Active microwave pulse compressor using an electron-beam triggered switch.

A high-power active microwave pulse compressor is described that operates by modulating the quality factor of an energy storage cavity by means of mode conversion controlled by a triggered electron-beam discharge across a switch cavity. This Letter describes the principle of operation, the design of the switch cavity, the configuration used for the tests, and the experimental results. The pulse compressor produced output pulses with 140-165 MW peak power, record peak power gains of 16∶1-20∶1, and FWHM pulse duration of 16-20 ns at a frequency of 11.43 GHz.

Asymmetric bimodal accelerator cavity for raising rf breakdown thresholds.

We consider an axisymmetric microwave cavity for an accelerator structure whose eigenfrequency for its second lowest TM-like axisymmetric mode is twice that of the lowest such mode, and for which the fields are asymmetric along its axis. In this cavity, the peak amplitude of the rf electric field that points into either longitudinal face can be smaller than the peak field which points out. Computations show that a structure using such cavities might support an accelerating gradient about 47% greater than that for a structure using similar single-mode cavities, without an increase in breakdown probability.

Observation of stimulated emission at high gyroharmonics: basis for a synchrotron resonance maser.

First experimental observations are reported on stimulated coherent synchrotron radiation from highly relativistic electrons in a strong magnetic field. The experiment employed a quasioptical millimeter-wave resonator and a 6-MeV electron beam gyrating in a field of up to 25 kG. Coherent radiation at 54 GHz, corresponding to the 11th gyroharmonic, was observed and characterized. These observations demonstrate the possibility of a synchrotron resonance maser.

Energy-gain measurements from a microwave inverse free-electron-laser accelerator.

Experiments are reported on inverse free-electron-laser acceleration, including for the first time observations of the energy change as a function of relative injection phase of the electron bunches. The microwave accelerating structure consists of a uniform circular waveguide with a helical wiggler and an axial magnetic field. Acceleration of the entire beam by 6% is seen for 6 MeV electron bunches at optimum relative phase. Experimental results compare favorably, for accelerating phases, with predictions of a three-dimensional simulation that includes large-orbit effects.

Laser-driven electron cyclotron autoresonance accelerator with production of an optically chopped electron beam.

Analysis is presented of the gyroresonant acceleration of electrons in a vacuum using a focused laser. Continuous and equal acceleration is shown for electrons injected at all optical phases over an interaction length of tens of centimeters. Beam stalling is avoided as beam energy increases. Acceleration from 50 to 178 MeV is predicted for a 4 TW, 10.6-microm laser focused to a waist radius of 1.0 mm; these parameters correspond to a planned experiment. A beam stop with an off-axis hole after acceleration is shown to create a train of optically chopped bunches with 3-fs bunch lengths and a 35-fs period.

Synthesis and characterization of all four isomers of the muscarinic agonist 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane].

The four separated isomers of the muscarinic agonist 1, previously known as AF30, have been synthesized by a route that has allowed the absolute stereochemistry of each isomer to be assigned. With the chirality of (-)-camphanic acid known, X-ray analysis of the more crystalline intermediate diastereomeric camphanate 5A allowed the absolute stereochemistry at the quinuclidine chiral center to be determined. Each diastereomer was separately transformed into the spirodioxolane with concomitant introduction of the second chiral center. Chromatographic separation followed by a second crystal structure determination revealed the absolute stereochemistry of all four isomers of 1. Detailed biological evaluation of each isomer indicated that while the 3(R),2'(S) isomer was the most active in binding studies, it was the 3(R),2'(R) isomer that displayed the largest functional selectivity between ganglion (M-1 site) and heart (M-2 site). With the same internal chiral standard, the absolute configuration of the more active enantiomer of 3 was shown to be S, confirming earlier literature reports.

Conformationally restricted inhibitors of angiotensin converting enzyme: synthesis and computations.

