation. We also extended our previous computational model of the mouse DA cell to include the new electrophysiological data. The model consisted of a membrane capacitance in parallel with eight currents: Na+ transient (I(Na,T)), Na+ persistent (I(Na,P)), delayed rectifier potassium (I(Kdr)), I(K,A), calcium-dependent potassium (I(K,Ca)), L-type Ca2+ I(Ca), hyperpolarization-activated cation current (I(h)), and a leak current (I(L)). Hodgkin-Huxley type equations were used to define the voltage- and time-dependent activation and inactivation. The simulations were implemented using the neurosimulator SNNAP. The model DA cell was spontaneously active from a wide range of initial membrane potentials. The spontaneous action potentials reached 35 mV at the peak and hyperpolarized to -76 mV between spikes. The spontaneous firing frequency in the model was 6 Hz. The model DA cell responded to prolonged depolarizing current injection by increasing its spiking frequency and eventually reaching a depolarization block at membrane potentials greater than -10 mV. The most important current for determining the firing rate was I(K,A). When the amplitude of I(K,A) was decreased, the firing rate increased. I(Ca) and I(K,Ca) also affected the width of action potentials but had only minor effects on the firing rate. Ih affected the firing rate slightly but did not change the waveform of the action potentials.

Action Potentials↗
PubMed2004

A computational model of the human respiratory control system: responses to hypoxia and hypercapnia.

Although recent models offer realistic descriptions of the human respiratory system, they do not fulfill all characteristics of a stable, comprehensive model, which would allow us to evaluate a variety of hypotheses on the control of breathing. None of the models offer completely realistic descriptions of the gaseous components of blood, and their description of delays associated with the propagation of changes in partial pressures of respiratory gases between the lungs and brain and tissue compartments have shortcomings. These deficiencies are of particular significance in an analysis of periodic breathing where dynamic alterations in the circulation and in blood chemical stimuli are likely to assume considerable importance. We developed a computational model of the human respiratory control system which is an extension of the model of Grodins et al. (F. S. Grodins, J. Buell, and A. J. Bart. J. Appl. Physiol. 22(2):260-276, 1967). Our model combines an accurate description of a plant with a novel controller design that treats minute ventilation as a sum of central and peripheral components. To ensure that the developed model is stable and sufficiently robust to act as a test platform for hypotheses about control of ventilation, we simulated a series of challenging physiological conditions, specifically, the response to eucapnic hypoxia, the development of periodic breathing during hypocapnic hypoxia, and the open loop response to hypercapnic step. These steady state and transient responses of the model were compared with results from similar physiological experiments. Our simulations suggest that for a particular value of arterial Po2, the steady state difference between brain and arterial Pco2 remains approximately constant as a function of arterial Pco2. The model indicates that hypoxia-induced changes in cerebral blood flow contribute significantly to the ventilatory decline observed during eucapnic hypoxia. The model exibits hypoxic-induced periodic breathing, which can be eliminated by small increases in F(I)co2. The dynamics of the model's open loop hypercapnic ventilatory response approximates experimental data well.

Computer Simulation↗
PubMed2005

Uranium speciation in moorland river water samples: a comparison of experimental results and computer model predictions.

An on-line method has been developed for separating inorganic and organic bound uranium species present in river water samples. The method utilised a small chelating resin (Hyphan) column incorporated into the sample introduction manifold of an ICP-MS instrument. The method was evaluated for samples from rivers on Dartmoor (Devon, UK), an area of granite overlain with peat bogs. The results indicate that organic-uranium species form a major proportion (80%) of the total dissolved uranium present. Further work with synthetic water samples indicated that the level of dissolved organic carbon played a greater role in determining the level of organic-uranium species than did sample pH. Computer models for the water samples were constructed using the WHAM program (incorporating uranium data from the Nuclear Energy Agency Thermochemical Database project) in order to predict the levels of organic-uranium species that would form. By varying the proportion of humic and fulvic acids used in the humic component, predictions within 10% of the experimental results were obtained. The program did exhibit a low bias at higher pH values (7.5) and low organic carbon concentrations (0.5 microg ml(-1)), but under the natural conditions prevalent in the Dartmoor water samples, the model predictions were successful.

Benzopyrans↗
PubMed1991

Multipolar mitosis in procaine-treated polyspermic sea urchin eggs and in eggs fertilized with UV-irradiated spermatozoa with a computer model to simulate the positioning of centrosomes.

