{"id":{"repo_id":"london-metro","oai_identifier":"oai:repository.londonmet.ac.uk:3008"},"canonical_url":"https://search.dev.ndltd.org/etd/london-metro/oai:repository.londonmet.ac.uk:3008","repository":{"repo_id":"london-metro","name":"London Metropolitan University","base_url":"https://repository.londonmet.ac.uk/cgi/oai2"},"display":{"title":"The synthesis and pharmacology of gamma-aminobutyric acid receptor mimetics","abstract":"Gamma-aminobutyric acid (GABA) has been shown to be an important inhibitory neurotransmitter in mammalian central nervous system (CNS). GABA receptors have been previously characterized in mammalian brain using 3H-GABA itself, a potent GABA agonist, 3H-muscimol, and the GABA antagonist, 3H-bicuculline methiodide. Recently, it has been suggested that 1,2,3,6 Tetrahydropyridine-4-carboxylic acid (Isoguvacine) is a potent GABA receptor agonist. It has also been reported to act as a mixed agonist/antagonist at the GABA-benzodiazepine receptor complex. The binding of 3H-Isoguvacine to frozen-thawed, rat brain synaptosomal membranes has been investigated and found to be saturable, specific and stereospecific. The pharmacology of this 3H-Isoguvacine binding site was seen to be consistent with an interaction at the postsynaptic GABA receptor site. The effects of detergent treatment on this binding site-were investigated and indicated a single site, both in control and in Triton X-lOO treated membranes. A series of benzodiazepines were shown to displace 3H-Isoguvacine bound to frozen-thawed rat synaptosomal membranes. This effect was shown to be temperature-dependent and could be blocked by picrotoxinin (10-4 M). Pentobarbitone was also seen to displace 3H-Isoguvacine binding, albeit at high IC5O values; an effect antagonized by picrotoxinin. Neither the benzodiazepines nor pentobarbitone had any effect on 3H-GABA binding in frozen-thawed membranes. In contrast, using fresh rat synaptosomal membranes, neither the benzodiazepines nor pentobarbitone had any effect on 3H-Isoguvacine binding, whereas both were shown to potentiate 3H-GABA binding. A series of conformationally-restricted analogues of GABA have been synthesized and tested using two in vitro assay systems, viz. the rat superior cervical ganglion and a radioligand binding assay. These studies revealed that the class of GABA agonist, in which the amino groups are incorporated into six-membered rings exhibit an unexpected variety of activities with respect to their ability to inhibit 3H-GABA binding; their affinity for GABA uptake sites and their interaction with the coupled GABA/benzodiazepine sites.","abstract_html":"Gamma-aminobutyric acid (GABA) has been shown to be an important inhibitory neurotransmitter in mammalian central nervous system (CNS). GABA receptors have been previously characterized in mammalian brain using 3H-GABA itself, a potent GABA agonist, 3H-muscimol, and the GABA antagonist, 3H-bicuculline methiodide. Recently, it has been suggested that 1,2,3,6 Tetrahydropyridine-4-carboxylic acid (Isoguvacine) is a potent GABA receptor agonist. It has also been reported to act as a mixed agonist/antagonist at the GABA-benzodiazepine receptor complex. The binding of 3H-Isoguvacine to frozen-thawed, rat brain synaptosomal membranes has been investigated and found to be saturable, specific and stereospecific. The pharmacology of this 3H-Isoguvacine binding site was seen to be consistent with an interaction at the postsynaptic GABA receptor site. The effects of detergent treatment on this binding site-were investigated and indicated a single site, both in control and in Triton X-lOO treated membranes. A series of benzodiazepines were shown to displace 3H-Isoguvacine bound to frozen-thawed rat synaptosomal membranes. This effect was shown to be temperature-dependent and could be blocked by picrotoxinin (10-4 M). Pentobarbitone was also seen to displace 3H-Isoguvacine binding, albeit at high IC5O values; an effect antagonized by picrotoxinin. Neither the benzodiazepines nor pentobarbitone had any effect on 3H-GABA binding in frozen-thawed membranes. In contrast, using fresh rat synaptosomal membranes, neither the benzodiazepines nor pentobarbitone had any effect on 3H-Isoguvacine binding, whereas both were shown to potentiate 3H-GABA binding. A series of conformationally-restricted analogues of GABA have been synthesized and tested using two in vitro assay systems, viz. the rat superior cervical ganglion and a radioligand binding assay. These studies revealed that the class of GABA agonist, in which the amino groups are incorporated into six-membered rings exhibit an unexpected variety of activities with respect to their ability to inhibit 3H-GABA binding; their affinity for GABA uptake sites and their interaction with the coupled GABA/benzodiazepine sites.","abstract_has_math":false,"creators":["McDonald, Jane Anne Margaret"],"institution":"City of London Polytechnic","degree_name":"phd","degree_level":"doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":1981,"date_issued":"1981-08","date_published":"1981-08","updated_at":"2026-07-24T02:54:27Z","subjects":["590 Animals (Zoology)"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.grantnumber","label":"Dc Identifier Grantnumber","values":["N/A"],"render_values":[{"text":"N/A","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.sponsor","label":"Sponsor","values":["London Metropolitan University"]},{"key":"dc:creator","label":"Author","values":["McDonald, Jane Anne Margaret"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["1981-08"]},{"key":"dc:date.issued","label":"Date","values":["1981-08"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["School of Human Sciences (SHSC)","Department of Chemistry"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["City of London Polytechnic"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://repository.londonmet.ac.uk/3008/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["phd"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["590 Animals (Zoology)"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.grantnumber","label":"Dc Identifier Grantnumber","values":["N/A"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://repository.londonmet.ac.uk/3008/1/276905.