Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: impact on functional activity and selectivity for dopamine D2/D3 receptors.
Modification of agonist binding moiety in hybrid derivative 5/7-{[2-(4-aryl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-1-ol/-2-amino versions: impact on functional activity and selectivity for dopamine D2/D3 receptors.
复制标题
DOI：
10.1016/j.bmc.2013.03.059
复制
发表时间：
2013-06-01
影响因子：
3.5
通讯作者：
Dutta, Aloke K.
中科院分区：
文献类型：
--
作者：
Gopishetty, Bhaskar;Zhang, Suhong;Kharkar, Prashant S.;Antonio, Tamara;Reith, Maarten;Dutta, Aloke K.
本研究的目的是探索，在我们以前开发的混合模板，引入额外的杂环（模拟儿茶酚羟基作为生物电子等排置换）的D3与D2受体的选择性和亲和力的影响。此外，我们希望探索我们早期从杂合模板开发的化合物中激动剂结合部分的官能团衍生化的影响。用氚化螺哌隆作为放射性配体和表达D2或D3受体的HEK-293细胞测量新化合物的结合亲和力（Ki）。在GTPγS结合试验中评估了选定化合物的功能活性。在咪唑系列中，化合物10a表现出最高的D3亲和力，而吲哚衍生物13表现出类似的高D3亲和力。用不同的磺胺衍生物对激动剂（+）-9d中的氨基进行官能化显著改善了D3亲和力，其中（+）-14f表现出最高的亲和力。然而，将15和（+）-9d（已知的激动剂和部分激动剂）的羟基和氨基官能化为磺酸酯和酰胺通常调节亲和力。在这两种情况下，激动剂效力的损失都是由这种衍生化引起的。
The goal of the present study was to explore, in our previously developed hybrid template, the effect of introduction of additional heterocyclic rings (mimicking catechol hydroxyl groups as bioisosteric replacement) on selectivity and affinity for the D3 versus D2 receptor. In addition, we wanted to explore the effect of derivatization of functional groups of the agonist binding moiety in compounds developed by us earlier from the hybrid template. Binding affinity (Ki) of the new compounds was measured with tritiated spiperone as the radioligand and HEK-293 cells expressing either D2 or D3 receptors. Functional activity of selected compounds was assessed in the GTPγS binding assay. In the imidazole series, compound 10a exhibited the highest D3 affinity whereas the indole derivative 13 exhibited similar high D3 affinity. Functionalization of the amino group in agonist (+)-9d with different sulfonamides derivatives improved the D3 affinity significantly with (+)-14f exhibiting the highest affinity. However, functionalization of the hydroxyl and amino groups of 15 and (+)-9d, known agonist and partial agonist, to sulfonate ester and amide in general modulated the affinity. In both cases loss of agonist potency resulted from such derivatization.
登录
查看更多内容
影响因子：
5
作者：
Perachon, S;Schwartz, JC;Sokoloff, P
通讯作者：
Sokoloff, P
影响因子：
6.7
作者：
Sukalovic, V;Andric, D;Soskic, V
通讯作者：
Soskic, V
影响因子：
7.3
作者：
Ghosh B;Antonio T;Zhen J;Kharkar P;Reith ME;Dutta AK
通讯作者：
Dutta AK
影响因子：
7.3
作者：
Elsner, J;Boeckler, F;Gmeiner, P
通讯作者：
Gmeiner, P
影响因子：
7.3
作者：
STJERNLOF, P;ENNIS, MD;WIKSTROM, H
通讯作者：
WIKSTROM, H