Thesis (M.D. 1974) from the Dept. of Medicine, University of Adelaide.

Thesis (Ph. D.)--University of Washington, 1990. / Vita. Includes bibliographical references (leaves [260]-274).

Preface: The general indications that the pineal gland might be involved in homeostasis, and more specifically the evidence suggesting a role in amelioration of seizure states warranted further investigation . No reports had examined a possible link between anticonvulsant drug administration and pineal gland function, and few enabled any type of presumption to be made as to possible effects. This study was an attempt to evaluate in which ways anticonvulsant drugs might alter pineal gland indole metabolism, with a view to increasing understanding of the role of the pineal in modulation of epileptic discharges. In order to make the study as meaningful as possible extensive preliminary investigations were necessary. Pharmacokinetic determinations gave an indication of tissue concentrations of the drugs, which could then be related to observed effects. As far as possible, where existing information was lacking, the catalytic behaviour of the various enzymes was characterised in order to explain any observed effects at a molecular level. An attempt was also made to characterise the regulatory mechanisms controlling indole metabolism, again in order to define the pharmacological effects exerted by the drugs used. The complexity of the system made it impossible to suggest a single uniform regulatory hypothesis, although some significant observations were made. Finally, the studies involving the anticonvulsant drugs were conducted on intact animals, isolated organs and individual enzymes in an attempt to determine whether the observed effects were occuring at a molecular, local or central level.

The development of tolerance to anticonvulsant drug effects has traditionally been studied in terms of pharmacological variables associated with the drug itself ; for example, the dose or the schedule of administration. This type of tolerance is referred to as pharmacologic drug tolerance. In contrast, we have demonstrated that the development of tolerance to ethanol's anticonvulsant effect is contingent upon the adminstration of convulsive stimulation during periods of ethanol exposure; we refer to this as contingent drug tolerance. The purpose of the first two experiments in the present thesis was to extend the phenomenon of contingent tolerance to the anticonvulsant effects of three clinically relevant antiepileptic drugs: carbamazepine (CBZ), diazepam (DZP), and sodium valproate (VPA). In Experiment 1, kindled rats that received an injection of CBZ (70 mg/kg, IP), DZP (2 mg/kg, IP), or VPA (250 mg/kg, IP) 1 hr before each of 10 bidaily (one every 48 hr) convulsive stimulations displayed a significant amount of tolerance to the drugs' anticonvulsant effects on the tolerance test trial ; in contrast, there was no evidence of tolerance in the rats from the three vehicle control groups. In Experiment 2, the development of tolerance to the anticonvulsant effects of CBZ, DZP, and VPA, administered on a bidaily basis, was shown to be contingent upon the administration of convulsive stimulation during the periods of drug exposure. Kindled rats in the three drug-before-stimulation groups rapidly developed tolerance to the anticonvulsant effects of CBZ, DZP, and VPA; in contrast, there was no evidence of tolerance i n the respective drug-afterstimulation groups, despite the fact that they had the same drug history. The purpose of the final three experiments was to compare contingent and pharmacologic tolerance to the anticonvulsant effects of DZP. Experiment 3 replicated earlier demonstrations of pharmacologic tolerance to DZP's anticonvulsant effect; kindled rats that received chronic DZP (2 mg/kg, every 8 hr, for 10 days) developed tolerance to the drug's anticonvulsant effect even though they did not receive convulsive stimulation during the periods of drug exposure. In Experiment 4, the rate of dissipation of pharmacologic and contingent tolerance to DZP's anticonvulsant effect was compared. Pharmacologic tolerance gradually dissipated over the 16-day retention interval ; in contrast, there was no evidence of dissipation of contingent tolerance after 16 days of drug withdrawal. These data suggest that different physiological changes are responsible for pharmacologic and contingent tolerance to DZP's anticonvulsant effect. This conclusion was supported by the results of Experiment 5, in which a single injection of the benzodiazepine receptor antagonist RO 15-1788 24 hr prior to a tolerance-retention test trial significantly reduced the expression of pharmacologic tolerance, but not contingent tolerance, to DZP's anticonvulsant effect. The results of these five experiments make two general points. First, concurrent convulsive stimulation can have an important effect on the development of tolerance to the anticonvulsant effects of antiepileptic drugs. And second, there are significant differences in the physiological changes responsible for the development and the dissipation of contingent and pharmacologic tolerance to DZP's anticonvulsant effect. Because traditional theories do not address these differences, a new model of contingent and pharmacologic tolerance is presented. / Arts, Faculty of / Psychology, Department of / [title page not included] / Graduate

