The design and synthesis of novel heterocycles as potential 5-HT receptor ligands

The seven transmembrane α-helices of the human 5 -HT_1A , 5-HT_1Dα and 5-HT_1Dβ 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=C0₂Et) was reduced to the hydroxymethyl derivative (C; R=CH₂0H) 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=CO₂Me, X=CN) was synthesised as a model compound and converted through to the <i>t</i>-BOC protected amines (D, R=NHCO₂C(CH₃)₃, X=CN) and (D, R=NHCO₂C(CH₃)₃ , X=CONH₂). The same reactions were applied to ethyl-3-(5-cyanothieno[2,3-b] pyridin-3-yl)propanoate (E, R=CO₂Et, X=CN) but this unfortunately could not be converted through to the required <i>t</i>-BOC protected 5-HT analog (E, R=NHCO₂C(CH₃)₃, X=CN).<br/>

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

University of Abertay Dundee

Year dc:date.issued

1997

Author dc:creator

• Wishart, Grant

Advisor dc:contributor.advisor

• Bremner, David

Language dc:language

eng

Identifier

oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc

OAI identifier oai:identifier

oai:rke.abertay.ac.uk:studenttheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc