
%0 Journal Article
%A Liu, Xiang 
%A Kassiou, Michael 
%A Christie, MacDonald J. 
%A Hambley, Trevor W. 
%T Trishomocubanes: Requirements for &#963; Receptor Binding and Subtype Selectivity
%J Australian Journal of Chemistry
%D 2001/05/31
%V 54
%N 1
%P 31-36
%K 
%R https://doi.org/10.1071/CH00107
%U https://www.publish.csiro.au/paper/CH00107 
%X Several new analogues of the &#963; 2 -selective trishomocubane N-(3.fluorophenyl)methyl-4-azahexacyclo &#91;5.4.1.02,6.03,10.05,9 .08,11&#93;dodecan-3-ol (3) have been synthesized and assessed for their ability to bind &#963; 1 and &#963; 2receptors. In an attempt to improve binding at the &#963;2 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 &#963; 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 &#963; 1 receptors (Ki = 10 nM, &#963;2 /&#963;1 = 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 &#963;1 receptors &#91; &#963;1 : Ki = 21 nM, &#963; 2 /.... 1 = 11.3 for (7), Ki = 9 nM, &#963; 2 /&#963; 1 = 19 for (8)&#93;. 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)&#8211;(12) and were devoid of any affinity for either of the &#963; -receptor subtypes (Ki = &#62;10 &#181;M for &#963; 1and &#963; 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) &#197; &#946; 104.286(3)&#176;, and Z 4. 
