Nm Of Displacement Research Articles

Development of mechanically-robust piezoelectric micromachined ultrasonic transducer based on island-shaped monocrystalline PZT thin film partially covered with polyimide

This paper describes a new design of piezoelectric micromachined ultrasonic transducer (pMUT) with a monocrystalline Pb(Zr,Ti)O3-based thin film (Mono-PZT) for enhancing the mechanical robustness. In this study, we investigated two design concepts to suppress crack generation in Mono-PZT. First, the area of Mono-PZT is limited by leaving an island Mono-PZT pattern only on the membrane of the pMUT. Second, the edge of Mono-PZT is covered with a polyimide (PI) thin film as a protection layer to prevent the peeling. We prepared three different designs, a new design with both concepts, another design with the first concept, and the conventional one with neither of them for comparison. The robust mechanical analyses of these devices were performed by driving resonantly and increasing the displacement of the membranes. As these results, the proposed structure with both concepts still stands well at the highest displacement, 1600 nm, while the undesired cracks occur on other structures with approximately 800 nm of displacement. The robustness could improve 50% in comparison to the other designs thanks to this unique design. Finite element method simulation results showed that this PI layer contributed to decrease the stress concentrated at the edge both in the static condition and in the dyanamic vibarion of the membrane. This layer also probably played a role in prevention of the peeling of the edge of the island-shaped Mono-PZT. In conclusion, the new design is useful for the Mono-PZT pMUT in terms of excellent mechanical robustness.

Giant Conductance Enhancement of Intramolecular Circuits through Interchannel Gating

Summary For neutral intramolecular circuits with two constitutionally identical branches, a maximum 4-fold increase in total conductance can be obtained according to constructive quantum interference (CQI). For charged intramolecular circuits, however, the strong electrostatic interactions entangle the quantum states of these two parallel pathways, thus introducing complicated transport behavior that warrants experimental investigation of the intramolecular circuit rules. Here, we report that a tetracationic cyclophane with parallel channels exhibits a 50-fold conductance enhancement compared with that of a single-channel control, an observation that supplements intramolecular circuit law in systems with strong Coulombic interactions. Flicker noise measurements and theoretical calculations show that strong electrostatic interactions between charged parallel channels—serving as the chemical gate to promote the effective conductance of each channel—and CQI boosts the total conductance of the two-channel circuit. The molecular design presented herein constitutes a proof-of-principle approach to charged intramolecular circuits that are desirable for quantum circuits and devices.

Mechanical and nanomechanical properties of MWCNT/PP nanocomposite

The mechanical and nanomechanical properties of multi-walled carbon nanotube-reinforced polypropylene (MWCNT/PP) nanocomposite were investigated through tension tests (conducted on 2 wt% and 5 wt% specimens) and nanoindentation tests (conducted on 2 wt% specimens). In addition, the structural properties and topography of the nanocomposite were characterized by means of scanning electron microscopy (SEM) and Scanning Probe Microscopy (SPM), respectively. The results from the tension tests reveal an enhancement and a considerable scatter in the Young’s modulus and maximum stress of the MWCNT/PP nanocomposite for both MWCNT content. For the specimens with mechanical properties lower than the average values, the SEM and SPM images revealed poor dispersion and formation of large agglomerates. The hardness (as resistance to applied load) and Young’s modulus were mapped at 300 nm of displacement, for a grid of 70 ´ 70 μm2. Through projection, the resistance is clearly divided into 3 regions, namely the PP matrix, the interphase (region close to/between MWCNTs) and the regions of the MWCNT agglomerates. The resistance deviates from low values (few MPas) to 1.8 GPa. The present experimental study provides all necessary data for the model creation and validation of the MWCNT/PP nanocomposite.

Regularities of Microstrain of Ultrahigh-Molecular-Weight Polyethylene Modified with Halloysite Additives

The effect of additives of 1 and 3 wt % of halloysite on the rate and small jumps of deformation under uniaxial compression of ultrahigh-molecular-weight polyethylene was investigated. A procedure for precision interference measurement with a resolution of 325 nm for displacement and 1 kHz for frequency enabled the detection of several levels of deformation in the micro- and nanometer ranges. The addition of halloysite results in a decrease in the strain rate under the same loading conditions and a change in the characteristics of the strain jumps. Calorimetric measurements showed that melting of polyethylene with a different concentration of halloysite causes a change in the transition energy and the degree of crystallinity.

