Trishomocubanes: Requirements for σ Receptor Binding and Subtype Selectivity

Abstract

Several new analogues of the σ ₂ -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 (3) have been synthesized and assessed for their ability to bind σ ₁ and σ ₂receptors. In an attempt to improve binding at the σ₂ receptor, structural variations were examined which involved altering the distance between the trishomocubane moiety and the aromatic ring by including 1, 2, 3, or 4 methylene groups. All synthesized compounds displayed varied affinities and subtype selectivity for σ receptors. Extending the methylene group to n = 2 resulted in (5) and a reversal in subtype selectivity, with high affinity and significant subtype selectivity for σ ₁ receptors (Ki = 10 nM, σ₂ /σ₁ = 37). The non-fluorinated analogues of (3) and (5), (4) and (6) respectively, retained the binding patterns of their fluorinated analogues though to a lesser extent. Extending the methylene group to n = 3 and n = 4 resulted in (7) and (8) respectively and retention of selectivity for σ₁ receptors [ σ₁ : Ki = 21 nM, σ 2 /.... 1 = 11.3 for (7), Ki = 9 nM, σ ₂ /σ ₁ = 19 for (8)]. Compounds derived from aniline with no methylene group between the trishomocubane moiety and the aromatic ring resulted in the formation of pentacycloundecylamine-3-ones (9)–(12) and were devoid of any affinity for either of the σ -receptor subtypes (Ki = >10 µM for σ ₁and σ ₂ receptors). The incorporation of fluorine in the ortho-, meta- or para- position of the aromatic ring had no influence on binding or selectivity. The structure of (9) has been confirmed by X-ray crystallography and was refined to an R value of 0.042 on 1477 observed reflections. Crystals are monoclinic, space group P2₁ /c, a 9.352(2), b 11.299(2), c12.258(2) Å β 104.286(3)°, and Z 4.