Procaine-treated eggs can be penetrated by more than one spermatozoon. Supernumerary male pronuclei can fuse with the female one giving raise to multipolar spindles or remain isolated within the egg's cytoplasm forming their own spindle. In all types of multiple mitotic figures (asters and spindles) the distribution of asters is equidistant either uniplanar or at maximum distance like at the apices of a polyhedron. Astral rays are not different from spindle fibers: they can attach to and attract chromosomes of "foreign" mitotic figures. When several mitotic figures are present in one egg, the partner asters are always of the same size, and microtubules of one aster never interdigitate with those of others. The hypothesis that positioning of centrosomes is brought about by spreading of a centrosome organizer in the form of an expanding calotte on the surface of the nucleus (Mazia, D., Int. Rev. Cytol. 100, 49-92 (1987)) is supported by a computer model.

Animals↗
PubMed1997

Computer model: investigating role of filopodia-based steering in experimental neurite galvanotropism.

Since early in this century developing axons and dendrites in culture have been reported to grow along electric field lines. It is only in the last score of years, however, that evidence suggests developing neurites actually orient in response to the electrical stimulus. We are interested in how an imposed electric field appears to speed neurite outgrowth in a field-related direction. We ask the question whether enhanced outgrowth in one direction results from streamlining outgrowth in that direction or from differentially catalysing the rate of outgrowth. Evidence for possible mechanisms of such neurite galvanotropism includes an electric field-dependent redistribution of filopodia, the finger-like structures that extend from the growing neurite tip. Using simple rules based on filopodia-mediated substrate sampling and orientation of extending neurites in vitro, we have built a computer model to test the streamlining theory. This in silico model of non-branching neurite outgrowth in two dimensions possesses the capacity to apportion its sampling efforts relative to a fixed reference representing the orientation of the field lines of a steady uniform electric field. Our model suggests that simple outgrowth patterns observed for experimental neurite galvanotropism-deflected and enhanced neurite growth toward the negative electrode and reduced neurite growth directed toward the positive electrode-may be simulated by tipping the balance of filopodia in the direction of the negative electrode. The existence of an analogous pattern-generating interaction between an applied electric field and extending neuronal processes would suggest a role for endogenous fields arising from naturally occurring potential gradients in developing organisms.

Animals↗
PubMed1994

Dynamic synaptic modification threshold: computational model of experience-dependent plasticity in adult rat barrel cortex.

Previous electrophysiological experiments have documented the response of neurons in the adult rat somatic sensory ("barrel") cortex to whisker movement after normal experience and after periods of experience with all but two whiskers trimmed close to the face (whisker "pairing"). To better understand how the barrel cortex adapts to changes in the flow of sensory activity, we have developed a computational model of a single representative barrel cell based on the Bienenstock, Cooper, and Munro (BCM) theory of synaptic plasticity. The hallmark of the BCM theory is the dynamic synaptic modification threshold, theta M, which dictates whether a neuron's activity at any given instant will lead to strengthening or weakening of the synapses impinging on it. The threshold theta M is proportional to the neuron's activity averaged over some recent past. Whisker pairing was simulated by setting input activities of the cell to the noise level, except for two inputs that represented untrimmed whiskers. Initially low levels of cell activity, resulting from whisker trimming, led to low values for theta M. As certain synaptic weights potentiated, due to the activity of the paired inputs, the values of theta M increased and after some time their mean reached an asymptotic value. This saturation of theta M led to the depression of some inputs that were originally potentiated. The changes in cell response generated by the model replicated those observed in in vivo experiments. Previously, the BCM theory has explained salient features of developmental experience-dependent plasticity in kitten visual cortex. Our results suggest that the idea of a dynamic synaptic modification threshold, theta M, is general enough to explain plasticity in different species, in different sensory systems, and at different stages of brain maturity.

Animals↗
PubMedDate not supplied

Propagation of normal beats and re-entry in a computational model of ventricular cardiac tissue with regional differences in action potential shape and duration.