Закономерности микродеформации сверхвысокомолекулярного полиэтилена, модифицированного добавками галлуазита

AbstractThe effect of additives of 1 and 3 wt % of halloysite on the rate and small jumps of deformation under uniaxial compression of ultrahigh-molecular-weight polyethylene was investigated. A procedure for precision interference measurement with a resolution of 325 nm for displacement and 1 kHz for frequency enabled the detection of several levels of deformation in the micro- and nanometer ranges. The addition of halloysite results in a decrease in the strain rate under the same loading conditions and a change in the characteristics of the strain jumps. Calorimetric measurements showed that melting of polyethylene with a different concentration of halloysite causes a change in the transition energy and the degree of crystallinity.

Micromachined Frequency-Output Force Probes

This letter presents a new class of microelectromechanical systems-based frequency output force and displacement probes with sub-nanometer displacement resolution. The force probe is a single layer monolithic crystalline silicon micro-structure comprised of a thermal-piezoresistive resonator embedded within a micro-cantilever. Deflection of the cantilever due to the applied force mechanically distorts the resonator modulating its resonance frequency. Such devices can be used as atomic force microscope probes or high-resolution surface profilometers with fully electrical operation eliminating the bulky and complex optical detectors typically used in such systems. A prototype sensor, operating at 7.5MHz, shows a displacement sensitivity of 2.5 Hz/nm. With a typical Allen deviation of 0.1-0.2 ppm for similar resonators operated as self-sustained oscillators, frequency resolution in the order of 1 Hz is expected to be achievable. This translates to 0.4 nm of displacement and 11 nN of force resolution for such sensors.

Beam geometry, alignment, and wavefront aberration effects on interferometric differential wavefront sensing

Heterodyne interferometry is a widely accepted methodology with high resolution in many metrology applications. As a functionality enhancement, differential wavefront sensing (DWS) enables simultaneous measurement of displacement, pitch, and yaw using a displacement interferometry system and a single beam incident on a plane mirror target. The angular change is measured using a weighted phase average between symmetrically adjacent quadrant photodiode pairs. In this paper, we present an analytical model to predict the scaling of differential phase signals based on fundamental Gaussian beams. Several numerical models are presented to discuss the effects of physical beam parameters, detector size, system alignment errors, and beam wavefront aberrations on the DWS technique. The results of our modeling predict rotational scaling factors and a usable linear range. Furthermore, experimental results show the analytically predicted scaling factor is in good agreement with empirical calibration. Our three degree-of-freedom interferometer can achieve a resolution of 0.4 nm in displacement and 0.2 μrad in pitch and yaw simultaneously.

Hardness and Elastic Modulus on Six-Fold Symmetry Gold Nanoparticles.

The chemical synthesis of gold nanoparticles (NP) by using gold (III) chloride trihydrate (HAuCl∙3H2O) and sodium citrate as a reducing agent in aqueous conditions at 100 °C is presented here. Gold nanoparticles areformed by a galvanic replacement mechanism as described by Lee and Messiel. Morphology of gold-NP was analyzed by way of high-resolution transmission electron microscopy; results indicate a six-fold icosahedral symmetry with an average size distribution of 22 nm. In order to understand the mechanical behaviors, like hardness and elastic moduli, gold-NP were subjected to nanoindentation measurements—obtaining a hardness value of 1.72 GPa and elastic modulus of 100 GPa in a 3–5 nm of displacement at the nanoparticle’s surface.

Effects of dynamic indentation on the mechanical response of materials

Dynamic indentation techniques are often used to determine mechanical properties as a function of depth by continuously measuring the stiffness of a material. The dynamics are used by superimposing an oscillation on top of the monotonic loading. Of interest was how the oscillation affects the measured mechanical properties when compared to a quasi-static indent run at the same loading conditions as a dynamic. Single crystals of nickel and NaCl as well as a polycrystalline nickel sample and amorphous fused quartz and polycarbonate have all been studied. With respect to dynamic oscillations, the result is a decrease of the load at the same displacement and thus lower measured hardness values of the ductile crystalline materials. It has also been found that the first 100 nm of displacement are the most affected by the oscillating tip, an important length scale for testing thin films, nanopillars, and nanoparticles.

