The pharmacology of the rat adipocyte beta-adrenoceptor has been examined using radioligand binding techniques as well as analysis of biochemical and functional effector responses. The ligand binding properties of beta-adrenoceptors on isolated adipocyte membranes have been compared to those in rat lung and whole fat pad membranes. This study demonstrated that binding sites could be identified on adipocytes which had all the characteristics expected of beta-adrenoceptors. Furthermore, inhibition of binding by agents selective for beta, or beta2 adrenoceptors indicated that the receptor subtype present on adipocytes was predominantly beta1 whereas lung and whole fat pad membranes contained mainly beta2 Adrenoceptors. The characteristics of the beta-adrenoceptor mediating lipolysis have also been examined. Evidence is presented which showed that inhibition of lipolysis stimulated through beta-adrenoceptors was inhibited by selective beta-adrenoceptor antagonists with a lower potency than that expected at beta1 or beta2 adrenoceptors. This suggested that an atypical beta-adrenoceptor was responsible for mediating the lipolytic response. The apparently atypical beta-adrenoceptor has been further investigated by analysis of cAMP-accumulation in whole cells and adenylate cyclase activity in membranes. These studies confirmed the results from lipolysis studies where it was again shown that antagonists had low potencies. In addition, the stereospecificity displayed by antagonist isomers was lower to that expected at typical beta-adrenoceptors. In order to investigate whether typical beta1 and atypical beta-adrenoceptors could be separated, an irreversible beta-adrenoceptor antagonist has been used to selectively inhibit typical beta-adrenoceptors. The results demonstrated that whereas beta1 binding sites could be irreversibly blocked, the beta-adrenoceptor-stimulated adenylate cyclase activity was unaffected. This further suggested that the receptors identified by binding studies are not the same as those mediating the lipolytic response to catecholamines.

Following an introduction into areas of memory and anxiety, detailed critical reviews of both anxiety and diazepam effects in memory are presented. Although detrimental effects of arousal have been frequently observed, the effects of state anxiety have not been so systmatically studied. Furthermore, although the deleterious effect of diazepam has often been observed in memory performance, one would expect a facilitative effect with subject stratified for symptoms of high anxiety. The first two experiments investigated the effects of diazepam in anxious and nonanxious volunteers in two different memory paradigms. In these experiments, encoding in short term memory and retrieval from semantic memory were both adversely affected by anxiety, and diazepam ameliorated this effect under certain test conditions. It seemed possible that the use of another group of anxiolytic agents whose mainly peripheral mode of anxiolytic activity should mimic the centrally-mediated facilitative effect of the drug by indirectly reducing the feedback of peripheral stimuli towards the central state of anxiety. This was investigated in Experiment 3 using an identical procedure to Experiment 1. Oxprenolol did not facilitate the performance of anxious subjects which either indicated that the facilitative effects of diazepam may be affecting underlying mechanisms more directly, or that an absence of heightened autonomic activity in normal subjects was responsible for these results. Experiment 4 repeated the procedure of earlier experiments in order to examine the robustness of the anxiety difference, and although not replicated several methodological explanations were given. The remaining two experiments explored the possibility that the drug-anxiety interactions observed previously were directly attributable to differences in strategy usage, flexibility and preferences underlying the two anxiety groups. There was no direct evidence of differences between anxious and nonanxious subjects and alternative explanations for these anxiety differences were discussed.

