{"id":{"repo_id":"abertay","oai_identifier":"oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"},"canonical_url":"https://search.dev.ndltd.org/etd/abertay/oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc","repository":{"repo_id":"abertay","name":"Abertay University","base_url":"https://rke.abertay.ac.uk/ws/oai"},"display":{"title":"The design and synthesis of novel heterocycles as potential 5-HT receptor ligands","abstract":"The seven transmembrane α-helices of the human 5 -HT<sub>1A</sub> , 5-HT<sub>1Dα</sub> and 5-HT<sub>1Dβ</sub> receptors have been modelled using the 3-dimensional coordinates of the seven transmembrane a-helices of the bacterial protein bacteriorhodopsin as a template. The probable 5-HT binding site was identified between helices 3, 4, 5 and 6. Interactions between the natural ligand 5-HT (A) and the receptor models are described in detail and the agonist binding site is further validated by the docking of four known 5-HT receptor ligands. The models are able to account qualitatively for the receptor binding affinities of the studied ligands.<br/><br/>Small molecule similarity studies suggest that a thieno[2,3-b]pyridine analog (B) of 5-HT could possibly act as a bio-isostere for 5-HT. This was further corroborated when (B) was docked into the 5-HT receptor models and was found to be accommodated easily in the 5-HT binding site participating in the same interactions as observed for 5-HT.<br/><br/>Thieno[2,3-b]pyridines similar to (B) were thus identified as synthetic target compounds. Furthermore, the models were used to provide suggestions for the design of novel, more selective, 5-HT receptor agonists.<br/><br/>The thieno[2,3-b]pyridine ester (C; R=C0<sub>2</sub>Et) was reduced to the hydroxymethyl derivative (C; R=CH<sub>2</sub>0H) but the methylthio group could not be successfully removed in the presence of the thiophene ring.<br/><br/>Using a different approach the thieno[2,3-b]pyridine (D; R=CO<sub>2</sub>Me, X=CN) was synthesised as a model compound and converted through to the <i>t</i>-BOC protected amines (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN) and (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub> , X=CONH<sub>2</sub>). The same reactions were applied to ethyl-3-(5-cyanothieno[2,3-b] pyridin-3-yl)propanoate (E, R=CO<sub>2</sub>Et, X=CN) but this unfortunately could not be converted through to the required <i>t</i>-BOC protected 5-HT analog (E, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN).<br/>","abstract_html":"The seven transmembrane α-helices of the human 5 -HT&lt;sub&gt;1A&lt;/sub&gt; , 5-HT&lt;sub&gt;1Dα&lt;/sub&gt; and 5-HT&lt;sub&gt;1Dβ&lt;/sub&gt; receptors have been modelled using the 3-dimensional coordinates of the seven transmembrane a-helices of the bacterial protein bacteriorhodopsin as a template. The probable 5-HT binding site was identified between helices 3, 4, 5 and 6. Interactions between the natural ligand 5-HT (A) and the receptor models are described in detail and the agonist binding site is further validated by the docking of four known 5-HT receptor ligands. The models are able to account qualitatively for the receptor binding affinities of the studied ligands.&lt;br/&gt;&lt;br/&gt;Small molecule similarity studies suggest that a thieno[2,3-b]pyridine analog (B) of 5-HT could possibly act as a bio-isostere for 5-HT. This was further corroborated when (B) was docked into the 5-HT receptor models and was found to be accommodated easily in the 5-HT binding site participating in the same interactions as observed for 5-HT.&lt;br/&gt;&lt;br/&gt;Thieno[2,3-b]pyridines similar to (B) were thus identified as synthetic target compounds. Furthermore, the models were used to provide suggestions for the design of novel, more selective, 5-HT receptor agonists.&lt;br/&gt;&lt;br/&gt;The thieno[2,3-b]pyridine ester (C; R=C0&lt;sub&gt;2&lt;/sub&gt;Et) was reduced to the hydroxymethyl derivative (C; R=CH&lt;sub&gt;2&lt;/sub&gt;0H) but the methylthio group could not be successfully removed in the presence of the thiophene ring.&lt;br/&gt;&lt;br/&gt;Using a different approach the thieno[2,3-b]pyridine (D; R=CO&lt;sub&gt;2&lt;/sub&gt;Me, X=CN) was synthesised as a model compound and converted through to the &lt;i&gt;t&lt;/i&gt;-BOC protected amines (D, R=NHCO&lt;sub&gt;2&lt;/sub&gt;C(CH&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;3&lt;/sub&gt;, X=CN) and (D, R=NHCO&lt;sub&gt;2&lt;/sub&gt;C(CH&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;3&lt;/sub&gt; , X=CONH&lt;sub&gt;2&lt;/sub&gt;). The same reactions were applied to ethyl-3-(5-cyanothieno[2,3-b] pyridin-3-yl)propanoate (E, R=CO&lt;sub&gt;2&lt;/sub&gt;Et, X=CN) but this unfortunately could not be converted through to the required &lt;i&gt;t&lt;/i&gt;-BOC protected 5-HT analog (E, R=NHCO&lt;sub&gt;2&lt;/sub&gt;C(CH&lt;sub&gt;3&lt;/sub&gt;)&lt;sub&gt;3&lt;/sub&gt;, X=CN).&lt;br/&gt;","abstract_has_math":false,"creators":["Wishart, Grant"],"institution":"University of Abertay Dundee","degree_name":"PhD","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Bremner, David"],"committee_chairs":[],"committee_members":[],"year":1997,"date_issued":"1997-1","date_published":"1997-1","updated_at":"2026-07-24T00:50:16Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"],"render_values":[{"text":"oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc","href":null,"code":true}]}]},"links":{"outbound_url":"https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Bremner, David"]},{"key":"dc:creator","label":"Author","values":["Wishart, Grant"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["1997-1"]},{"key":"dc:date.issued","label":"Date","values":["1997-1"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["University of Abertay Dundee"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Abertay Dundee"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc","https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://rke.abertay.ac.uk/files/15627149/Wishart_1997_The_design_and_synthesis_of_PhD.