Design and Operation of a MEMS-Based Material Testing System for Nanomechanical Characterization

<para xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <emphasis emphasistype="boldital">In situ</emphasis> mechanical characterization of nanostructures, such as carbon nanotubes and metallic nanowires, in scanning and transmission electron microscopes is essential for the understanding of material behavior at the nanoscale. This paper describes the design, fabrication, and operation of a novel microelectromechanical-systems (MEMS)-based material testing system used for <emphasis emphasistype="boldital">in situ</emphasis> tensile testing of nanostructures. The device consists of an actuator and a load sensor with a specimen in between. Two types of actuators, in-plane thermal and comb drive actuators, are used to pull the specimens in displacement control and force control modes, respectively. The load sensor works based on differential capacitive sensing, from which the sensor displacement is recorded. By determining sensor stiffness from mechanical resonance measurements, the load on the specimen is obtained. Load sensors with different stiffness were fabricated. The best resolutions were achieved with load sensors that are designed for testing nanotubes, reaching 0.05 fF in capacitance, 1 nm in displacement, and 12 nN in load. For the first time, this MEMS-based material testing scheme offers the possibility of continuous observation of the specimen deformation and fracture with subnanometer resolution, while simultaneously measuring the applied load electronically with nano-Newton resolution. The overall device performance is demonstrated by testing freestanding cofabricated polysilicon films and multiwalled carbon nanotubes.<formula formulatype="inline"><tex>$\hfill$</tex> </formula>[1670] </para>

Load-dependent kinetics of force production by smooth muscle myosin measured with optical tweezers.

Muscle contraction is driven by the cyclical interaction of myosin with actin, coupled with ATP hydrolysis. Myosin attaches to actin, forming a crossbridge that produces force and movement as it tilts or rocks into subsequent bound states before finally detaching. It has been hypothesized that the kinetics of one or more of these mechanical transitions are dependent on load, allowing muscle to shorten quickly under low load, but to sustain tension economically, with slowly cycling crossbridges under high load conditions. The idea that muscle biochemistry depends on mechanical output is termed the 'Fenn effect'. However, the molecular details of how load affects the kinetics of a single crossbridge are unknown. Here, we describe a new technique based on optical tweezers to rapidly apply force to a single smooth muscle myosin crossbridge. The crossbridge produced movement in two phases that contribute 4 nm + 2 nm of displacement. Duration of the first phase depended in an exponential manner on the amplitude of applied load. Duration of the second phase was much less affected by load, but was significantly shorter at high ATP concentration. The effect of load on the lifetime of the bound crossbridge is to prolong binding when load is high, but to accelerate release when load is low or negative.

Induced potential model of muscular contraction mechanism and myosin molecular structure

The proposed model is characterized by the constant r (Eq. 2-1), the induced potential (Fig. 1), two attached states of a myosin head (Fig. 1), the nonlinear elastic property of the crossbridge (Eq. 2-7), and the expression of U* (Eqs. 3-8 and 3-9), which led us to the following conclusions. 1. The following various magnitudes of myosin head motion are compatible with each other: about 2 nm of the quantity called power stroke by Irving (27), which is the mean moving distance of myosin head in the isometric tension in our model, 4-5 nm of the displacement of a single myosin head during one ATP hydrolysis cycle (Molloy et al. (20)) or a few tens of nm when the actin and myosin filaments are set parallel (Tanaka et al. (21) and Kitamura et al. (42)), and more than 200 nm of the myosin head displacement in a multi-myosin head system below 22 degrees C (Harada et al. (19)). 2. There is one-to-one coupling between the ATP hydrolysis cycle and the attachment-detachment cycle of a myosin head in accordance with the generally accepted concept of chemical reactions, since the head is trapped in the spatially shifting wide potential well (Fig. 1) until epsilon ATP is exhausted. Here, an actin filament interacts with a myosin head like a single molecule. 3. The calculated tension dependence of muscle stiffness agrees well with the observations by Ford et al. (12), as shown in Fig. 9. 4. The calculated shortening velocity V of muscle as a function of P/P0 agreed very well with experimental results as shown in Fig. 13. The deviation from the Hill equation (34) observed by Edman (32) is related with U* being effectively infinite for f1 < kappa b yc0 (Fig. 10). 5. Calculated energy liberation rate W + H as a function of P/P0 has characteristics almost the same as the Hill equation (33), and agrees well with the experimental results as shown in Fig. 14. 6. The time course of tension recovery after a quick length change is determined by four parameters: kappa f, kappa b, a, and Z0. Among them, kappa f, kappa b (Eq. 2-22) and a (Eq. 4-21) are readily determined by analysis of the steady filament sliding and p0. Calculations of T1/T0 and T2/T0 with these three parameters are in very good agreement with experimental data (Fig. 21). Calculated tension variations by assigning the value in Eq. 4-23 to Z0 agree with the observation (Fig. 17). 7. The model suggests that large fluctuations exist in relative positions between the actin and myosin filaments even when the load on a muscle is kept constant (Fig. 23). Taking this fluctuation into account, the time course of the isotonic velocity transient shown in Fig. 22 becomes understandable referring to Fig. 24. 8. The experimental data of the delta yhs vs. delta P/P0 relationship (Fig. 25) is explained. The delta yhs value at delta P/P0 = 0 (about 5 nm) supports the two-attached-state model and thus indicates that the incremental unit step of a myosin head motion along an actin filament is close to L (5.46 nm).