A series of inhibitors of angiotensin converting enzyme (ACE, dipeptidyl carboxypeptidase, EC 3.4.15.1) is described which addresses certain conformational aspects of the enzyme-inhibitor interaction. In this study the alanylproline portion of the potent ACE inhibitor enalaprilat (2) is replaced by a series of monocyclic lactams containing the required recognition and binding elements. In order to more fully assess the lactam ring conformations and the key backbone angle psi as defined in 3 with respect to possible enzyme-bound conformations, a series of model lactams was investigated with use of molecular mechanics. The results point to a correlation between inhibitor potency (IC50) and the computed psi angle for the lowest energy conformation of the model compounds. Thus the psi angle as defined in 3 is an important determinant in the binding of inhibitors to ACE. The inhibition data in conjunction with the computational data have served to define a window of psi angles from 130 degrees to 170 degrees which seems to be acceptable to the ACE active site.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 3. 7-(3,5-Disubstituted [1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives.

The syntheses of a series of 7-(3,5-disubstituted [1,1'-bephenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactones are reported. Intrinsic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity is enhanced markedly when the biphenyl moiety is substituted by chloro or methyl groups at positions 3 and 5 and a fluoro group at position 4'. These substitutions, followed by resolution, provided compounds 100(+) and 110(+) with 2.8 times the intrinsic inhibitory activity of compactin. Compound 100(+) was shown to possess the same chirality in the lactone ring as compactin by single-crystal X-ray crystallography.

Synthesis of 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, a new class of dopamine agonists.

A series of tricyclic oxazines, namely, the 4-substituted 2H-naphth[1,2-b]-1,4-oxazines, have been synthesized and assayed for dopamine agonist activity. One of the members of this series, compound (+)VII-15, was found to be a remarkably potent agonist in vivo when tested in the standard 6-hydroxydopamine lesioned rat assay. The absolute configuration of the compound corresponds to that found in the active isomer of apomorphine. Its activity at the alpha 2 receptor (vs. [3H]clonidine) is relatively low. It also failed to stimulate the synthesis of cAMP in the carp retina assay, thus giving the compound a highly selective profile in favor of the D2 receptor.

Synthesis of (7R)-7H-indolo[3,4-gh][1,4]benzoxazines, a new class of D-heteroergolines with dopamine agonist activity.

Synthesis of several members of the 9-oxaergoline ring system is presented. Both the C/D cis and the C/D trans isomers of 4,6,6a,8,9,10a-hexahydro-7-ethyl-7H-indolo[3,4-gh] [1,4]benzoxazine were prepared, and the C/D trans isomer was resolved into its optical isomers. The enantiomer having the highest affinity for the [3H]apomorphine binding site, (-)-trans-6-ethyl-9-oxaergoline [(-)-6b], was shown to have the same absolute configuration as the natural ergolines, namely, 6aR, 10aR. In vivo and in vitro pharmacological evaluation shows these 9-oxaergolines to possess potent dopamine agonist properties.

Coronary-artery spasm immediately after myocardial revascularization: recognition and management.

We investigated coronary-artery spasm in six patents who had had unexpected hemodynamic collapse within two hours after cardiopulmonary bypass for myocardial revascularization. All six had profound hypotension and recurrent ST-segment elevation in electrocardiographic Leads II, III, and aVF. All had either normal or noncritical luminal irregularities of dominant right coronary arteries and more than 75 per cent occlusions in the left coronary circulation. Right-coronary-artery spasm, which was reversed after intracoronary nitroglycerin, was demonstrated angiographically in one patient; a patent right coronary artery was found at autopsy in another patient. Three patients died despite large intravenous doses of nitroglycerin. Two patients who had been unresponsive to intravenous nitroglycerin recovered after direct infusion of nitroglycerin into the right coronary artery. Coronary-artery spasm immediately after myocardial revascularization may cause circulatory collapse and death; although the spasm may be refractory to usual therapy, it may respond to intracoronary nitroglycerin.

Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.

Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.