Holladay M W, Bai H, Li Y, Lin N H, Daanen J F, Ryther K B, Wasicak J T, Kincaid J F, He Y, Hettinger A M, Huang P, Anderson D J, Bannon A W, Buckley M J, Campbell J E, Donnelly-Roberts D L, Gunther K L, Kim D J, Kuntzweiler T A, Sullivan J P, Decker M W, Arneric S P
Neurological and Urological Diseases Research, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Bioorg Med Chem Lett. 1998 Oct 6;8(19):2797-802. doi: 10.1016/s0960-894x(98)00504-6.
Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.
制备了吡啶环上具有不同取代基的A-98593（1）及其对映体ABT-594（2）的类似物，并测试了它们对大鼠脑烟碱型乙酰胆碱受体结合位点的亲和力以及在小鼠热板试验中的镇痛活性。多种类型的修饰与对[3H]金雀花碱结合位点的高亲和力一致。相比之下，只有特定的修饰能使镇痛效力保持在与1和2相同的范围内。还制备了氮杂环丁烷环3位带有一个或两个甲基取代基的2的类似物，发现它们在两种试验中的活性都显著降低。