Induced potential model of muscular contraction mechanism and myosin molecular structure

The proposed model is characterized by the constant r (Eq. 2-1), the induced potential (Fig. 1), two attached states of a myosin head (Fig. 1), the nonlinear elastic property of the crossbridge (Eq. 2-7), and the expression of U∗ (Eqs. 3-8 and 3-9), which led us to the following conclusions. 1. The following various magnitudes of myosin head motion are compatible with each other: about 2 nm of the quantity called power stroke by Irving (27), which is the mean moving distance of myosin head in the isometric tension in our model, 4–5 nm of the displacement of a single myosin head during one ATP hydrolysis cycle (Molloy et al. (20)) or a few tens of nm when the actin and myosin filaments are set parallel (Tanaka et al. (21) and Kitamura et al. (42)), and more than 200 nm of the myosin head displacement in a multi-myosin head system below 22 °C (Harada et al. (19)). 2. There is one-to-one coupling between the ATP hydrolysis cycle and the attachment-detachment cycle of a myosin head in accordance with the generally accepted concept of chemical reactions, since the head is trapped in the spatially shifting wide potential well (Fig. 1) until εATP is exhausted. Here, an actin filament interacts with a myosin head like a single molecule. 3. The calculated tension dependence of muscle stiffness agrees well with the observations by Ford et al. (12), as shown in Fig. 9. 4. The calculated shortening velocity V of muscle as a function of PP0 agreed very well with experimental results as shown in Fig. 13. The deviation from the Hill equation (34) observed by Edman (32) is related with U∗ being effectively infinite for fJ < κbyc0 (Fig. 10). 5. Calculated energy liberation rate W + H as a function of PP0 has characteristics almost the same as the Hill equation (33), and agrees well with the experimental results as shown in Fig. 14. 6. The time course of tension recovery after a quick length change is determined by four parameters: κf, κb, a, and Z0. Among them, κf, κb (Eq. 2–22) and a (Eq. 4-21) are readily determined by analysis of the steady filament sliding and p0. Calculations of T1T0 and T2T0 with these three parameters are in very good agreement with experimental data (Fig. 21). Calculated tension variations by assigning the value in Eq. 4-23 to Z0 agree with the observation (Fig. 17). 7. The model suggests that large fluctuations exist in relative positions between the actin and myosin filaments even when the load on a muscle is kept constant (Fig. 23). Taking this fluctuation into account, the time course of the isotonic velocity transient shown in Fig. 22 becomes understandable referring to Fig. 24. 8. The experimental data of the δyhs vs. ΔPP0 relationship (Fig. 25) is explained. The δyhs value at ΔPP0 = 0 (about 5 nm) supports the two-attached-state model and thus indicates that the incremental unit step of a myosin head motion along an actin filament is close to L (5.46 nm).

Laser Doppler Vibrometry: A Review of Advances and Applications

The use of laser Doppler vibrometry (LDVi) offers great potential for the improvement of the investigation capability of experimental vibration testing. Because of this, this technique is studied and applied with increasing interest in several industrial and scientific areas of research, including biomedical engineering. In particular, the traditional fields of vibration testing, such as damage detection, system identification, and model updating, benefit from the use of these novel techniques. In fact, they significantly extend measurement capabilities with respect to traditional accelerometers, as they allow remote, nonintrusive, high-spatial resolution measurements with reduced testing time and increased performances (bandwidth up to 200 kHz, velocity range of ±10 m/s, resolution of about 8 nm in displacement and 0.5 μm/s in velocity). In this work, the state of the art in LDVi technique is addressed, and the new instrument configurations, such as those for in-plane and rotational vibration measurements, are described. A review of the most innovative LDVi advances is presented with reference to recent publications, and the different methodologies are categorized according to their relative fields of application. Interesting results achieved by continuously controlling the movement of scanning LDVi mirrors are shown: measurements in tracking mode on rotating objects or continuous scanning for operational mode shapes determination are examples of these activities. Also, actual limits and fields of future research are discussed. The main limitations in LDVi instrumentation are actually represented by speckle effects and poor signal-to-noise ratio when measuring on low diffusive surfaces. For these problems, the research is continuing to develop, and important improvements are expected within the next few years.