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The aim of this programme was to design and synthesize triazinobenzimidazoles that are analogous to the antihypertensive agents, hydralazine and dihydralazine. Retrosynthetic analysis of these analogues showed that the key intermediates in the synthesis were the novel [1,2,4]triazino[4,5-a]benzimidazol-l-ones and the related 1,4-diones. Existing routes to this tricyclic ring system were either limited in scope or needed expensive starting materials. Therefore, a new synthetic route to these compounds was developed using the readily available 2-acylbenzimidazoles as starting materials. These acyl derivatives were converted to hydrazones, ethoxycarbonylhydrazones and benzimidazole-2-carboxylic acid ethoxycarbonylhydrazides. The substituted hydrazines were cyclized to the desired tricyclic lactam intermediates either thermally, or acylatively using ethyl chloroformate in pyridine. The versatility of these cyclization methods has been demonstrated by the synthesis of a variety of novel N-2 substituted [1,2,4]triazino[4,5-a]benzimidazol- 1-ones which may or may not have a substituent at C-4. In addition, it has been shown that these types of cyclizations provide a better route to existing triazinobenzimidazoles. Although attempts to chlorinate or thiate these lactams were unsuccessful, use of the dithio analogue of ethyl carbazate, methyl dithiocarbazate, afforded sulphur-containing hydrazones which were cyclized to the desired [1,2,4]triazino[4,5-a]benzimi dazole-1-thiones. Displacement of the enolized 1-thione by hydrazine produced the desired target molecules, 1-hydrazino- [1,2,4]triazino[4,5-a]benzimidazoles. In preliminary screening, these compounds exhibited in vivo vasodilatory activity. In an attempt to vary the 4-substituent of the tricyclic system further, the synthesis of a variety of modified 2-acylbenzimidazoles was undertaken. In particular, the structure and reactions of one of these modified ketones, 2-bromoacetylbenzimidazole, was investigated in an attempt to explain its bromination pattern. Other workers have suggested that the unusual bromination pattern of 2-acetyl and 2-bromoacetylbenzimidazole may arise from the influence of intramolecular hydrogen bonding between the imine proton and the carbonyl group. However, a computer-aided reinvestigation of this reaction has shown that a more plausible intermediate is an intramolecularly hydrogen bonded enol of the ketone. The synthesis of two novel triazepinobenzimidazole ring systems has been examined. The acylative-cyclization (ethyl chloroformate-pyridine) developed for the preparation of the novel triazines has been extended to the synthesis of the hitherto unknown [1,2,4]triazepino[4,5-a]benzimidazole ring system. A series of new 1,2-diacylbenzimidazoles were prepared as precursors to [1,2,5]triazepino[5,4-a]benzimidazoles. However, attempts to add hydrazine across the dicarbonyl groups gave only novel benzimidazole hydrazine or hydrazide derivatives instead of the desired triazepinobenzimidazoles. Many of the compounds described in this thesis have been screened for possible pharmacological activity.

