Stereoselective synthesis and structure-affinity relationships of bicyclic κ receptor agonists
Stereoselective synthesis and structure-affinity relationships of bicyclic κ receptor agonists
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DOI：
10.1039/b915180j
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发表时间：
2010-01-01
影响因子：
3.2
通讯作者：
Wuensch, Bernhard
中科院分区：
文献类型：
--
作者：
Kracht, Daniel;Rack, Elisabeth;Wuensch, Bernhard
双环酮4的还原胺化反应导致非对映选择性地生成内构胺，并转化为酰胺7-10。只有在1，4-二氮杂双环[3.3.1]壬烷体系的两个N原子失活后，才能成功地合成在6位具有外构型氨基部分的非对映异构体25。具有N-4-对甲苯磺酰基的N-1-氧化物19是关键中间体，它允许S(N)2在6位构型反转的情况下与NaN3取代。内型的吡咯烷7a(WMS-1302)与kappa受体的亲和力为73 nM，而外型的非对映异构体25a在kappa受体(K-1>；1muM)上几乎不起作用。用其他酰基和磺酰基取代3，4-二氯苯乙酰残基表明，它是高卡帕亲和力所必需的。构象受限的吡咯烷7a和25a的kappa受体亲和力与二面角N(吡咯烷)-C-C-N(乙酰胺)相关。对有效但灵活的kappa激动剂2的系统构象分析表明，168度的二面角(如25a)比58度(7a)的二面角在能量上更不利。然而，即使二面角为58度的构象也不代表能量最小，这可能解释了7a的卡帕亲和力降低的原因。
Reductive amination of the bicyclic ketone 4 led diastereoselectively to endo-configured amines, which were transformed into the amides 7-10. The synthesis of the diastereomers 25 with an exo-configured amino moiety at position 6 was only successful after deactivation of both N-atoms of the 1,4-diazabicyclo[3.3.1]nonane system. The N-1-oxide 19 with an N-4-tosyl moiety was the crucial intermediate, which allows S(N)2 substitution with NaN3 under inversion of the configuration at position 6. Whereas the endo-configured pyrrolidine 7a (WMS-1302) revealed a kappa receptor affinity of 73 nM, the exo-configured diastereomer 25a was almost inactive at the kappa receptor (K-i > 1 mu M). Replacement of the 3,4-dichlorophenylacetyl residue by other acyl and sulfonyl residues showed that it is essential for high kappa affinity. The kappa receptor affinities of the conformationally constrained pyrrolidines 7a and 25a were correlated with the dihedral angle N(pyrrolidine)-C-C-N(acetamide). A systematic conformational analysis of the potent but flexible kappa agonist 2 showed that a dihedral angle of 168 degrees (as in 25a) is energetically more disfavored than a dihedral angle of 58 degrees (7a). However, even the conformation with a dihedral angle of 58 degrees does not represent an energy minimum, which might explain the reduced kappa affinity of 7a.