157 Effect of a low osmolality nonionic contrast medium on thrombin generation and fibrinolysis in patients subjected to coronary angiography

The proposed model is characterized by the constant r (Eq. 2-1), the induced potential (Fig. 1), two attached states of a myosin head (Fig. 1), the nonlinear elastic property of the crossbridge (Eq. 2-7), and the expression of U∗ (Eqs. 3-8 and 3-9), which led us to the following conclusions. 1.1. The following various magnitudes of myosin head motion are compatible with each other: about 2 nm of the quantity called power stroke by Irving (27), which is the mean moving distance of myosin head in the isometric tension in our model, 4–5 nm of the displacement of a single myosin head during one ATP hydrolysis cycle (Molloy et al. (20)) or a few tens of nm when the actin and myosin filaments are set parallel (Tanaka et al. (21) and Kitamura et al. (42)), and more than 200 nm of the myosin head displacement in a multi-myosin head system below 22 °C (Harada et al. (19)).2.2. There is one-to-one coupling between the ATP hydrolysis cycle and the attachment-detachment cycle of a myosin head in accordance with the generally accepted concept of chemical reactions, since the head is trapped in the spatially shifting wide potential well (Fig. 1) until εATP is exhausted. Here, an actin filament interacts with a myosin head like a single molecule.3.3. The calculated tension dependence of muscle stiffness agrees well with the observations by Ford et al. (12), as shown in Fig. 9.4.4. The calculated shortening velocity V of muscle as a function of PP0 agreed very well with experimental results as shown in Fig. 13. The deviation from the Hill equation (34) observed by Edman (32) is related with U∗ being effectively infinite for fJ < κbyc0 (Fig. 10).5.5. Calculated energy liberation rate W + H as a function of PP0 has characteristics almost the same as the Hill equation (33), and agrees well with the experimental results as shown in Fig. 14.6.6. The time course of tension recovery after a quick length change is determined by four parameters: κf, κb, a, and Z0. Among them, κf, κb (Eq. 2–22) and a (Eq. 4-21) are readily determined by analysis of the steady filament sliding and p0. Calculations of T1T0 and T2T0 with these three parameters are in very good agreement with experimental data (Fig. 21). Calculated tension variations by assigning the value in Eq. 4-23 to Z0 agree with the observation (Fig. 17).7.7. The model suggests that large fluctuations exist in relative positions between the actin and myosin filaments even when the load on a muscle is kept constant (Fig. 23). Taking this fluctuation into account, the time course of the isotonic velocity transient shown in Fig. 22 becomes understandable referring to Fig. 24.8.8. The experimental data of the δyhs vs. ΔPP0 relationship (Fig. 25) is explained. The δyhs value at ΔPP0 = 0 (about 5 nm) supports the two-attached-state model and thus indicates that the incremental unit step of a myosin head motion along an actin filament is close to L (5.46 nm).

Crack Propagation Experiments on Flip Chip Solder Joints

ABSTRACTThe paper presents crack propagation experiments on real flip chip specimens applied to reversible shear loading. Two specially designed micro testers will be introduced. The first tester provides very precise measurements of the force displacement hysteresis. The achieved resolutions have been I mN for force and 20 nm for displacement. The second micro tester works similar to the first one, but is designed for in-situ experiments inside the SEM. Since it needs to be very small in size it reaches only resolutions of 10 mN and 100nm, which is sufficient to achieve equivalence to the first tester. A cyclic triangular strain wave is used as load profile for the crack propagation experiment. The experiment was done with both machines applying equivalent specimens and load. The force displacement curve was recorded using the first micro mechanical tester. From those hysteresis, the force amplitude has been determined for every cycle. All force amplitudes are plotted versus the number of cycles in order to quantify the crack length. With the second tester, images were taken at every 10th … 100th cycle in order to locate the crack propagation. Finally both results have been linked together for a combined quatitive and spatial description of the crack propagation in flip chip solder joints.

