Item – Theses Canada

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OCLC number
46560733
Link(s) to full text
LAC copy
LAC copy
Author
Milne, Paul Harvey,1967-
Title
The design and synthesis of antiepileptic agents based on neurotransmitter and neural metal-mediated inhibition.
Degree
Ph. D. -- Queen's University, 1998
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [1999]
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
Conventional anticonvulsant drugs suffer from serious drawbacks. They are effective in only 60-65% of patients, their use is associated with significant side-effects in 40-45% of patients, and they treat the symptoms of epilepsy (ie, seizures, ictogenesis) but not the underlying disease process (ie, epileptogenesis). The need for a useful antiepileptic drug, defined as efficacious, non-toxic, anti-ictogenic and antiepileptogenic, is thus a neuropharmacologic priority. To meet that need, an unprecedented rational drug design strategy, based solidly on a mechanistic understanding of neurotransmitter and neural metal mediated inhibition, has been used to design antiepileptic agents with hybrid anti-ictogenic/antiepileptogenic activity. A survey of the pathogenesis of epilepsy has revealed that: (i) the neurochemical aetiology of epileptogenesis (epilepsy focus generation) arises from an altered ratio of excitatory/inhibitory neurotransmitter stimulation, and (ii) ictogenesis (seizure generation) and epileptogenesis are distinct phenomena which act as reciprocal determinants. Thus, the discovery of an antiepileptic drug was postulated to involve the design and synthesis of molecules with combined anticonvulsant and antiepileptogenic properties that exploit agonists and antagonists of inhibitory and excitatory neurotransmitters, respectively. After extensive literature evaluation, $\beta$-alanine was identified as a prototype anti-ictogenic/antiepileptogenic neurotransmitter analogue which derives its biological activity from simultaneously (i) inhibiting excitatory processes via antagonism of the NMDA receptor glycine co-agonist site and (ii) stimulating inhibitory processes via blockade of glial GABA uptake. This presumably accounts for $\beta$-alanine's anti-ictogenic/antiepileptogenic activity, confirmed using the Spontaneous Recurrent Seizure (SRS) model of epileptogenesis. Consequently, a versatile, novel synthesis was developed to manufacture $\beta$-alanine analogues: alkyl $\beta$-aminothiophenecarboxylates were N-acylated, reductively desulfurized and doubly deprotected to yield $\alpha$- or $\beta$-substituted $\beta$-amino acids in reasonable yield. Four of eight $\beta$-amino acids demonstrated anti-ictogenic activity in rat seizure models. $\alpha$-(4-Phenylcyclohexyl)-$\beta$-alanine$\cdot$HCl, anti-ictogenic at ip doses of 50 mg/kg, demonstrated significant antiepileptogenic activity in the SRS model, reducing seizure frequency by 80%. The design of congeners with optimal antiepileptic activity was also proposed. A second approach to the design and synthesis of antiepileptic drugs, based on neural metal mediated inhibition involving brain Zn(II) abstraction and Cu(II) supplementation, was also profiled.
ISBN
0612278409
9780612278400