Department of Radiology, Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO 63110, USA.
Bioorg Med Chem. 2013 Jun 1;21(11):2988-98. doi: 10.1016/j.bmc.2013.03.074. Epub 2013 Apr 6.
A series of N-(2-methoxyphenyl)homopiperazine analogs was prepared and their affinities for dopamine D2, D3, and D4 receptors were measured using competitive radioligand binding assays. Several ligands exhibited high binding affinity and selectivity for the D3 dopamine receptor compared to the D2 receptor subtype. Compounds 11a, 11b, 11c, 11f, 11j and 11k had K(i) values ranging from 0.7 to 3.9 nM for the D3 receptor with 30- to 170-fold selectivity for the D3 versus D2 receptor. Calculated logP values (logP=2.6-3.6) are within the desired range for passive transport across the blood-brain barrier. When the binding and the intrinsic efficacy of these phenylhomopiperazines was compared to those of previously published phenylpiperazine analogues, it was found that (a) affinity at D2 and D3 dopamine receptors generally decreased, (b) the D3 receptor binding selectivity (D2:D3 K(i) value ratio) decreased and, (c) the intrinsic efficacy, measured using a forskolin-dependent adenylyl cyclase inhibition assay, generally increased.
一系列 N-(2-甲氧基苯基)高哌嗪类似物被制备出来，并通过竞争性放射性配体结合测定法来测量它们对多巴胺 D2、D3 和 D4 受体的亲和力。与 D2 受体亚型相比，一些配体对 D3 多巴胺受体表现出高结合亲和力和选择性。化合物 11a、11b、11c、11f、11j 和 11k 对 D3 受体的 K(i)值范围为 0.7 至 3.9 nM，对 D3 与 D2 受体的选择性为 30 至 170 倍。计算得到的 logP 值（logP=2.6-3.6）在被动穿透血脑屏障所需的范围内。当比较这些苯基高哌嗪与先前发表的苯基哌嗪类似物的结合和内在效力时，发现：(a) 在 D2 和 D3 多巴胺受体上的亲和力普遍降低，(b) D3 受体结合选择性（D2:D3 K(i)值比）降低，(c) 内在效力，通过 forskolin 依赖性腺苷酸环化酶抑制测定法测量，普遍增加。