Smooth muscle and skeletal muscle myosins produce similar unitary forces and displacements in the laser trap

Purified smooth muscle myosin in the in vitro motility assay propels actin filaments at 1/10 the velocity, yet produces 3-4 times more force than skeletal muscle myosin. At the level of a single myosin molecule, these differences in force and actin filament velocity may be reflected in the size and duration of single motion and force-generating events, or in the kinetics of the cross-bridge cycle. Specifically, an increase in either unitary force or duty cycle may explain the enhanced force-generating capacity of smooth muscle myosin. Similarly, an increase in attached time or decrease in unitary displacement may explain the reduced actin filament velocity of smooth muscle myosin. To discriminate between these possibilities, we used a laser trap to measure unitary forces and displacements from single smooth and skeletal muscle myosin molecules. We analyzed our data using mean-variance analysis, which does not rely on scoring individual events by eye, and emphasizes periods in the data with constant properties. Both myosins demonstrated multiple but similar event populations with discrete peaks at approximately +11 and -11 nm in displacement, and 1.5 and 3.5 pN in force. Mean attached times for smooth muscle myosin were longer than for skeletal-muscle myosin. These results explain much of the difference in actin filament velocity between these myosins, and suggest that an increased duty cycle is responsible for the enhanced force-generating capacity of smooth over skeletal-muscle myosin.

Imidazo[1,2-b]pyridazines. XXIV Syntheses of Some 3-(Variously Substituted) Imidazo[1,2-b] pyridazines, 6-Substituted 2-Benzoyl- imidazo[1,2-b]pyridazines and Pyrimido[1,2-b]pyridazin- 5-ium-3-olates and their Interaction with Central and Mitochondrial Benzodiazepine Receptors

The syntheses of some ethyl 2-{2′-aryl-6′-(chloro, iodo and methoxy)imidazo[1,2-b]pyridazin-3′-yl}-2-(acetoxy, acylamino, hydroxy and methoxy)acetates, 6-methyl-2-(p-tolyl)- and 6-chloro-2-(4′-chlorophenyl)-3-trimethylammoniomethylimidazo[1,2-b]pyridazine iodides (and reactions thereof), 2-benzoyl 6-substituted imidazo[1,2-b]pyridazines and 7-(methoxy, chloro and phenylthio)-2-phenylpyrimido-[1,2-b]pyridazin-5-ium-3-olates are reported. The ability of these compounds to displace [3H]diazepam from rat forebrain membrane [central benzodiazepine receptor (BZR)] and rat kidney membrane [mitochondrial (peripheral-type) benzodiazepine receptor (PBR)] has been examined. The most active compound was ethyl 2-{6′-chloro-2′-(p-tolyl)imidazo[1,2-b]pyridazin-3′-yl}-2-hydroxyacetate with IC50 24 nM for displacement from the BZR and 91% displacement at 1000 nM from the PBR; the most selective for the PBR was 6-methyl-3-methylsulfonylmethyl-2-(p-tolyl)imidazo[1,2-b]pyridazine (PBR, IC50 92 nM; BZR, 15% inhibition of binding by [3H]diazepam at 1000 nM).

Synthesis and properties of three fluorescent derivatives of gastrin

As a first step in the study of hormone interaction with gastrin receptor-expressing cells, three fluorescent derivatives of heptagastrin were synthesized, characterized and tested for specificity and affinity towards gastrin/CCKB receptor by means of confocal laser scanning microscopy (CLSM). Cyanine dye Cy3.29 and borfluoropyrromethene (BODIPY) derivatives of the hormone were found to be absorbed into the cells and concentrated in perinuclear organelles by a non-receptor mediated process. The BODIPY derivative turned out to be chemically unstable and was bleached by the laser beam very rapidly. Rhodamine Green-heptagastrin retained a high affinity toward the gastrin receptor (Kd=45 nm in displacement of 125I-labeled cholecystokinin-8) and showed specific binding to NIH/3T3 cells stably transfected with human gastrin/CCKB receptor cDNA, but not to nontransfected 3T3 cells. The fluorescent signal of all three dyes was sufficiently intense for localization of the compounds in cells by means of CLSM. Rhodamine Green derivative was found to be a useful tool for the study of endocytosis of the hormone. It can also be utilized for quantitative estimation of binding and determination of Kd instead of the traditionally used radiolabeled derivatives of gastrin.

Synthesis, structure-activity relationships, and pharmacological evaluation of a series of fluorinated 3-benzyl-5-indolecarboxamides: identification of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyl indol- 3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide, a potent, orally active antagonist of leukotrienes D4 and E4.

The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 mumol/kg opposite LTD4-induced bronchoconstriction in guinea pigs. The R enantiomer was found to be modestly more potent than the S enantiomer 38o. Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity. Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist. The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.