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Gamma-aminobutyric acid (GABA) has been shown to be an important inhibitory neurotransmitter in mammalian central nervous system (CNS). GABA receptors have been previously characterized in mammalian brain using 3H-GABA itself, a potent GABA agonist, 3H-muscimol, and the GABA antagonist, 3H-bicuculline methiodide. Recently, it has been suggested that 1,2,3,6 Tetrahydropyridine-4-carboxylic acid (Isoguvacine) is a potent GABA receptor agonist. It has also been reported to act as a mixed agonist/antagonist at the GABA-benzodiazepine receptor complex. The binding of 3H-Isoguvacine to frozen-thawed, rat brain synaptosomal membranes has been investigated and found to be saturable, specific and stereospecific. The pharmacology of this 3H-Isoguvacine binding site was seen to be consistent with an interaction at the postsynaptic GABA receptor site. The effects of detergent treatment on this binding site-were investigated and indicated a single site, both in control and in Triton X-lOO treated membranes. A series of benzodiazepines were shown to displace 3H-Isoguvacine bound to frozen-thawed rat synaptosomal membranes. This effect was shown to be temperature-dependent and could be blocked by picrotoxinin (10-4 M). Pentobarbitone was also seen to displace 3H-Isoguvacine binding, albeit at high IC5O values; an effect antagonized by picrotoxinin. Neither the benzodiazepines nor pentobarbitone had any effect on 3H-GABA binding in frozen-thawed membranes. In contrast, using fresh rat synaptosomal membranes, neither the benzodiazepines nor pentobarbitone had any effect on 3H-Isoguvacine binding, whereas both were shown to potentiate 3H-GABA binding. A series of conformationally-restricted analogues of GABA have been synthesized and tested using two in vitro assay systems, viz. the rat superior cervical ganglion and a radioligand binding assay. These studies revealed that the class of GABA agonist, in which the amino groups are incorporated into six-membered rings exhibit an unexpected variety of activities with respect to their ability to inhibit 3H-GABA binding; their affinity for GABA uptake sites and their interaction with the coupled GABA/benzodiazepine sites."]},{"key":"dc:format","label":"Dc Format","values":["text"]},{"key":"dc:title","label":"Title","values":["The synthesis and pharmacology of gamma-aminobutyric acid receptor mimetics"]}]}],"canonical_facts":{"dc:contributor.sponsor":["London Metropolitan University"],"dc:creator":["McDonald, Jane Anne Margaret"],"dc:date":["1981-08"],"dc:date.issued":["1981-08"],"dc:description.abstract":["Gamma-aminobutyric acid (GABA) has been shown to be an important inhibitory neurotransmitter in mammalian central nervous system (CNS). GABA receptors have been previously characterized in mammalian brain using 3H-GABA itself, a potent GABA agonist, 3H-muscimol, and the GABA antagonist, 3H-bicuculline methiodide. Recently, it has been suggested that 1,2,3,6 Tetrahydropyridine-4-carboxylic acid (Isoguvacine) is a potent GABA receptor agonist. It has also been reported to act as a mixed agonist/antagonist at the GABA-benzodiazepine receptor complex. The binding of 3H-Isoguvacine to frozen-thawed, rat brain synaptosomal membranes has been investigated and found to be saturable, specific and stereospecific. The pharmacology of this 3H-Isoguvacine binding site was seen to be consistent with an interaction at the postsynaptic GABA receptor site. The effects of detergent treatment on this binding site-were investigated and indicated a single site, both in control and in Triton X-lOO treated membranes. A series of benzodiazepines were shown to displace 3H-Isoguvacine bound to frozen-thawed rat synaptosomal membranes. This effect was shown to be temperature-dependent and could be blocked by picrotoxinin (10-4 M). Pentobarbitone was also seen to displace 3H-Isoguvacine binding, albeit at high IC5O values; an effect antagonized by picrotoxinin. Neither the benzodiazepines nor pentobarbitone had any effect on 3H-GABA binding in frozen-thawed membranes. In contrast, using fresh rat synaptosomal membranes, neither the benzodiazepines nor pentobarbitone had any effect on 3H-Isoguvacine binding, whereas both were shown to potentiate 3H-GABA binding. A series of conformationally-restricted analogues of GABA have been synthesized and tested using two in vitro assay systems, viz. the rat superior cervical ganglion and a radioligand binding assay. These studies revealed that the class of GABA agonist, in which the amino groups are incorporated into six-membered rings exhibit an unexpected variety of activities with respect to their ability to inhibit 3H-GABA binding; their affinity for GABA uptake sites and their interaction with the coupled GABA/benzodiazepine sites."],"dc:format":["text"],"dc:identifier.grantnumber":["N/A"],"dc:identifier.uri":["https://repository.londonmet.ac.uk/3008/1/276905.pdf"],"dc:publisher.department":["School of Human Sciences (SHSC)","Department of Chemistry"],"dc:publisher.institution":["City of London Polytechnic"],"dc:relation.isreferencedby":["https://repository.londonmet.ac.uk/3008/"],"dc:subject":["590 Animals (Zoology)"],"dc:title":["The synthesis and pharmacology of gamma-aminobutyric acid receptor mimetics"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["doctoral"],"dc:type.qualificationname":["phd"]},"updated_at":"2026-07-24T02:54:27Z"}