Deutsch H M, Collard D M, Zhang L, Burnham K S, Deshpande A K, Holtzman S G, Schweri M M
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332-0400, USA.
J Med Chem. 1999 Mar 11;42(5):882-95. doi: 10.1021/jm980566m.
As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.
作为开发针对可卡因滥用的位点特异性药物计划的一部分，合成了一系列2-(氨甲基)-3-苯基双环[2.2.2]-和-[2.2.1]烷衍生物，并在使用大鼠纹状体组织的[3H]WIN 35,428结合和[3H]多巴胺摄取试验中测试了其抑制效力。在大鼠药物辨别试验中测试了选定化合物替代可卡因的能力。通过一系列狄尔斯-阿尔德反应完成合成，使用顺式和反式肉桂酸衍生物（腈、酸、酰氯）与环己二烯和环戊二烯。通过标准操作产生氨甲基侧链。许多化合物以高亲和力（中位IC50 = 223 nM）与由[3H]WIN 35,428标记的可卡因结合位点结合。芳香环3位和/或4位上的氯原子强烈增强了结合试验中的效力，而相应的甲氧基对此影响很小。在[2.2.2]系列中，顺式和反式化合物之间或N,N-二甲胺与伯胺之间的效力差异很小。在[2.2.1]系列中，反式外型化合物对结合的效力往往最低，而顺式外型化合物效力最高（4-氯顺式外型：IC50 = 7.7 nM，比4-氯反式外型强27倍）。尽管双环衍生物在结合和摄取试验中的效力高度相关，但一些化合物在抑制[3H]多巴胺摄取方面的效力比[3H]WIN 35,428结合低5-7倍（相比之下，可卡因的辨别率（DR）较低，为2.5）。与顺式-[2.2.2]系列相比，几乎所有伯胺和顺式-[2.2.2]系列的DR值都更高。除了[2.2.2] 3,4-二氯衍生物的nH值约为2.0外，大多数化合物的希尔系数接近1。在大鼠药物辨别试验中，有两种化合物被证明能完全替代可卡因，其中一种作用持续时间很长。
