City Research Online

Abstract

In this study, two amino-acid transmitter systems have been investigated - the GABA system and the glutamate system. Pharmacological information on each has been collated from the literature, providing a basis for structure-activity studies.

To obtain structural information on the transmitters, which are nearly all flexible molecules, conformational investigations have been carried out using a variety of methods. Crystal structure data has been gathered, both from the literature and from two X-ray crystal structure determinations carried out in the course of the work. One of these employs a novel method for least-squares refinement of charged moieties. Conformational congruences are apparent among the solid-state conformations of agonists in each transmitter system.

Information on conformation in solution has also been obtained, two methods having been applied. The first, more sophisticated, method is a continuum model treatment based on molecular orbital calculations. The second technique is a simple potential energy method, applicable to a wider range of compounds. A tendency towards partially folded molecules in solution is apparent in both sets of results for GABA agonists. The second method has also been applied to some transmitters in the glutamate system.

Following the conformational investigations, structure-activity schemes have been developed which draw together pharmacological and conformational results in the GABA system. Crystal structure results indicate possible congruent receptor-active conformations, and solution conformations correlate quantitatively with transmitter potency. The results for the glutamate system also indicate possible receptor-active congruent conformations.

In conclusion, the structure-activity results lead on to discussion of possible receptor structure and the mode of action of GABA agonists. The inferences of the present work are compatible with suggestions on GABA receptor structure derived by other techniques.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QC Physics R Medicine > RM Therapeutics. Pharmacology
Departments:	School of Science & Technology > School of Science & Technology Doctoral Theses Doctoral Theses

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