Munro Thomas A, Ho Douglas M, Cohen Bruce M
McLean Hospital, Belmont, MA, USA ; Harvard Medical School, Department of Psychiatry, Boston, MA, USA.
Acta Crystallogr Sect E Struct Rep Online. 2012 Nov 1;68(Pt 11):o3225-6. doi: 10.1107/S1600536812043449. Epub 2012 Oct 27.
The title compound [MOM-SalB; systematic name: methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-fur-yl)-9-meth-oxy-meth-oxy-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octa-hydro-1H-benzo[f]isochromene-7-carboxyl-ate], C(23)H(30)O(8), is a deriv-ative of the κ-opioid salvinorin A with enhanced potency, selectivity, and duration of action. Superimposition of their crystal structures reveals, surprisingly, that the terminal C and O atoms of the MOM group overlap with the corresponding atoms in salvinorin A, which are separated by an additional bond. This counter-intuitive isosterism is possible because the MOM ether adopts the 'classic anomeric' conformation (gauche-gauche), tracing a helix around the planar acetate of salvinorin A. This overlap is not seen in the recently reported structure of the tetra-hydro-pyranyl ether, which is less potent. The classic anomeric conformation is strongly favoured in alk-oxy-methyl ethers, but not in substituted acetals, which may contribute to their reduced potency. This structure may prove useful in evaluating models of the activated κ-opioid receptor.
标题化合物[MOM-SalB；系统名称：甲基(2S,4aR,6aR,7R,9S,10aS,10bR)-2-(3-呋喃基)-9-甲氧基甲氧基-6a,10b-二甲基-4,10-二氧代-2,4a,5,6,7,8,9,10a-八氢-1H-苯并[f]异苯并二氢吡喃-7-羧酸酯]，C(23)H(30)O(8)，是κ-阿片样物质萨尔维诺林A的衍生物，具有增强的效力、选择性和作用持续时间。令人惊讶的是，它们晶体结构的叠加显示，MOM基团的末端C和O原子与萨尔维诺林A中的相应原子重叠，而这些原子被一个额外的键隔开。这种违反直觉的等电子体现象是可能的，因为MOM醚采用了“经典异头物”构象（gauche-gauche），围绕萨尔维诺林A的平面乙酸酯形成一个螺旋。在最近报道的效力较低的四氢吡喃基醚结构中没有看到这种重叠。经典异头物构象在烷氧基甲基醚中强烈有利，但在取代缩醛中则不然，这可能导致它们效力降低。该结构可能有助于评估活化的κ-阿片样物质受体模型。
