Deconstructing 14-phenylpropyloxymetopon: Minimal requirements for binding to mu opioid receptors
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- 作者：Lidiya Stavitskaya ; Jihyun Shim ; Jason R. Healy ; Rae R. Matsumoto ; Alex ; er D. MacKerell Jr. ; Andrew Coop
- 关键词：Opioid ; Phenylpropyloxyethylamine ; Conformationally sampled pharmacophore
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2012
- 出版时间：15 July, 2012
- 年：2012
- 卷：20
- 期：14
- 页码：4556-4563
- 全文大小：962 K
文摘
A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for ¦Ì opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the ¦Ì opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.