There is substantial experimental evidence from studies using both intact tissue and isolated single cells to support the existence of different cell types within the ventricular wall of the heart, each possessing different electrical properties. However other studies have failed to find these differences, and instead support the idea that electrical coupling in vivo between regions with different cell types smoothes out differences in action potential shape and duration. In this study we have used a computational model of electrical activation in heterogenous 2D and 3D cardiac tissue to investigate the propagation of both normal beats and arrhythmias. We used the Luo-Rudy dynamic model for guinea pig ventricular cells, with simplified Ca2+ handling and transmural heterogeneity in IKs and Ito. With normal cell-to-cell coupling, a layer of M cells was not necessary for the formation of an upright T wave in the simulated electrocardiogram, and the amplitude and configuration of the T wave was not greatly affected by the thickness and configuration of the M cell layer. Transmural gradients in repolarisation pushed re-entrant waves with an intramural filament towards either the base or the apex of the ventricles, and caused transient break up of re-entry with a transmural filament.

Action Potentials↗
PubMed1985

Computer modeling studies of the structure of a repressor.

Due to advances in molecular biology the DNA sequences of structural genes coding for proteins are often known before a protein is characterized or even isolated. The function of a protein whose amino acid sequence has been deduced from a DNA sequence may not even be known. This has created greater interest in the development of methods to predict the tertiary structures of proteins. The a priori prediction of a protein's structure from its amino acid sequence is not yet possible. However, since proteins with similar amino acid sequences are observed to have similar three-dimensional structures, it is possible to use an analogy with a protein of known structure to draw some conclusions about the structure and properties of an uncharacterized protein. The process of predicting the tertiary structure of a protein relies very much upon computer modeling and analysis of the structure. The prediction of the structure of the bacteriophage 434 cro repressor is used as an example illustrating current procedures.

Amino Acid Sequence↗
PubMed2004

A stylized computational model of the rat for organ dosimetry in support of preclinical evaluations of peptide receptor radionuclide therapy with (90)Y, (111)In, or (177)Lu.

UNLABELLED: The therapeutic effects of peptide receptor-based radionuclide therapy are extensively being investigated in rats bearing tumors. Both the dose to the tumor and the therapy-limiting dose to normal tissues, such as kidneys and bone marrow, are of interest for these preclinical studies. The aim of this work was to develop a generalized computational model for internal dosimetry in rats. METHODS: Mature rats were dissected and the relative positions, dimensions, and weights of all of their major organs were measured. A mathematic model was set up for the rat body and its internal organs to enable Monte Carlo radiation transport calculations to determine estimates for both tumor and organ self-doses as cross-organ doses for (90)Y, (111)In, and (177)Lu. The organs and body were mostly of ellipsoid shape with the axes given as the measured length, width, and height normalized to values that, together with the measured weights, are consistent with the recommended soft-tissue and bone densities. A spheric tumor of 0.25 g was positioned on the right femur. Calculations were performed with the Monte Carlo neutral particle transport code MCNP for the beta-emitters (maximum energy, 2.28 MeV) and (177)Lu (maximum energy, 0.497 MeV) and for the gamma-emissions from (177)Lu and from (111)In. The presented absorbed dose S values are used to calculate the absorbed dose estimates for the rat organs in a study on the biodistribution of (177)Lu-DOTA-Tyr(3)-octreotate (DOTA is 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid). Three activity distributions were considered in the kidney: uniform in the whole kidney, in the cortex, or in the outer 1-mm-thick rim of the cortex. Isodose curves and dose volume histograms were calculated for the dose distribution to the kidneys. RESULTS: Depending on the activity distribution in the kidneys, the renal dose for (177)Lu-DOTA-Tyr(3)-octreotate is 0.13-0.17 mGy/MBq. CONCLUSION: The renal dose of 70-95 Gy for an injected activity of 555 MBq will likely cause radiation damage, although the higher amount of peptide with this activity may influence the dosimetry by partial receptor saturation. Dose volume histograms show that (111)In and (177)Lu are likely to have a higher threshold for renal damage than (90)Y.

Animals↗
PubMed1993

CO2 homeostasis during periodic breathing: predictions from a computer model.

