Thesis (Ph. D.)--University of Wisconsin--Madison, 1943. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Bibliographies: leaves 60-89, 126-135.

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When the research, which forms the basis of this thesis was started in 1979, the theoretically attractive situation of transient focal cerebral ischaemia simulating a cerebral vessel occlusion followed by re-vascularization, had not been specifically investigated with barbiturate treatment. Cerebral infarction is progressive and evolves over hours, proceeding from ischaemia and functional loss to cell death. Sundt et al (1969), Crowell et al (1970), Hayakawa and Waltz (1975). Complete recovery is possible if re-vascularization is instituted in time. This time interval depends on the regional cerebral bloodflow during the period of the vessel occlusion and this bloodflow is provided by the collateral circulation. Thus, whether infarction results and the extent of it, becomes a factor of the period of ischaemia and the collateral circulation present. Dujovny et al (1976), Morawetz et al (1978), Ojeman et al (1979), Kieck and Crowell (1979), Jones et al (1981). This ischaemic period may vary tremendously from less than an hour to as much as 5 hours and occlusion times of up to an hour can be tolerated without infarction at very low regional cerebral bloodflow levels. Morawetz et al (1978), Kieck and Crowell (1979), Jones et al (1981). In the clinical situation there would be an obligatory delay from the onset of ischaemia to the institution of barbiturate treatment and completion of re-vascularization. Treatment during this period would thus be a major contribution if it could afford protection so as to allow restitution of cerebral bloodflow before irreversible infarction took place. The South African Vervet monkey was chosen for the investigation of the effect of barbiturate treatment on transient focal cerebral ischaemia in a model simulating the clinical event. In this experiment pentobarbital therapy would be delayed for 1 hour to provide for the expected delay that would occur from the onset of ischaemia to the institution of treatment. Similarly, ischaemia was to last 4 hours to allow for a minimum time interval necessary to complete the re-vascularization. It was also borne in mind that many stroke patients would be older people; the barbiturate dose of 30mg/kg would be such as to induce prolonged coma but not major cardiovascular disturbances with a fall in blood pressure and/or cardiac arrest.

Call number: LD2668 .T4 1955 O88 / Master of Science

Alzheimer's Disease (AD) is the most common cause of dementia in elderly people. Although the exact pathogenesis of AD remains unclear, accumulation of β- amyloid (Aβ) plaques seems to be among the causative events. In view of this, Aβ- PET imaging is considered to be a powerful non-invasive diagnostic tool that could also contribute to the development of therapies by monitoring responses. However, Aβ-PET ligands approved so far can only detect heavy plaque load and cannot replace post-mortem examination of brain tissue. The aim of this multidisciplinary study was to develop structurally novel PET tracers for AD. We focused on barbiturates for two main reasons: (i) barbiturates have an excellent ability to cross the blood-brain-barrier, (ii) they are chelators of cations involved in AD. A group of seven “cold” fluorinated barbiturates, along with the corresponding precursors for the “hot” radiosyntheses, was designed and synthesised. All the experimental logP values fell into the optimum range for brain uptake. Barbiturate 1a (Figure I) was selected for further investigations. Upon assessment of its affinity and specificity for Aβ, the radiosynthesis of [18F]1a was optimised. The imaging potential of this tracer was investigated in vivo in pre-clinical mouse models of AD. Brain PET/CT scans with [18F]1a showed reproducible brain uptake and clearance in three different mouse genotypes (WT, APP/PS1 and PLB2-Tau). The significantly higher uptake observed in APP/PS1 mice provided evidence for (i) the in vivo targeting of Aβ- plaques and (ii) the specificity of the tracer towards Aβ pathology. Finally, we designed a second-generation of barbiturates incorporating stilbene groups as dual metal/Ab targeting tracers and we developed a partial synthesis. With this study we paved the way for a larger scale research endeavour that may ultimately result in the rational design of an optimised lead tracer with the potential to ultimately translate into clinical use.

Supramolecular chemistry (chemistry beyond the molecule) is the study and synthesis of complex molecular architectures from simple subunits using non-covalent interactions. The types of non-covalent interactions that are used for the self-assembly of these complex molecular architectures include electrostatic interactions (e.g. ionic, halogen, and hydrogen bonding), π-effects, van der Waals interactions, metal coordination, and hydrophobic effects. While these interactions are often used in concert, some of the most successful and ubiquitous approaches for the design and construction of new host–guest architectures are the incorporation of hydrogen bonding motifs. A popular class of molecules capable of making strong, highly directional hydrogen bonds is barbiturates. Barbiturates have a well-known reputation as potent hypnotics, anticonvulsants, and anxiolytics but recent years have seen a renewed interest in these molecules due to their unique, symmetric acceptor-donor-acceptor hydrogen bonding motif. In addition, receptors with complementary hydrogen bonding motifs capable of binding barbiturates have also been reported, namely those based on the work of Hamilton et al. Collectively, barbiturates and their receptors have seen widespread use in a variety of applications including sensing, optoelectronics, catalysis, and the design of soft materials. The work presented in this dissertation describes the development of novel Hamilton receptors for supramolecular catalysis and barbiturate sensing, as well as the design of new synthetic barbiturates. Together this body of research aims to extend the utility of these types of host–guest systems as well as continue to develop and refine the supramolecular design principles that govern the binding interactions between barbiturates and a variety of Hamilton-type receptors. This dissertation includes both previously published/unpublished and co-authored material.

This study is an attempted synthesis of dithienyl barbituric acid.

A study of the synthesis of 5- (2-Thienyl) barbituric acid.

The use of Attenuated Total Reflectance as an analytical technique in infrared spectroscopy has become increasingly important in the past few years. ATR (Attenuated Total Reflectance) is a relatively new analytical method. Producing spectra of compounds by this method requires no solvent for dissolving the sample and no salts for making pellets. The only requirements for spectra production, similar in quality to those produced by conventional methods, are that there is enough sample to cover both sides of the reflector be similar. The index of the sample is fixed; therefore, the index of the reflector is controlled by selecting a reflector with one similar to the sample. Reflectors with indices from 1.2 to 4.12 are commercially produced. Since no solvents or salts are used in ATR, this method allows complete recovery of the sample without using separation or abstraction processes. The elimination of solvents and salts should also lower the cost of spectra production. The ATR method eliminates the weighing and measuring of samples and salts and the time consuming process of pellet making; therefore, it should be a quicker method than any of the conventional methods. The principles of ATR have been applied to several fields of infrared analysis. Harris and Svoboda used ATR as a means of determination of Alkyl and Monomer Modified Resins; Katlaksky and Keller used ATR to study aqueous solutions. Ahliyah and MOoney used ATR in preparing spectra of Polyatomic Anions, and Deley and Liotti used ATR as a means of identifying coating on paper. Materials for which ATR has been useful in analysis include fabrics, polymers which cannot be easily prepared for other types of analysis, and surfaces of semiconductors. In this project, spectra of several pure barbiturates, drug compositions containing barbiturates, and several related compounds were prepared using ATR; these were compared to spectra produced by the conventional pellet method.

The reaction of 5-bromo-5-ethylbarbituric acid with mercaptan and pyridine in cold ether solution was studied and was found to be satisfactory for the preparation of the compounds reported in this work.