Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Bioorg Med Chem Lett. 2010 Oct 1;20(19):5749-52. doi: 10.1016/j.bmcl.2010.08.001. Epub 2010 Aug 5.
Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective κ opioid receptor (KOPR) agonist. Based on the SAR, its C-2 position is one of the key binding sites and has very little space tolerance (3-4 carbons atoms) and limited to only lipophilic groups. In our attempt to prepare PET brain imaging agent for mapping KOPR, a series of C-2 halogenated analogs have been synthesized and screened for binding affinity at κ (KOPR), μ (MOPR), and δ (DOPR). These C-2 halogenated analogs with sequential changes of atomic radius and electron density serve as excellent molecular probes for further investigating the binding pocket at C-2, particularly on the effects of α verses β configuration at C-2 position. The results of KOPR binding and functional studies reveal β isomer in general binds better than α isomer with the exception of iodinated analogs and none of the C-2 halogenated analogs shows any improvement of KOPR binding affinity. Interestingly, functional assay has characterized that 6b is a partial agonist with E(max) of 46% of the kappa receptor full agonist U50,488H at 250 nM (K(i)). We have also observed that the affinity to the kappa receptor increases with atomic radius (I>Br>Cl>F) which is in good agreement with halogen bonding interactions reported in the literature.
Salvinorin A（1）是 Salvia divinorum 的主要活性成分，是一种有效的κ阿片受体（KOPR）激动剂。基于 SAR，其 C-2 位是关键结合位点之一，空间容忍度非常小（3-4 个碳原子），并且仅限于亲脂性基团。在我们尝试为 KOPR 映射制备 PET 脑成像剂时，已经合成了一系列 C-2 卤代类似物，并对其在 κ（KOPR）、μ（MOPR）和 δ（DOPR）上的结合亲和力进行了筛选。这些 C-2 卤代类似物具有顺序变化的原子半径和电子密度，可作为进一步研究 C-2 结合口袋的优异分子探针，特别是研究 C-2 位α对β构型的影响。KOPR 结合和功能研究的结果表明，β异构体通常比α异构体结合得更好，除了碘代类似物外，没有任何 C-2 卤代类似物显示出对 KOPR 结合亲和力的任何改善。有趣的是，功能测定将 6b 鉴定为部分激动剂，在 250 nM（K(i)）时，其对κ受体的效力为全激动剂 U50,488H 的 46%（E(max)）。我们还观察到，对 κ 受体的亲和力随原子半径增加（I>Br>Cl>F），这与文献中报道的卤键相互作用一致。
