Coupled motion of microscale and nanoscale elastic objects in a viscous fluid.

We study the coupled dynamics of two closely spaced micron or nanoscale elastic objects immersed in a viscous fluid. The dynamics of the elastic objects are coupled through the motion of the surrounding viscous fluid. We consider two cases: (i) one object is driven externally by an imposed harmonic actuation force and the second object is passive and (ii) both objects are driven by a Brownian force to yield stochastic dynamics. Using a harmonic oscillator approximation for the elastic objects and the unsteady Stokes equations to describe the fluid dynamics, we develop analytical expressions for the amplitude and phase of the displacement of the oscillating objects. For the case of an imposed actuation we use an impulse in force to determine the resulting dynamics over all frequencies. For the Brownian-driven objects the stochastic dynamics are found using the fluctuation-dissipation theorem. We validate our theoretical expressions by comparison with results from finite-element numerical simulations of the complete fluid-solid interaction problem. Our results yield interesting features in the amplitude and phase of the displacement of the elastic objects due to the fluid motion. We find that the dynamics depend on the separation of the objects, a measure of the mass loading due to the fluid, and the frequency parameter which acts as a frequency-based Reynolds number. Our results are valid over the range of parameters typical of micron and nanoscale elastic objects in fluid. The range of dynamics found can be understood in terms of the interplay between the viscous and potential components of the fluid flow field described by the unsteady Stokes equation for an oscillating cylinder. For small values of the frequency parameter, typical of nanoscale elastic objects, the dynamics are overdamped due to the dominance of viscous forces over inertial forces. For moderate and large values of the frequency parameter, typical of micron-scale elastic objects, we find that the dynamics of the fluid-coupled objects exhibits an interesting mode splitting to yield a bimodal signature in the amplitude-frequency plots. We find that the mode splitting can be described using a normal mode analysis containing only potential fluid interactions between the cylinders.

Beta-adrenergic receptor and platelet inhibitory activities of a new series of trimetoquinol and related benzazepine analogs.

1. A series of dimethoxy and methylenedioxy analogs of trimetoquinol (TMQ) and structurally related 7-membered ring benzazepines (BA) were evaluated for their pharmacological effects in beta-adrenergic (atria, trachea) and thromboxane A2/prostaglandin H2 receptor systems (aorta, platelets). 2. Results show that both the 6,7-dihydroxy (catechol) moiety of trimetoquinol and an intact tetrahydroisoquinoline nucleus are essential for maintaining potent beta-stimulating and antithromboxane A2 activities. 3. By contrast, ring enlargement, as in the BA analogs, or masking of the catechol with dimethoxy or methylenedioxy functional groups enhanced the potency of inhibitors on thromboxane A2-independent activation of human platelets induced by bacterial phospholipase C (PLC). 4. The selective blockade of this pathway by these compounds suggests that they may represent a new and novel class of antiplatelet drugs.

Seating accuracy and fracture strength of vented and nonvented ceramic crowns luted with three cements.

Methods to facilitate the seating of artificial crowns can improve the gingival margins and ensure longevity. This study examined the effects of venting and different luting agents on the seating accuracy and compressive strength of Dicor ceramic crowns. Vented and unaltered anterior restorations were tested using zinc phosphate cement (ZnPO4), glass ionomer, and composite resin cement. Rexillium metal dies of a tooth preparation of a maxillary canine were provided and standardized crowns were fabricated. The artificial crowns were evaluated for adaptation of the finish line before and after cementation, then were compressively loaded to failure. Under the conditions of this study, neither the design of the artificial crown nor the luting agent had a significant effect on the compressive strength. Composite resinous cement appeared to enhance seating of the crown, whereas ZnPO4 cement inhibited seating.

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

Synthesis and alpha 2-adrenoceptor effects of substituted catecholimidazoline and catecholimidazole analogues in human platelets.

