Australian Journal of Chemistry Australian Journal of Chemistry Society
An international journal for chemical science

Synthesis and Binding Studies of Trishomocubanes: Novel Ligands for σ Binding Sites

Xiang Liu, Michael Kassiou and MacDonald J. Christie

Australian Journal of Chemistry 52(7) 653 - 656
Published: 1999


Five new analogues of the σ2-selective trishomocubane N-(3′-fluorophenyl)methyl-4-azahexacyclo- [ 2;6 .0 3;10 .0 5;9 .0 8;11 ]dodecan-3-ol (2) have been synthesized and assessed for their anities at both σ1 and σ2 sites. The structural requirements which influence σ binding of functionalized trishomocubanes were investigated with a view to develop more potent σ ligands, with particular emphasis on the σ2 subtype. All synthesized compounds displayed moderate anity to σ binding sites. Binding at the σ1 site ranged from 107 to 1100 nМ while binding at the σ2 site ranged from 135 to 250 nМ. The subtype selectivity was influenced by the nature and position of substitution on the aromatic ring. Fluorine substitution in the meta position, as in (2), is favoured over ortho, or para or meta and para difluoro substitution for σ2 selectivity. Compounds (3)–(5) not only demonstrated lower anity at the σ2 site but a reversal of subtype selectivity with preferential binding at the σ1 site (σ1/σ2: 0 . 8 for (3); 0 . 4 for (4); 0 . 8 for (6)). Introduction of CF3 and NO2 groups into the meta position in compounds (6) and (7) retained σ2 selectivity although to a lesser extent when compared to (2) (σ1/σ2: 7 . 6 for (2); 2 . 0 for (6); 4 . 5 for (7)).

© CSIRO 1999

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