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The seven transmembrane α-helices of the human 5 -HT<sub>1A</sub> , 5-HT<sub>1Dα</sub> and 5-HT<sub>1Dβ</sub> receptors have been modelled using the 3-dimensional coordinates of the seven transmembrane a-helices of the bacterial protein bacteriorhodopsin as a template. The probable 5-HT binding site was identified between helices 3, 4, 5 and 6. Interactions between the natural ligand 5-HT (A) and the receptor models are described in detail and the agonist binding site is further validated by the docking of four known 5-HT receptor ligands. The models are able to account qualitatively for the receptor binding affinities of the studied ligands.<br/><br/>Small molecule similarity studies suggest that a thieno[2,3-b]pyridine analog (B) of 5-HT could possibly act as a bio-isostere for 5-HT. This was further corroborated when (B) was docked into the 5-HT receptor models and was found to be accommodated easily in the 5-HT binding site participating in the same interactions as observed for 5-HT.<br/><br/>Thieno[2,3-b]pyridines similar to (B) were thus identified as synthetic target compounds. Furthermore, the models were used to provide suggestions for the design of novel, more selective, 5-HT receptor agonists.<br/><br/>The thieno[2,3-b]pyridine ester (C; R=C0<sub>2</sub>Et) was reduced to the hydroxymethyl derivative (C; R=CH<sub>2</sub>0H) but the methylthio group could not be successfully removed in the presence of the thiophene ring.<br/><br/>Using a different approach the thieno[2,3-b]pyridine (D; R=CO<sub>2</sub>Me, X=CN) was synthesised as a model compound and converted through to the <i>t</i>-BOC protected amines (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN) and (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub> , X=CONH<sub>2</sub>). The same reactions were applied to ethyl-3-(5-cyanothieno[2,3-b] pyridin-3-yl)propanoate (E, R=CO<sub>2</sub>Et, X=CN) but this unfortunately could not be converted through to the required <i>t</i>-BOC protected 5-HT analog (E, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN).<br/>"]},{"key":"dc:title","label":"Title","values":["The design and synthesis of novel heterocycles as potential 5-HT receptor ligands"]}]}],"canonical_facts":{"dc:contributor.advisor":["Bremner, David"],"dc:creator":["Wishart, Grant"],"dc:date":["1997-1"],"dc:date.issued":["1997-1"],"dc:description.abstract":["The seven transmembrane α-helices of the human 5 -HT<sub>1A</sub> , 5-HT<sub>1Dα</sub> and 5-HT<sub>1Dβ</sub> receptors have been modelled using the 3-dimensional coordinates of the seven transmembrane a-helices of the bacterial protein bacteriorhodopsin as a template. The probable 5-HT binding site was identified between helices 3, 4, 5 and 6. Interactions between the natural ligand 5-HT (A) and the receptor models are described in detail and the agonist binding site is further validated by the docking of four known 5-HT receptor ligands. The models are able to account qualitatively for the receptor binding affinities of the studied ligands.<br/><br/>Small molecule similarity studies suggest that a thieno[2,3-b]pyridine analog (B) of 5-HT could possibly act as a bio-isostere for 5-HT. This was further corroborated when (B) was docked into the 5-HT receptor models and was found to be accommodated easily in the 5-HT binding site participating in the same interactions as observed for 5-HT.<br/><br/>Thieno[2,3-b]pyridines similar to (B) were thus identified as synthetic target compounds. Furthermore, the models were used to provide suggestions for the design of novel, more selective, 5-HT receptor agonists.<br/><br/>The thieno[2,3-b]pyridine ester (C; R=C0<sub>2</sub>Et) was reduced to the hydroxymethyl derivative (C; R=CH<sub>2</sub>0H) but the methylthio group could not be successfully removed in the presence of the thiophene ring.<br/><br/>Using a different approach the thieno[2,3-b]pyridine (D; R=CO<sub>2</sub>Me, X=CN) was synthesised as a model compound and converted through to the <i>t</i>-BOC protected amines (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN) and (D, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub> , X=CONH<sub>2</sub>). The same reactions were applied to ethyl-3-(5-cyanothieno[2,3-b] pyridin-3-yl)propanoate (E, R=CO<sub>2</sub>Et, X=CN) but this unfortunately could not be converted through to the required <i>t</i>-BOC protected 5-HT analog (E, R=NHCO<sub>2</sub>C(CH<sub>3</sub>)<sub>3</sub>, X=CN).<br/>"],"dc:identifier":["oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc","https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"],"dc:identifier.uri":["https://rke.abertay.ac.uk/files/15627149/Wishart_1997_The_design_and_synthesis_of_PhD.pdf"],"dc:language":["eng"],"dc:publisher.department":["University of Abertay Dundee"],"dc:publisher.institution":["University of Abertay Dundee"],"dc:relation.isreferencedby":["https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc"],"dc:title":["The design and synthesis of novel heterocycles as potential 5-HT receptor ligands"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral Thesis"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T00:50:16Z"}