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. 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. 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. 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. 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).
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:337800 |
| Date | January 1997 |
| Creators | Wishart, Grant |
| Contributors | Bremner, David |
| Publisher | Abertay University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://rke.abertay.ac.uk/en/studentTheses/bfc1f404-1d94-4881-afc6-7c18bd649cdc |
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