Dasher W E, Klein P, Nelson W L
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
J Med Chem. 1992 Jun 26;35(13):2374-84. doi: 10.1021/jm00091a005.
O6-Ether derivatives of 6 beta-naltrexol in which the ether substituent includes various electrophilic groups have been synthesized in an effort to examine structure-activity requirements at the 6 beta-substituent for receptor affinity and irreversibility of binding in opioid receptor preparations. A series of tethered 6 beta-ethers having terminal epoxides, alpha-methylene-gamma-lactones, and an isothiocyanate group were prepared. The stereochemistry of the alpha-methylene-gamma-lactones was established by convergent synthesis of their reduction products from epoxides of known absolute stereochemistry. In general, the tested compounds showed comparable affinity and selectivity for the receptor subtypes. All were found with high affinity for mu-sites. The terminal epoxide ether diastereomers 8 and 9 were not bound irreversibly in the assay for total opioid receptors. The alpha-methylene-gamma-lactone diastereomers 10 and 11, and their O14-acetyl precursors 20 and 21, respectively, varied in their irreversible effects, but where noted these effects were mu-site selective. Methacrylate ether 7 and isothiocyanate ether 12 were bound irreversibly at both mu- and delta-sites.
已合成了6β-纳曲醇的O6-醚衍生物，其中醚取代基包含各种亲电基团，旨在研究6β-取代基对阿片受体制剂中受体亲和力和结合不可逆性的构效关系要求。制备了一系列带有末端环氧化物、α-亚甲基-γ-内酯和异硫氰酸酯基团的连接6β-醚。通过从已知绝对立体化学的环氧化物收敛合成其还原产物，确定了α-亚甲基-γ-内酯的立体化学。一般来说，测试的化合物对受体亚型表现出相当的亲和力和选择性。所有化合物对μ位点都具有高亲和力。在总阿片受体测定中，末端环氧化物醚非对映异构体8和9没有不可逆结合。α-亚甲基-γ-内酯非对映异构体10和11及其O14-乙酰基前体20和21的不可逆作用各不相同，但在有记录的情况下，这些作用对μ位点具有选择性。甲基丙烯酸酯醚7和异硫氰酸酯醚12在μ和δ位点均不可逆结合。
