Miyata Kengo, Möller Guido, Schepmann Dirk, Wünsch Bernhard
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Research Center for Materials Science and Department of Chemistry, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Bioorg Med Chem. 2014 Aug 1;22(15):4277-84. doi: 10.1016/j.bmc.2014.05.033. Epub 2014 May 22.
Spirocyclic benzopyrans 2 interact with high affinity and selectivity with σ₁ receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ₁ affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported. Homologation of the aldehyde 6 to afford the pyridylacetaldehyde derivative 8 was performed by a Wittig reaction. Bromine lithium exchange of the bromopyridine 8, addition to 1-benzylpiperidin-4-one and cyclization led to the spirocyclic pyrranopyridine 10. Hydrogenolytic removal of the N-benzyl moiety of 10 provided the secondary amine 11, which allowed the introduction of various N-substituents (12a-d). Cyclization of the hydroxy acetal 9 with HCl led to various modifications of the substituent in 3'-position. Generally the σ₁ affinity of the pyridine derivatives is reduced compared with those of the benzene and thiophene derivatives 2 and 3. However, the relationships between the structure and the σ₁ affinity follow the same rules as for the benzene and thiophene derivatives. The most promising σ₁ ligand within this class of compounds is the pyranopyridine 15 with a double bond in the pyran ring revealing a Ki-value of 4.6 nM and a very high selectivity (>217-fold) over the σ₂ subtype.
螺环苯并吡喃2与σ₁受体具有高亲和力和选择性相互作用。用富电子的噻吩环（3）对苯并吡喃亚结构的苯环进行生物电子等排体替换导致σ₁亲和力增加。本文报道了缺电子吡啶生物电子等排体4的合成及药理学评价。通过维蒂希反应将醛6进行同系化反应得到吡啶基乙醛衍生物8。对溴吡啶8进行溴锂交换，加成到1-苄基哌啶-4-酮上并环化得到螺环吡喃并吡啶10。通过氢解去除10的N-苄基部分得到仲胺11，这使得能够引入各种N-取代基（12a-d）。羟基缩醛9与HCl环化导致3'-位取代基的各种修饰。一般来说，吡啶衍生物的σ₁亲和力与苯和噻吩衍生物2和3相比有所降低。然而，结构与σ₁亲和力之间的关系遵循与苯和噻吩衍生物相同的规律。这类化合物中最有前景的σ₁配体是吡喃并吡啶15，其吡喃环中有一个双键，其Ki值为4.6 nM，对σ₂亚型具有非常高的选择性（>217倍）。
