布托啡诺的疏水酯类和醚类在阿片受体处的合成及药理学评价
Synthesis and pharmacological evaluation of hydrophobic esters and ethers of butorphanol at opioid receptors.
作者信息
Fulton Brian S, Knapp Brian I, Bidlack Jean M, Neumeyer John L
机构信息
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
出版信息
Bioorg Med Chem Lett. 2008 Aug 15;18(16):4474-6. doi: 10.1016/j.bmcl.2008.07.054. Epub 2008 Jul 17.
Abstract
We synthesized several hydrophobic esters and ethers of butorphanol and assessed their affinities at opioid receptors in CHO cell membranes. Tested compounds displayed moderate to high affinities to the mu and kappa receptors. The findings accord with previous evidence of a lipophilic binding pocket in the opioid receptors that can be accessed to afford good binding affinity without the need for a phenolic hydrogen-bond donor group. The most potent (K(i)=61 pM at mu and 48 pM at kappa) novel agent was (-)-N-cyclobutylmethylmorphinan-3-yl-14-ol phenoxyacetate (4d).
摘要
我们合成了几种丁丙诺啡的疏水酯和醚，并评估了它们在CHO细胞膜中对阿片受体的亲和力。测试的化合物对μ和κ受体表现出中度至高亲和力。这些发现与先前关于阿片受体中存在亲脂性结合口袋的证据一致，该口袋可以被利用以提供良好的结合亲和力，而无需酚类氢键供体基团。最有效的新型药物（μ受体的K(i)=61 pM，κ受体的K(i)=48 pM）是(-)-N-环丁基甲基吗啡喃-3-基-14-醇苯氧基乙酸酯（4d）。
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