Lager Erik, Andersson Pierre, Nilsson Jakob, Pettersson Ingrid, Nielsen Elsebet Østergaard, Nielsen Mogens, Sterner Olov, Liljefors Tommy
Department of Organic Chemistry, Lund University, P.O.B. 124, SE-221 00 Lund, Sweden.
J Med Chem. 2006 Apr 20;49(8):2526-33. doi: 10.1021/jm058057p.
The 3-ethoxycarbonyl-4-quinolone compound 1 has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2S) and alpha(3)beta(2)gamma(2S) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1)- versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2S) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.
3-乙氧羰基-4-喹诺酮化合物1先前已通过数据库搜索被鉴定为一种有趣的先导化合物，可在GABA(A)受体的苯二氮䓬位点进行配体结合（Kahnberg等人，《分子图形与建模杂志》，2004年，23卷，253 - 261页）。对该先导化合物进行药效团导向的优化产生了许多对苯二氮䓬位点具有高亲和力的配体，包括显示出亚纳摩尔亲和力的化合物20以及23 - 25。其中一些化合物已在α(1)β(2)γ(2S)和α(3)β(2)γ(2S) GABA(A)受体亚型上进行了测试，并且其中两种化合物（5和19）对含α(1)受体与含α(3)受体的选择性分别为22倍和27倍。这种对α(1)β(2)γ(2S)的选择性与著名的α(1)亚基选择性化合物唑吡坦处于相同范围。