The Bohr/Riley model of CO2 homeostasis describes the relationship between CO2 production, ventilation, and arterial PCO2 and assumes that ventilation and CO2 delivery to the lung are both anatomically and temporally well matched. In contrast to normal breathing, periodic patterns of ventilation show temporal mismatch of ventilation to CO2 delivery. We developed a computer model of lung CO2 clearance that uses CO2 transfer equations to generate iterative solutions for PCO2 in multiple body compartments as a function of time. During continuous ventilatory patterns our model predicts steady-state arterial PCO2 identical to that of the Bohr model. During periodic ventilation, we predict mean PCO2 will be elevated unless mean ventilation is increased above that required by the Bohr model. Waxing and waning tidal volumes, low functional residual capacity, and low capillary blood volume potentiate the hypercapnia. However, if cardiac output oscillates in phase with breathing, hypercapnia is minimized. This analysis suggests a new mechanism for the development of sustained hypercapnia, separate from absolute hypoventilation or the presence of lung disease.

Carbon Dioxide↗
PubMed2006

Paroxysmal coughing, subdural and retinal bleeding: a computer modelling approach.

Unexplained subdural and retinal haemorrhages in an infant are commonly attributed to 'shaking', the mechanism of which is believed to be traumatic venous rupture. However, the haemorrhagic retinopathy reported as a result of Valsalva manoeuvres and the subdural bleeding that is a rare complication of pertussis together demonstrate that if a sustained rise in intrathoracic pressure is transmitted to cerebral and retinal vessels, it may result in bleeding, similar to that reported in inflicted injury. Such haemorrhages would be expected to occur whenever severe paroxysmal coughing were induced, whatever the cause. This study used a computer modelling approach to investigate feeding accidents as the trigger for bleeding. A dynamic circulatory model of a 3-month-old infant was induced to 'cough', and the response to changes in physiological variables monitored. It showed that coughing causes intracranial pressures to build up exponentially to approach a maximum, proportional to the amount of pressure the musculature of the thorax can produce, as venous return is impeded. They do not have time to become dangerous during individual coughs, as blood quickly returns after the cough is over, reestablishing normal pressures. Paroxysmal coughing, however, does not allow blood to return between coughs, with the result that very high luminal pressures may be generated, sufficient to damage veins. A history of coughing, vomiting or choking is not uncommon in otherwise normal infants with retinal and subdural bleeding. Our findings suggest that paroxysmal coughing could account for such bleeding in some cases.

Brain↗
PubMed1992

Preferred antagonist binding state of the NMDA receptor: synthesis, pharmacology, and computer modeling of (phosphonomethyl)phenylalanine derivatives.

A series of substituted [phosphono-, sulfo-, carboxy-, and (N-hydroxycarbamoyl)methyl]phenylalanines were synthesized as probes for the investigation of the preferred antagonist state of the NMDA receptor antagonists. The potency of these compounds was evaluated by measuring electrophysiological responses induced by NMDA in cultured mouse cortical neurons. 3-(Phosphonomethyl)phenylalanine [1(m)] a formal AP7 analogue, has been shown to be the most potent antagonist in this study with an IC50 of around 5 microM. The isomeric 2-(phosphonomethyl)phenylalanine [1(o)] was about half as active as 1(m) and as active as compound 5(3), a derivative which is cis-hydrogenated on the phenyl ring of 1(m). Replacement of a phosphono by a sulfo group led to a large reduction in the ability of these compounds to antagonize NMDA responses, although the ortho and meta isomers retained some activity in their reduced forms. In both series the para isomers were almost completely inactive at 100 microM. Introduction of a carboxyl or a bidentate HONHCO group in place of the phosphono moiety in the 3-position results in compounds devoid of activity. The active and inactive compounds of this study were used in conjunction with the most potent linear and cyclic phosphono-containing NMDA antagonists reported to date to determine, via computer modeling techniques, a three-dimensional model corresponding to a antagonist preferring state of the NMDA binding site. This structure defines a pharmacophore which is characterized by (i) well-defined distances between the central atoms of the polar groups PO3H-, NHn+, (n = 2, 3), and COO- (P-N = 5.89 +/- 0.12 A, P-C = 6.66 +/- 0.08 A, and N-C = 2.28 +/- 0.01 A), (ii) a sterically allowed region between the C5 methylene and the PO3H- group, and (iii) a molecular electrostatic field in which the positive, neutral, and negative potential zones are self-contained--with the negative potential zone connecting the PO3H- and COO- groups as the largest. We have compared our results to a preliminary model of the NMDA antagonist site by Hutchison et al. and to a topological model of the NMDA-glycine receptor site by Cordi et al. Our proposed steric-electrostatic pharmacophore which refines, simplifies, and improves these models has now to be validated by the design of new NMDA antagonists.

Animals↗