Doctor of Philosophy
School of Chemistry
Inamdar, Amar P., Ligand-based pharmacophore studies in the dopaminergic system, Doctor of Philosophy thesis, School of Chemistry, University of Wollongong, 2011. http://ro.uow.edu.au/theses/3535
The dopamine receptor complex and the dopamine transporter system (DAT) are implicated in neuropsychological disorders. The aim of our research project was to design, synthesise and evaluate high affinity and selective (over D2 receptor subtype) dopamine D4 receptor subtype ligands, as well as dopamine reuptake inhibitors. Preliminary D4 and D2 pharmacophore studies led to the synthesis of minimal ligands based on the readily available tetrahydroisoquinoline structure with N-propyl, N-butyl and N-phenethyl substituents. These minimal ligands were proposed based on the minimal features necessary for D4 binding of the aromatic group at a distance of 3.8 Å from the basic nitrogen. Further refined D4 and D2 receptor pharmacophore modelling studies led to the design and synthesis of new molecules of the tetrahydroisoquinoline class based on a refined D4 pharmacophore. These compounds featured the further addition on nitrogen of bulkier hydrophobic groups, namely 2-(trans-2-phenyl-1-cyclopropyl)methyl-1,2,3,4-tetrahydroisoquinoline 11, (E)-2-cinnamyl-1,2,3,4-tetrahydroisoquinoline 23 and (E)-2-(4-stilbenyl)methyl-1,2,3,4-tetrahydroisoquinoline 24. These compounds had D4 receptor affinities (Ki) of 930 nM, 880 nM and 880 nM respectively. Following the availability of data on other structurally diverse high affinity and selective D4 (over D2) ligands in the literature, a new second generation D4 over D2 selective pharmacophore was developed with a wider set of training set compounds than was available for the initial preliminary and refined D4 pharmacophores. This new D4 pharmacophore model was different from others reported in the literature and was validated using known D2 and D4 not used in the training set, as well as through the synthesised and tested tetrahydroisoquinoline analogues. This second generation pharmacophore showed reasonable predictive capability for D4 binding.
With a view to the design of new DAT inhibitors, a DAT pharmacophore model was generated. Following the preliminary DAT pharmacophore studies using only one class (tropane) of training set compounds, further work led to the generation of a refined, less-biased DAT pharmacophore using a structurally diverse training set compared to the other reported DAT pharmacophores in the literature. Compared to reported DAT pharmacophore models in the literature, our refined DAT pharmacophore was unique since it was generated using structurally diverse training set compounds. A new compound based on the 6,7-dehydrotropane structure was designed similar to the benztropine class of compounds. This new compound, 3α-[1-(4-chlorophenyl)-1-phenyl]methoxy-8-methyl-8-azabicyclo[3.2.1]oct-6-ene 32, showed high DAT affinity with a Ki value of 49 nM. Another quite different new compound, 1-(3-chloro-benzothiophene-2-carbonyl)-4-phenylpiperazine 39, a benzothiophene-based analogue, was also synthesized and was shown to have a moderate DAT affinity of 320 nM. This compound is a promising new lead for the potential development of structurally different DAT inhibitors for combating cocaine abuse.