3,6-二氮杂双环[3.1.1]庚烷作为阿片受体新型配体的合成

Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for the opioid receptors.

作者信息

Loriga Giovanni, Manca Ilaria, Murineddu Gabriele, Chelucci Giorgio, Villa Stefania, Gessi Stefania, Toma Lucio, Cignarella Giorgio, Pinna Gerard A

机构信息

Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, via F. Muroni 23/A, 07100 Sassari, Italy.

出版信息

Bioorg Med Chem. 2006 Feb 1;14(3):676-91. doi: 10.1016/j.bmc.2005.09.045. Epub 2005 Oct 20.

DOI:10.1016/j.bmc.2005.09.045

PMID:16243530

Abstract

In an effort to improve diazabicycloalkane-based opioid receptor ligands, N-3(6)-arylpropenyl-N-6(3)-propionyl-3,6-diazabicyclo[3.1.1]heptanes (3A,Ba-i) were synthesized and their affinity and selectivity towards mu-, delta- and kappa-receptors were evaluated. The results of the current study revealed a number of compounds (3Bb, 3Bg and 3Bh) having a high affinity for mu (Ki at mu-receptors ranging from 2.7 to 7.9 nM) versus delta (Ki at delta-receptors > 2000 nM) and versus kappa (Ki at kappa-receptors > 5000 nM) receptors. Molecular modelling carried out on the pair 3Aa/3Ba and on the 3Bh was consistent with the hypothesis that the two series of compounds 3A and 3B interact with the mu-receptor in very different ways.

摘要

为了改进基于二氮杂双环烷烃的阿片受体配体，合成了N-3(6)-芳基丙烯基-N-6(3)-丙酰基-3,6-二氮杂双环[3.1.1]庚烷(3A,Ba-i)，并评估了它们对μ、δ和κ受体的亲和力和选择性。当前研究结果显示，一些化合物(3Bb、3Bg和3Bh)对μ受体具有高亲和力(Ki在μ受体处为2.7至7.9 nM)，而对δ受体(Ki在δ受体处>2000 nM)和κ受体(Ki在κ受体处>5000 nM)则不然。对3Aa/3Ba对和3Bh进行的分子建模与以下假设一致：3A和3B这两个系列的化合物与μ受体的相互作用方式非常不同。