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Abstract

The experimental work detailed here falls into four main areas.

(1) Quantitative structure activity relationship (QSAR) studies
These were used to investigate the "active" conformations of the three neuroexcitant amino acids listed below. A 3—point electrostatic interaction with the receptor was assumed in each case.

(a) L-Glutamate. Conformational analysis yielded two possible "active" conformations by careful comparison of the conformational modes of L-ibotenate with those of 1-amino-1,3-dicarboxy cyclopentane — both L-glutamate agonists.

(b) L-Aspartate. Due to the lack of a suitably active conformationally restricted ligand it was unfortunately not possible to predict an "active" conformation.

(c) Kainate. The ideal situation arose. A single "active" conformation was defined by comparison of the L-glutamate analogue L-ibotenate with kainate itself — both conformationally restricted. A further hydro- phobic binding site might also exist.

(2) Radiolabelled ligand binding studies
These provided the databases for the QSAR studies above. Two binding studies were performed.

(a) In vitro L-[3 H] aspartate studies yielded a hierarchy of potencies for various active displacing ligands for use in the L-aspartate QSAR study above.

(b) [3H] Kainate studies also produced a potency data set for use in the kainate QSAR study.

(3) Crystal structure determinations
These were performed to provide detailed information in support of the above areas. Two reported excitatory amino acid antagonists were investigated.

(a) HA—966

(b) (Please refer to thesis for Mathematical symbol) — Methyl — D L — glutamate

(4) Conformational analysis of the prostaglandins
A computer theoretical study of prostaglandin flexibility was performed. A start was made on correlating potency with a PG molecule's ability to adopt an aligned side chain conformation. During the course of this work a series of papers on the same topic appeared in the literature from Japan. A comparison with that work is included here.

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

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