Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the μ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the μ receptor independently of their N-substituents. SYK-385 (19b), one of the μ-selective double-capped triplet drugs, showed the highest selectivity for the μ receptor among the reported μ-selective nonpeptide ligands.
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【Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet).].
【具有1,3,5-trioxazatriquinane骨架的新型三联体药物的合成及其药理作用。 3：合成具有双（环氧基甲烷）或双（二甲基环氧基甲烷）结构的新型三联体药物（双封端的三联体）。】
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DOI：10.1016/j.bmcl.2012.10.023文章类型：杂志文章
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合成了具有一个药效团单元和两个环氧亚甲基或二甲基环氧亚甲基结构（分别称为帽或二甲基-帽结构）的新型双封端三联体药物。源自丙酮的关键中间体恶唑啉16能够有效合成双封三胞胎。具有N-环丙基甲基取代基和帽结构的SYK-134（7a）和SYK-135（8a）对κ阿片受体具有选择性。另一方面，N-Me系列对μ阿片受体具有选择性。具有diMe-cap结构的双封端三联体药物优选μ受体，而与它们的N取代基无关。微米选择性双封端三联体药物之一SYK-385（19b）在已报道的微米选择性非肽配体中显示出对微米受体的最高选择性。
