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

  • Grant Wishart

    Student thesis: Doctoral Thesis


    The seven transmembrane α-helices of the human 5 -HT1A , 5-HT1Dα and 5-HT1Dβ 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=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.

    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 t-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 t-BOC protected 5-HT analog (E, R=NHCO2C(CH3)3, X=CN).
    Date of AwardJan 1997
    Original languageEnglish
    SupervisorDavid H. Bremner (Supervisor)

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