Harrison Bryce A, Gierasch Tiffany Malinky, Neilan Claire, Pasternak Gavril W, Verdine Gregory L
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
J Am Chem Soc. 2002 Nov 13;124(45):13352-3. doi: 10.1021/ja027150p.
In this communication, we report the synthesis of an exhaustively stereodiversified library of 16 1,5-enediols (2) and the screening of these compounds for mu opioid receptor (MOR) binding. The stereochemical configuration of 2 strongly impacted the binding affinity, and (S,S,S,R)-2 exhibited a Ki of 8.8 nM for MOR, comparable to that of endomorphin-2 (Ki = 1.2 nM). Moreover, compounds 2 exhibited 5-86-fold selectivity for MOR over delta opioid receptor (DOR) and 16-150-fold selectivity for MOR over kappa opioid receptor (KOR). Additionally, analogues of 2 were synthesized which showed the importance of the trans olefin for receptor binding but that modifications of the C-terminal amino acid were well tolerated. Ligand 11 is noteworthy because it retains only one of the amide bonds present in 1, but binds MOR with an affinity of 10 nM and 110- and 600-fold selectivity for MOR over DOR and KOR. These results demonstrate the utility of stereochemical diversity in the discovery of bioactive small molecules.
在本通讯中，我们报道了16种1,5 - 烯二醇（2）的全立体多样化库的合成以及这些化合物对μ阿片受体（MOR）结合的筛选。2的立体化学构型对结合亲和力有强烈影响，(S,S,S,R)-2对MOR的Ki为8.8 nM，与内吗啡肽 - 2（Ki = 1.2 nM）相当。此外，化合物2对MOR的选择性比对δ阿片受体（DOR）高5 - 86倍，对MOR的选择性比对κ阿片受体（KOR）高16 - 150倍。另外，合成了2的类似物，结果表明反式烯烃对受体结合很重要，但C端氨基酸的修饰具有良好的耐受性。配体11值得注意，因为它仅保留了1中存在的一个酰胺键，但对MOR的结合亲和力为10 nM，对MOR的选择性比对DOR和KOR分别高110倍和600倍。这些结果证明了立体化学多样性在发现生物活性小分子中的实用性。