It is known that the steric requirements for the interactions of catecholamines and catecholimidazolines with alpha 1- and alpha 2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with alpha 2-adrenoceptors in human platelets. With the exception of 3, all compounds were selective for alpha-adrenoceptor-mediated responses in human platelets. Introduction of a double bond in imidazoline 1 to give an imidazole 3 or the introduction of a benzylic hydroxyl group to 3, as in 4, reduced the inhibition of platelet aggregation with a rank order potency of 1 greater than 3 greater than 4. Fluorine atom substitution at the 2-, 5-, or 6-positions only slightly modified the inhibitory activity of 1. Each analogue (1, 3-7) produced alpha 2-mediated inhibition of platelet adenylate cyclase and can be classified as a partial agonist. The inhibition potency of S-8 and R-8 against epinephrine-induced aggregatory responses were greatly different, and only R-8 and 4 were alpha 2-agonists on human platelet function. Our studies provide further evidence for the differential interaction of catecholamines and catecholimidazolines in alpha 1- and alpha 2-adrenoceptor systems.

Activation of alpha-1 adrenoreceptors of rat aorta by analogs of imidazoline.

New analogs of desoxycatecholimidazoline were synthesized for elucidating the steric requirements for the activation of alpha-1 adrenoreceptors. The compounds tested on rat thoracic aorta in this study were: desoxycatecholimidazole with and without bridge carbon hydroxyl group, analogs of desoxycatecholamidazoline with fluorine substitution at position 2, 5 or 6 of the catechol ring and hydroxybenzyl group at carbon-4 of the imidazoline part of the molecule. The addition of a double bond in the imidazoline to give an imidazole results in a decrease in potency and the introduction of benzylic hydroxyl group also reduces its activity by 4- and 6-fold, respectively. 2-Fluoro and 5-fluoro catecholimidazoline possess full agonist activity; their potencies being even higher than the parent molecule. The 6-fluoro analog is a partial agonist inasmuch as it produces a response that is only 30% of the maximum response produced by other analogs of imidazoline. In the present study, 4-substituted imidazolines retain their agonist activity, although weaker than desoxycatecholimidazoline. The potency of R- and S-isomers of 4-substituted catecholbenzyl imidazoline were similar. Although these isomers exhibit apparent chemical similarity to catecholamines, small differences between the activity of stereoisomers indicate that the mode of interaction of these molecules at alpha adrenoreceptor may differ from that of stereoisomers of epinephrine.

Substituted 2-(2-hydroxyphenyl)benzimidazoles as potential agents for the control of periodontal diseases.

A series of 16 substituted 2-(2-hydroxphenyl)benzimidazoles was synthesized and evaluated in vitro for antibacterial activity against bacteria associated with periodontal diseases. Several compounds demonstrated a high level of activity, in tube dilution assay, against Actinomycetes viscosus and Bacteriodes gingivalis. These results indicate that several of these compounds may serve as topical antibacterial agents for the control of acute marginal inflammatory gingivitis and periodontitis.

5-fluoro- and 8-fluorotrimetoquinol: selective beta 2-adrenoceptor agonists.

The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol.

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.

5-(Alkylsulfonyl)salicylanilides as potential dental antiplaque agents.

A series of 22 5-(alkylsulfonyl)salicylanilides was synthesized and evaluated for in vitro antibacterial and antiplaque activity against Actinomyces viscosus and Streptococcus mutans, adherent microorganisms implicated in periodontal disease and dental caries. The minimum inhibitory concentrations of 25 salicylanilides (including 5-acyl-, 5-alkyl-, and 5-(alkylsulfonyl)-4'-bromo- and -4'-(trifluoromethyl)salicylanilides) were found to correlate (r = 0.94) with estimated log D values. Several salicylanilides, such as 5-(decylsulfonyl)- and 5-(dodecylsulfonyl)-4'-(trifluoromethyl)salicylanilides (15 and 19) were found to exhibit high levels of in vitro antibacterial and antiplaque activity against A. viscosus and S. mutans.

Tris buffer attenuates acetylcholine responses in Aplysia neurons.

The commonly used buffering agent tris(hydroxymethyl)methylamine (tris) antagonizes the action of iontophoretically applied acetylcholine on neurons of Aplysia californica. Concentrations of 5 to 10 millimolar tris markedly reduced both excitatory and inhibitory responses.