Item – Theses Canada

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OCLC number
46549156
Author
Dakin, Kelly Andrea,1969-
Title
Design and synthesis of anticonvulsant drugs based on endogenous anticonvulsant and antiepileptogenic factors.
Degree
Ph. D. -- Queen's University at Kingston, 1997
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [1998]
Description
5 microfiches.
Notes
Includes bibliographical references.
Abstract
Endogenous neuromodulatory factors, such as peptides, are selected as the prototype molecules for the rational design of anticonvulsant and antiepileptogenic drugs. The structural features required for anticonvulsant activity are investigated using theoretical investigations (molecular modelling) and synthetic projects (solid phase peptide synthesis and classical solution phase peptide synthesis) in combination with in vivo anticonvulsant assessment in established seizure models. Theoretical investigations employ molecular mechanics (MM) and semiempirical (SE) calculations. MM or SE geometry optimization routines are used to identify the local minimum energy conformation of a molecule. Monte Carlo (MC) and molecular dynamics (MD) are used to identify families of low energy conformers in search of the global minimum energy conformation. These techniques are used to investigate two topics towards a common end goal: the rational design of anticonvulsant drugs. Theoretical investigations include: (1) a molecular similarity study exploring the structural commonality contributing to the toxicity of current exogenous anticonvulsant molecules; and (2) a theoretical conformational analysis revealing the putative bioactive conformations for selected peptides. The techniques of solid phase peptide synthesis (SPPS), and classical solution phase peptide synthesis are employed for the synthesis of putative anticonvulsant molecules. Tetrapeptide analogues of the molecular prototype (FMRF-NH$\sb2)$ are synthesized by SPPS using the Rink amide resin, and cyclic thioether peptides are synthesized by SPPS using the Wang resin. Protected dipeptide mimics of the molecular prototype (FMRF-NH$\sb2)$ are synthesized by classical solution phase synthesis. The assessment of tetrapeptide anticonvulsant activity is conducted using an acute model of seizures induced by the chemical convulsant, pentylenetetrazol. The assessment of protected dipeptide mimics is conducted through the Antiepileptic Drug Development (ADD) program of the National Institutes of Health (NIH) Epilepsy Branch.
ISBN
0612224538
9780612224537