Valproic acid (2-propylpentanoic acid) is an antiepileptic drug widely used for treatment of absence seizures. Valproic acid has a unique chemical structure which does not contain the imide structure found in most conventional antiepileptic drugs. An in vivo study of the antagonism of pentylenetetrazol-induced clonic seizures by alkyl-substituted carboxylic acids and tetrazoles was of interest owing to the known bioisosterism between the carboxylic and the tetrazolyl moiety. The main objective of this study was to investigate the role played by the lipophilicity, the electronic properties and the steric influence of compounds on their anticonvulsant potency. Quantitative structure-activity relationships of the aliphatic and alicyclic substituted carboxylic acids and tetrazoles have been performed using the Hansch linear free-energy relationships model. The study proceeded by synthesis of compounds using known procedures. The di-unsaturated derivatives of valproic acid, 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid and 2-[(Z)-l'-propenyl]-(E)-2-pentenoic acid were prepared via a stereoselective synthetic route. The synthesized di-unsaturated acids were used in identification of the major diunsaturated metabolite of valproic acid as 2-[(E)-l'-propenyl]-(E)-2-pentenoic acid. The anticonvulsant potency of test compounds was determined in mice (CD1 strain, 20-32g) by the standard subcutaneous pentylenetetrazole seizure threshold test. The pentylenetetrazole clonic seizure test was found to be more sensitive to structural effects than the pentylenetetrazole mortality assay. The lipophilicity (octanol-water partition coefficient) of compounds was determined indirectly by reversed phase liquid chromatography employing an octadecylsilane column (Hypersil ODS) and mobile phase as 70% methanol : 30% phosphate buffer (pH 3.5). The electronic character of the compounds was monitored by the apparent acid ionization constant obtained from potentiometric titration in 10% raethanol-water system. The ED₅₀ of 0.70 mmol/kg found for valproic acid was similar to literature values. 5-Heptyltetrazole was found to be the most potent compound in the series of analogues studied. The carboxylic plus tetrazole group gave a low correlation (r = 0.63) between the anticonvulsant potency and a linear combination of lipophilicity and apparent ionization constant. However, in the series of active carboxylic acids, the anticonvulsant activity was noted to be significantly correlated with lipophilicity and apparent ionization constant (r = 0.91). The usefulness of the electronic parameters, acid ionization constant and dipole moment, were explored in an extensive set of alkyl-substituted anticonvulsant compounds with different polar moieties. Addition of the dipole moment term to the lipophilicity term led to significantly better correlations (r = 0.81) as compared to that with an added pKa term. The negative dependency of anticonvulsant activity on dipole moment supported previous findings in studies of 1,4-benzo-diazepines and phenyl-substituted anticonvulsant compounds. There were some exceptions to the dependence of anticonvulsant activity on lipophilicity and dipole moment or pKa. N,N-dibutyl-succinamic acid showed convulsant properties at sublethal doses. The lack of activity of cyclohexylacetic acid and 5-cyclohexylmethyltetra-zole, in comparison to the active l-methylcyclohexanecarboxylic acid, has some pharmacological significance. It shows a certain degree of molecular specificity in the anticonvulsant action of valproic acid analogues. The cyclohexylmethyl conformation was suggested, from aproposed model, to be less effective in hydrophobic binding due to a steric effect at a stereoselective position on the hydrophobic site of the GABA receptor complex. Thus it can be concluded that while lipophilicity governed access to sites of action, the dependence of activity on the polar character may explain the diverse structures of anticonvulsants provided that the steric requirements of the hydrophobic binding site are met. Steric effects may lead to inactivity or even convulsant properties of alkyl-substituted compounds. / Pharmaceutical Sciences, Faculty of / Graduate

This thesis describes the process of synthesizing 5-substituted-mercapto derivatives of hydantoin in which the sulfur of the side chain is attached directly to the hydantoin nucleus.

This study involves compounds of the barbituric acid series are well known for their use as anesthetics and sedatives.

This thesis describes the synthesis of a series of 5-alkideniminoxy-5-phenylhydantoins for the purpose of studying their anticonvulsant properties.

No description available.

A series of 2-alkyl-3-arylpyrido[2,3-d]pyrimidones were synthesized for testing as potential antiepileptic drugs. The goal was to achieve better neurological activity and/or lower toxicity than displayed by a series of 2-alkyl-3-aryl-4(3H)-quinazolinones prepared previously in our research group. From the pharmacological testing data of these target compounds, we have found that the additional nitrogen at the C-8 position of the quinazolinone framework increased the anticonvulsant activity. However, the neurological toxicity increased as well. The anticonvulsant and neurotoxic activity seen in the variuos 2-alkyl side chains and 3-aryl substituents incorporated into these new pyridopyrimidones was consistent with the activity observed with the same substituents on the 4(3H)-quinazolinones. The 3-aryl group consists of various ortho-substituted phenyl rings, while the 2-alkyl chain consists of a 2-(2-aryl-2-oxo)ethyl or 2-arylethenyl group. / Master of Science