This thesis is 'concerned with aspects of dynamic compaction of pharmaceutical powders. The research is mainly aimed at the influence of compression rates on the residual resilience and strength of the tablet. A wide range of compression strain rates (103 - 10 per sec. ) is covered for di-pac-sugar, sodium chloride, potassium bromide, paracetamol, copper sulphate, avicel, lactose and calcium phosphate. The influence of compression rate on the form of the pressure-density relationship including the IHeckel and 1: awakita diagrams is investigated. Theoretical and experimental work are conducted on the relationship between radial and axial pressures during uniaxial straining. The general tendency for all the powders tested except for the paracetamol d. c., is to exhibit increased compaction pressure with strain rate up to 105 per sec. Due to morphological and compositional factors paracetamol d. c. softens with the rate of straining up to about 102 per sec. At higher rates it behaves like other powders. Generally, at high strain rates, the brittle behaviour dominates the process and tablet capping becomes more evident. The scope, origin and the main objectives of the present work are presented in Chapter 1. A brief historical account of the development of uniaxial compression techniques is given in'Chapter 2. Past work in the field of uniaxial compaction is reviewed and. classified. Various dynamic processes are classified according to the rates of compaction. Discussion of the various mechanisms responsible for, and governing, the way in which a powder consolidates when subjected to uniaxial compaction is presented together with a brief discussion of the capping phenomenon. Chapter 3 describes the construction and operation of a specially designed die incorporating a pressure pin for radial pressure measurement. The effect of compression rate on the form of the characteristic compaction curves, for all powders, is investigated using the above die on a servohydratlic variable speed machine (ICI simulator) at constant compression rate conditions (10-110 per sec). Investigations, using this apparatus indicate that all materials tested exhibit strain rate sensitivity to varying degrees (i. e. increased resistance to compaction as the speed is increased). In Chapter 4a brief review and discussion of viscoelastic aspects and theoretical modelling of the compaction process are presented. By plotting axial versus radial pressures during successive compression and decompression cycles at various speeds and by observing the decay of both pressures under constant volume conditions, it is possible toi draw certain conclusions about the relative elastic-plastic behaviour of each material. Investigations ' indicate that the use of linear viscoelastic theory could be useful in predicting the general trend of the process but insufficient to model the response of the various powders to the different loading conditions. Accurate modelling would require more experimental work and analysis of a high level. Also, the elastic recovery of all the compacts within the die is found to range from 8-120. Chapter 5 describes various aspects of forming and testing of tablets on an Instron machine at constant speed. Crack initiation, propagation and modes of failure during the Brazilian test are investigated by employing -high speed photography. An analysis of the effect of die and punch rigidity on the Kawakita relationship is attempted. An account of 'the variation of the. ejection pressure and the residual tensile strength with the maximum applied pressure is given. in this-chapter, the effect of ageing time and the effect of the ejection speed, for both straight and tapered dies, are also examined. Investigations indicate that, during the Brazilian test, in all compacts for all materials, the crack starts at the centre of the tablet and propogate up and down towards the plattens. Three main types (modes) of failure are observed: The 'traditional' mode of failure, in compacts of elastic-plastic deforming materials , (such like di-pac-sugar, paracetamol); The (random) mode of failure in plastically deforming compacts (such like sodium chloride potassium bromide), End capping which is observed in almost all materials compacted at high speeds. The values of the constant "b" (in the Kawakita Equation) is significantly influenced by the die and punch materials while the constant "a" remains unchanged. Also, the ejection pressure is increased with the increased axial maximum pressure and decreases with increasing speeds of compaction. All materials tested, show slight increase in the compact tensile strength as the. ageing time is increased - Also all compacts formed in the tapered die show higher tensile strength than those formed in the straight die over the range of ejection speed tested. Chapter 6 describes the construction and operation of an apparatus used for quasistatic"and medium rate (10 2_ 103 per sec) uniaxial compaction of powders. This apparatus allows the powder volume, 'axial and radial compaction pressures to be measured simultaneously. The investigations indicate that the properties of the resulting compacts are influenced by the compaction rate employed. Also, the compact tensile strength at this range is found to decrease together with the capping pressures. Chapter 7 describes the construction and operation of especially designed high pressure air projectile launcher compaction apparatus suitable for high rate uniaxial compaction of powders. Both, the axial pressure and powder volume can be measured on this apparatus. Problems of stress wave reflections in the system are overcome by using long load cells which enable accurate measurements to be obtained. Almost in all compacts, formed on this apparatus, ' end capping is observed. Chapter 8 gives a detailed description of the design, construction and operation of a high pressure triaxial cell working at pressures of up to 207 MPa, together with the associated equipment. Also, the sample preparation procedure is established. Preliminary, tests carried out on di-pac-sugar, lactose and paracetamol d. c. indicate that the powder characteristics can be designed by controlling the axial-and radial stresses. Chapter 9 describes the theory, equipment and the experimental results of a new technique based on the Split Hopkinson Bar principle to determine 'tension and compression Young's moduli of'a. tablet. The investigation indicates that the modulus in compression is higher than that in tension (in some cases by almost 20t). Finally, chapter 10 outlines general conclusions and suggestions for further work.

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a diverse group of antitumour antibiotics in which there has been growing interest over the past 30 years. These compounds bind covalently within the minor groove of DNA via the formation of an aminal bond between the N10-C11 imine functionality of the PBD and the exocyclic C2-NH2 of a guanine base, resulting in the inhibition of processes including DNA replication and transcription, thus leading to cell death. PBD `dimers' have the ability to form irreversible interstrand cross-links with DNA. One example, DSB-120, has been shown to recognise six base pairs compared to the monomer DC-81 that recognises only three. A second example, SJG-136, has unsaturation at the C2 position and is cytotoxic at the picomolar level in glutathione-rich cell lines resistant to a number of agents including DSB-120. The major part of this project concerns the synthesis of novel PBD dimers specifically designed to investigate the effect of sp1 hybridisation at the C2 position of the molecule. One problem has been that only small amounts of PBD dimers were previously available through the original synthetic routes. Through this project, three new synthetic methodologies have been devised to produce two novel PBD dimers KEC-570 and KEC-5130, as well as the known PBD dimers SJG-136 and DSB-120. These syntheses utilise novel cyclisation procedures that involve fewer steps than existing synthetic methods and afford cleaner products in higher yields and on a larger scale. This has allowed, for the first time, a full pharmacological evaluation of these molecules. KEC-570 has been shown to form interstrand DNA cross-links and to be cytotoxic in three human carcinoma cell lines. Presently, both KEC-570 and DSB-120 are being evaluated across the standard panel of tumour cell lines at the National Cancer Institute. SJG-136 has proved successful in the NCI's Hollow Fibre assay and has progressed to in vivo xenograft assays at the NCI.

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No description available.

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