Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76109, USA.
Synapse. 2010 Mar;64(3):251-66. doi: 10.1002/syn.20725.
A panel of structurally related substituted 4-phenylpiperazines with nanomolar affinity and selectivity at D3 dopamine receptors has been synthesized. Compounds in which a heterocyclic (2-phenyl pyridyl, 3-phenyl pyridyl, benzothiophene, or benzofuran) moiety is adjacent to the amide was varied and/or a double bond (trans-butenyl) replaced the four-carbon aliphatic chain linking the arylamide with the 4-phenylpiperazine moiety were compared for (a) affinity at human D2 and D3 dopamine receptors, (b) intrinsic efficacy using an adenylyl cyclase inhibition assay, and (c) intrinsic efficacy using a mitogenic assay. All 16 compounds were (a) more efficacious for the D3 receptor cyclase inhibition assay than for the D3 receptor mitogenic assay and (b) exhibited the same or greater efficacy at D3 compared to D2 receptor (with the exception of one compound). Although the heterocyclic amide moiety appears to be the pivotal structural element determining the intrinsic efficacy of our D3 receptor selective compounds, the magnitude of the efficacy is modulated by the (a) substituent(s) on the phenyl piperazine and (b) the saturation of the four-carbon chain that links the arylamide and the phenylpiperazine. In addition, our ligands are functionally selective, because they can have differing intrinsic efficacies for the cyclase inhibition and the mitogenic activation signaling pathways. Compounds that are essentially full agonists at the cyclase assay appear to be only partial agonists in the mitogenic assay and compounds that are partial agonists in our cyclase assay are partial agonists or antagonists in the mitogenic assay.
已经合成了一组结构相关的取代 4-苯基哌嗪，它们对 D3 多巴胺受体具有纳摩尔亲和力和选择性。对酰胺基相邻的杂环（2-苯基吡啶基、3-苯基吡啶基、苯并噻吩或苯并呋喃）部分进行了变化和/或用双键（反式丁烯基）取代将芳酰胺与 4-苯基哌嗪部分连接的四个碳原子的脂肪链的化合物，比较了它们在（a）与人 D2 和 D3 多巴胺受体的亲和力、（b）使用腺苷酸环化酶抑制测定的内在效力和（c）使用促有丝分裂测定的内在效力。所有 16 种化合物均（a）对 D3 受体环化酶抑制测定的效力大于对 D3 受体促有丝分裂测定的效力，并且（b）与 D2 受体相比，对 D3 受体具有相同或更高的效力（除了一种化合物）。尽管杂环酰胺部分似乎是决定我们的 D3 受体选择性化合物内在效力的关键结构元素，但效力的大小受（a）苯并哌嗪上的取代基和（b）连接芳酰胺和苯并哌嗪的四个碳原子链的饱和度的调节。此外，我们的配体是功能选择性的，因为它们在环化酶抑制和促有丝分裂激活信号通路中可能具有不同的内在效力。在环化酶测定中基本上是完全激动剂的化合物在促有丝分裂测定中似乎只是部分激动剂，而在我们的环化酶测定中是部分激动剂的化合物在促有丝分裂测定中是部分激动剂或拮抗剂。
