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

Abstract

Five new analogues of the σ₂-selective trishomocubane N-(3′-fluorophenyl)methyl-4-azahexacyclo- [5.4.1.0 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)).