City Research Online

Abstract

The researches described here were motivated by a desire to investigate the mechanisms of drug-receptor systems. Three such systems have been explicitly considered (a) the CNS inhibitory system of GABA, (b) the CNS excitatory system of glutamic acid, and (c) the multi-functional prostaglandin system. The GABA transmitter-receptor system is the least complex of the three considered, and has thus been the prime object of study. In seeking a fundamental understanding of drug action at the molecular level the macroscopic physico-chemical parameter approach (Hansch analysis) has been abandoned in favour of the methods of theoretical quantum chemistry.

Various theoretical methods have been considered and compared, with CNDO/2 being chosen as appropriate to the present study. The CNDO/2 method has been used to investigate some aspects of the gasphase properties of GABA and GLU agonists. These aspects include the variation of atomic charges during conformational changes, the intramoleculer hydrogen-bonding between terminal groups of a,w amino-carboxydic acids and the intermolecular invariance in electron distribution of functional groups. The use of the electrostatic potential as a means of probing the interaction sites of a drug has also been considered in detail.

Acknowledging that drug-receptor events occur in the biophase (rather than gas-phase), the possibility of allowing for the solvent effect in theoretical conformation studies has been discussed. Three theoretical solvent effect methods have been compared using B-alanine as a test solute. A continuum approximation to the solvent has been found to be appropriate for use with CNDO/2 and GABA-type molecules.

This point represents the end of the preparatory stage, and it is considered that our techniques are sufficiently developed to attempt an elucidation of GABA and GLU transmitter-receptor interactions. It subsequently proved possible to develop working hypotheses concerning the requirements for agonism, antagonism and inactivity.

A feasibility study on the use of quantum methods with the prostaglandins concluded that only if a ‘molecular fragment' approach was used can conformational problems be contemplated. The ‘molecular fragment' idea was outlined and a brief example of its use given.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QC Physics
Departments:	School of Science & Technology > School of Science & Technology Doctoral Theses Doctoral Theses

Export

Downloads